WO2022132992A1 - Lots hautement purifiés de composés de 1-désoxygalactonojirimycine de qualité pharmaceutique - Google Patents

Lots hautement purifiés de composés de 1-désoxygalactonojirimycine de qualité pharmaceutique Download PDF

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Publication number
WO2022132992A1
WO2022132992A1 PCT/US2021/063653 US2021063653W WO2022132992A1 WO 2022132992 A1 WO2022132992 A1 WO 2022132992A1 US 2021063653 W US2021063653 W US 2021063653W WO 2022132992 A1 WO2022132992 A1 WO 2022132992A1
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WIPO (PCT)
Prior art keywords
compound
deoxygalactonojirimycin
salt
less
migalastat
Prior art date
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PCT/US2021/063653
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English (en)
Inventor
Kamlesh Sheth
Sergey TESLER
Original Assignee
Amicus Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US17/148,817 external-priority patent/US11623916B2/en
Application filed by Amicus Therapeutics, Inc. filed Critical Amicus Therapeutics, Inc.
Priority to CN202180085473.4A priority Critical patent/CN116710185A/zh
Priority to JP2023536402A priority patent/JP2023554394A/ja
Priority to EP21841141.1A priority patent/EP4263505A1/fr
Priority to IL303654A priority patent/IL303654A/en
Priority to AU2021401732A priority patent/AU2021401732A1/en
Priority to KR1020237023996A priority patent/KR20230121834A/ko
Priority to BR112023011905A priority patent/BR112023011905A2/pt
Priority to CA3202291A priority patent/CA3202291A1/fr
Publication of WO2022132992A1 publication Critical patent/WO2022132992A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • B01D9/0013—Crystallisation cooling by heat exchange by indirect heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/004—Fractional crystallisation; Fractionating or rectifying columns
    • B01D9/0045—Washing of crystals, e.g. in wash columns

Definitions

  • Migalastat was developed for the treatment of Fabry disease. It is desirable to develop methods for producing batches of migalastat hydrochloride that have increased purity, and for purifying batches of migalastat hydrochloride of intermediate grade.
  • [0002] Provided are methods of producing a batch of 1,2,3,6-tetrapivaloyl-D-galactofuranoside, the methods comprising: reacting D-(+)-galactose with pivaloyl imidazole to produce 1, 2,3,6- tetrapivaloyl-D-galactofuranoside, wherein the 1,2,3,6-tetrapivaloyl-D-galactofuranoside contains 3% area or less of Compound B.
  • the method comprising performing a chromatographic test on the batch to determine that the batch has 3% or less of Compound B.
  • Some embodiments comprise performing high performance liquid chromatography (HPLC) on the batch to identify a peak associated with the Compound B, and determining that the area under the second peak is 3% or less of a total area under the identified HPLC peaks.
  • HPLC high performance liquid chromatography
  • the batch has 2.9% area or less of the Compound B.
  • the batch has from 1.5-2.5% area of the Compound B.
  • Also provided are methods of producing a batch of 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside comprising: activating 1,2,3,6-tetrapivaloyLD- galactofuranoside with trifluoromethanesulfonic acid anhydride; reacting the activated 1, 2,3,6- tetrapivaloyl-D-galactofuranoside with water to produce 1,2,3,6-tetrapivaloyLa-L- altrofuranoside; activating the 1,2,3,6-tetrapivaloyLa-L-altrofuranoside with trifluoromethanesulfonic acid anhydride; reacting the activated 1,2,3,6-tetrapivaloyl-a-L- altrofuranoside with sodium azide to produce 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside
  • Some embodiments comprise performing high performance liquid chromatography (HPLC) on the batch to identify one or more of a first peak associated with the 1, 2,3,6- tetrapivaloyl-D-galactofuranoside, a second peak associated with the Compound E, a third peak associated with the Compound G, a fourth peak associated with the Compound J, a fifth peak associated with the Compound I, a sixth peak associated with the Compound K, a seventh peak associated with the Compound N, and an eighth peak associated with the Compound O, and determining that one or more of the area under the first peak is 0.6% or less of a total area under identified HPLC peaks, the area under the second peak is 0.3% or less of the total area under identified HPLC peaks, the area under the third peak is 0.3% or less of the total area under identified HPLC peaks, the area under the fourth peak is 3% or less of the total area under identified HPLC peaks, the area under the fifth peak is 0.6% or less of the total area under identified HPLC peaks,
  • the batch has 0.16 - 0.36% area of 1,2,3,6-tetrapivaloyl-D- galactofuranoside, 0.06% area or less of Compound E, 0.03% area or less of Compound G, 0.86 - 1.67% area of Compound J, 0.35% area or less of Compound I, 0.08 - 0.11% area of Compound K, 0.06 - 0.28% area of Compound N, and 0.12 - 0.17% area of Compound O.
  • the batch has less than 12 pg of Compound F per g of 5-azido-5-deoxy-
  • the sodium azide is in DMSO
  • the 5-azido-5-deoxy-l,2,3,6- tetrapivaloyl-D-galactofuranoside is isolated by washing the 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside with methanol and drying the 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside under a vacuum, and the 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside has 0.01% w/w or less of DMSO.
  • HPLC
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside sample synthesizing Compound G from 1, 2,3,6- tetrapivaloyl-D-galactofuranoside and using the synthesized Compound G as a reference standard in an HPLC test conducted to determine the amount of Compound G in the 5-azido-5- deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside sample; isolating Compound J from a batch of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside produced from 1, 2,3,6- tetrapivaloyl-D-galactofuranoside and using the isolated Compound J as a reference standard in an HPLC test conducted to determine the amount of Compound J in the 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside sample; synth
  • Also provided are methods of producing a batch of intermediate grade migalastat hydrochloride comprising: reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst; allowing the reduced 5-azido-5- deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside to undergo a rearrangement and hydrogenation to produce Compound S; adding sodium methoxide to the Compound S to produce migalastat; treating the migalastat with hydrochloric acid to produce an aqueous migalastat hydrochloride solution in hydrochloric acid; and isolating the intermediate grade migalastat hydrochloride from the aqueous migalastat hydrochloride solution; wherein the isolated intermediate grade migalastat hydrochloride contains 0.4% area or less of Compound U, 0.4% area or less of Compound V,
  • the batch of intermediate grade migalastat hydrochloride has 0.67% w/w or less of Compound U, 0.42% w/w or less of Compound V, 0.41% w/w or less of Compound Y, 0.15% w/w or less of Compound W, and 0.39% w/w or less of Compound BB, based on the weight of the intermediate grade migalastat hydrochloride.
  • the batch of intermediate grade migalastat hydrochloride contains 0.25% area or less of Compound Z and 0.15% area or less of Compound AA.
  • the batch of intermediate grade migalastat hydrochloride has 0.4% w/w or less of Compound Z and 0.41% w/w or less of Compound AA, based on the weight of the intermediate grade migalastat hydrochloride. In some embodiments, the batch of intermediate grade migalastat hydrochloride contains 1.0 pg or less of each of Compound Q and Compound P per gram of the isolated intermediate grade migalastat.
  • the batch of intermediate grade migalastat hydrochloride contains 2.0 pg or less of Compound X per gram of the isolated intermediate grade migalastat.
  • the batch of intermediate grade migalastat hydrochloride has one or more of: no detectable Compound U, 0.13% w/w or less of Compound V, 0.1% w/w or less of Compound Y, 0.04% w/w or less of Compound W, 0.15% w/w or less of Compound BB, 0.4% w/w or less of Compound Z, and 0.09% w/w or less of Compound AA, based on the weight of the intermediate grade migalastat hydrochloride.
  • the intermediate grade migalastat hydrochloride has a residue on ignition of 7% w/w or less, based on the weight of the intermediate grade migalastat hydrochloride. In some embodiments, the intermediate grade migalastat hydrochloride has a residue on ignition of from 1.2% to 2.1% w/w, based on the weight of the intermediate grade migalastat hydrochloride.
  • the step of reducing 5-azido-5-deoxy- 1,2,3, 6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed at a temperature of from 35°C-55°C. In some embodiments, the step of reducing 5-azido-5-deoxy- 1,2,3, 6-tetrapivaloyl- D-galactofuranoside using hydrogen and a palladium catalyst is performed at a temperature of from 40°C-50°C.
  • the step of reducing 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside using hydrogen and a palladium catalyst is performed at a temperature of 45 °C.
  • the step of reducing 5-azido-5-deoxy- 1,2,3, 6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed with a palladium catalyst quantity of from 0.5 mol% to 2.5 mol%.
  • the step of reducing 5-azido-5-deoxy- 1,2,3, 6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed with a palladium catalyst quantity of from 0.007-0.013 molar equivalents. In some embodiments, the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside using hydrogen and a palladium catalyst is performed with a palladium catalyst quantity of 0.013 molar equivalents.
  • the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed in 6-10 volumes of methanol. In some embodiments, the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed in 7-9 volumes of methanol. In some embodiments, the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed in 9 volumes of methanol.
  • the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed at a hydrogen pressure of from 6-10 bar gauge (5-9 bar absolute). In some embodiments, the step of reducing 5-azido- 5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside using hydrogen and a palladium catalyst is performed at a hydrogen pressure of from 7-9 bar gauge (8-10 bar absolute).
  • the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside using hydrogen and a palladium catalyst is performed at a hydrogen pressure of 8 bar gauge.
  • the step of reducing 5-azido-5-deoxy- 1,2,3, 6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed for 44 hours or more. In some embodiments, the step of reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside using hydrogen and a palladium catalyst is performed for 68 hours.
  • the palladium catalyst is removed before adding the sodium methoxide.
  • the step of treating the migalastat with hydrochloric acid comprises adding the hydrochloric acid to the migalastat to produce a migalastat I hydrochloric acid mixture, heating the migalastat I hydrochloric acid mixture for an age time to precipitate sodium chloride out of the mixture, cooling the mixture, and filtering out the sodium chloride.
  • the filtering is at a filtration temperature of from 25 °C to 40°C.
  • the hydrochloric acid has a concentration of from 35%-37% hydrochloric acid. In some embodiments, the hydrochloric acid has a concentration of 37% hydrochloric acid.
  • the age time is from 1 to 10 hours.
  • the heating is from 40 C to 55 C.
  • the step of adding sodium methoxide to the Compound S to produce migalastat further comprises adding methanol to the Compound S, wherein the method further comprises removing the methanol by distillation before adding the hydrochloric acid, and wherein the residual weight of the migalastat after distillation is 0.5-0.9 weights.
  • the step of isolating the intermediate grade migalastat hydrochloride from the aqueous migalastat hydrochloride solution comprises treating the aqueous migalastat hydrochloride solution with charcoal and then crystallizing the intermediate grade migalastat hydrochloride with ethanol, wherein the ethanol is at a temperature of 15 °C or higher, and wherein the ethanol is added over a period of 12 minutes or more.
  • the ethanol is at a temperature of from 15°C to 25°C.
  • the ethanol is added over a period of from 12 minutes to 50 minutes. In some embodiments, the ethanol is added over a period of 30 minutes or more.
  • Some embodiments comprise determining that batch of intermediate grade migalastat hydrochloride has 0.25% w/w or less of Compound Z and 0.15% w/w or less of Compound AA, based on the weight of the intermediate grade migalastat hydrochloride.
  • Some embodiments comprise performing high performance liquid chromatography (HPLC) on the batch of intermediate grade migalastat hydrochloride to identify one or more of a first peak associated with the Compound U, a second peak associated with the Compound V, a third peak associated with the Compound Y, a fourth peak associated with the Compound W, a fifth peak associated with the Compound BB, a sixth peak associated with the Compound Z, and a seventh peak associated with the Compound AA, and determining that one or more of the area under the first peak is 0.4% or less of a total area under identified HPLC peaks, the area under the second peak is 0.4% or less of the total area under identified HPLC peaks, the area under the third peak is 0.25% or less of the total area under identified HPLC peaks, the area under the fourth peak is 0.15% or less of the total area under identified HPLC peaks, the area under the fifth peak is 0.3% or less of the total area under identified HPLC peaks, the area under the sixth peak is 0.25% or less of
  • Also provided are methods for determining an amount of one or more of Compound U, Compound V, Compound Y, Compound W, Compound BB, Compound Z, and Compound AA in an intermediate grade migalastat hydrochloride sample the method comprising one or more of: preparing Compound U by hydrogenating 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside and then treating it with sodium methoxide, and then using the prepared Compound U as a reference standard in a high performance liquid chromatography (HPLC) test conducted to determine the amount of Compound U in the intermediate grade migalastat hydrochloride sample; preparing Compound V by hydrogenation between migalastat hydrochloride and formaldehyde, and then using the prepared Compound V as a reference standard in an HPLC test conducted to determine the amount of Compound V in the intermediate grade migalastat hydrochloride sample; isolating Compound Y, from a
  • Also provided are methods of producing a batch of migalastat hydrochloride comprising: crystallizing intermediate grade migalastat hydrochloride twice in a mixture of water and ethanol to give migalastat hydrochloride, and isolating the batch of migalastat hydrochloride, wherein the batch of migalastat hydrochloride contains 0.15% w/w or less of Compound W, 0.15% w/w or less of Compound U, 0.15% w/w or less of Compound V, 0.15% w/w or less of Compound Y, 0.15% w/w or less of Compound BB, 0.3% w/w or less of methanol, 0.5% w/w or less of ethanol, 0.2% w/w or less of water, and 0.2% w/w or less of residue on ignition, each based on the weight of the migalastat hydrochloride, and 0.15 ppm or less of arsenic, 0.5
  • Also provided are methods of determining the purity of a batch of migalastat hydrochloride comprising measuring an amount of Compound W, Compound U, Compound V, Compound Y, Compound BB, methanol, ethanol, water, residue on ignition, arsenic, cadmium, mercury, lead, and palladium in the batch of migalastat hydrochloride, wherein the batch of migalastat hydrochloride contains 0.15% w/w or less of Compound W, 0.15% w/w or less of Compound U, 0.15% w/w or less of Compound V, 0.15% w/w or less of Compound Y, 0.15% w/w or less of Compound BB, 0.3% w/w or less of methanol, 0.5% w/w or less of ethanol, 0.2% w/w or less of water, and 0.2% w/w or less of residue on ignition, each based on the weight of the migalastat hydroch
  • the batch of migalastat hydrochloride contains 0.10% w/w or less of any other particular impurity.
  • the Compound W and Compound U are measured using high performance liquid chromatography (HPLC), and the Compound V, Compound Y, and Compound BB are measured using hydrophilic interaction liquid chromatography (HILIC),
  • total impurities measured using high performance liquid chromatography (HPLC) and hydrophilic interaction liquid chromatography (HILIC) are 0.5% w/w or less.
  • the water is measured via Karl Fischer titration.
  • the methanol and the ethanol are measured via gas chromatography.
  • the arsenic, the cadmium, the mercury, the lead, and the palladium are measured via inductively coupled plasma mass spectroscopy.
  • the migalastat hydrochloride is identified via (i) an infrared spectroscopy spectrum that is concordant with that of a migalastat hydrochloride reference material and (ii) a high performance liquid chromatography (HPLC) retention time that matches a migalastat hydrochloride reference standard.
  • HPLC high performance liquid chromatography
  • the migalastat hydrochloride contains 0.2% area or less of Compound CC, 1.4% area or less of Compound A, 0.6% area or less of Compound EE, and 4.1% area or less of Compound DD. In some embodiments, the migalastat hydrochloride has less than 0.1% w/w of each of Compound CC, Compound A, Compound EE, and Compound DD.
  • each gram of the isolated migalastat hydrochloride contains less than 12 pg of each of Compound D, Compound F, 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside, Compound N, Compound Q, Compound P, Compound X, ethyl chloride, and methyl chloride.
  • the batch of migalastat hydrochloride is produced with a first crystallization step that comprises: admixing the intermediate grade migalastat hydrochloride in water at a first crystallization temperature to produce a first migalastat hydrochloride slurry or solution; adding ethanol to the first migalastat hydrochloride slurry or solution to induce a first crystallized migalastat hydrochloride; cooling the first migalastat hydrochloride slurry or solution to a first isolation temperature to isolate the first crystallized migalastat hydrochloride; then filtering the first crystallized migalastat hydrochloride; washing the filtered first crystallized migalastat hydrochloride with ethanol; and drying the washed first crystallized migalastat hydrochloride.
  • Some embodiments comprise methods of producing the migalastat hydrochloride that comprise a second crystallization step that comprises: dissolving the dried first crystallized migalastat hydrochloride in water at a second crystallization temperature to produce a second migalastat hydrochloride slurry or solution; adding a first portion of ethanol to the second migalastat hydrochloride slurry or solution to induce a second crystallized migalastat hydrochloride; adding a second portion of ethanol to the second migalastat hydrochloride slurry or solution after a hold time; then cooling the second migalastat hydrochloride slurry or solution to a second isolation temperature to isolate the second crystallized migalastat hydrochloride; then filtering the second crystallized migalastat hydrochloride; washing the filtered second crystallized migalastat hydrochloride with ethanol; and drying the washed second crystallized migalastat hydrochloride to
  • Also provided are methods of producing a batch of migalastat hydrochloride comprising dissolving intermediate grade migalastat hydrochloride in water at a first crystallization temperature to produce a first migalastat hydrochloride slurry or solution; adding ethanol to the first migalastat hydrochloride slurry or solution to induce a first crystallized migalastat hydrochloride; cooling the first migalastat hydrochloride slurry or solution to a first isolation temperature to isolate the first crystallized migalastat hydrochloride; filtering the first crystallized migalastat hydrochloride; washing the filtered first crystallized migalastat hydrochloride with ethanol; drying the washed first crystallized migalastat hydrochloride; dissolving the dried first crystallized migalastat hydrochloride in water at a second crystallization temperature to produce a second migalastat hydrochloride slurry or solution;
  • the dissolving the intermediate grade migalastat hydrochloride and/or the dried first crystallized migalastat hydrochloride is in from 1.0- 1.6 weights of water. In some embodiments, the dissolving the intermediate grade migalastat hydrochloride and/or the dried first crystallized migalastat hydrochloride is in from 1.1 -1.4 weights of water. In some embodiments, the dissolving the intermediate grade migalastat hydrochloride and/or the dried first crystallized migalastat hydrochloride is in 1.3 weights of water.
  • the first crystallization temperature and/or the second crystallization temperature is within a range of from 30°C to 60°C. In some embodiments, the first crystallization temperature and/or the second crystallization temperature is within a range of from 40°C to 60°C. In some embodiments, the first crystallization temperature and/or the second crystallization temperature is 50°C.
  • the ethanol added to the first migalastat hydrochloride slurry or solution and/or the combination of the first portion of ethanol and second portion of ethanol added to the second migalastat hydrochloride slurry or solution is from 1-11.4 weights of ethanol. In some embodiments, the ethanol added to the first migalastat hydrochloride slurry or solution and/or the combination of the first portion of ethanol and second portion of ethanol added to the second migalastat hydrochloride slurry or solution is from 4.8-11.4 weights of ethanol.
  • the ethanol added to the first migalastat hydrochloride slurry or solution and/or the combination of the first portion of ethanol and second portion of ethanol added to the second migalastat hydrochloride slurry or solution is from 8.4-10.6 weights of ethanol. In some embodiments, the ethanol added to the first migalastat hydrochloride slurry or solution and/or the combination of the first portion of ethanol and second portion of ethanol added to the second migalastat hydrochloride slurry or solution is 9.5 weights of ethanol.
  • the first isolation temperature and/or the second isolation temperature is within a range of from 5 °C to 35 °C. In some embodiments, the first isolation temperature and/or the second isolation temperature is 20°C.
  • the combination of the first portion of ethanol and the second portion of ethanol is from 1.0-11.4 weights of ethanol.
  • the first portion of ethanol comprises 1.8 to 2.0 weights of ethanol.
  • the first portion of ethanol is 1.9 weights of ethanol.
  • the second portion of ethanol comprises 6.7 to 8.4 weights of ethanol.
  • the ethanol is added to the first migalastat hydrochloride slurry or solution over a period of from 0 to 65 min. In some embodiments, the ethanol is added to the first migalastat hydrochloride slurry or solution over a period of 60 min.
  • the first portion of ethanol is added over a period of 5 min or more. In some embodiments, the first portion of ethanol is added over a period of from 5 min to 60 min.
  • the hold time is 5 min or more. In some embodiments, the hold time is from 5 min to 60 min.
  • the second portion of ethanol is added over a period of from 15 min to 60 min.
  • the batch of migalastat hydrochloride comprises 0.6 kg or more of migalastat hydrochloride. In some embodiments, the batch of migalastat hydrochloride comprises 23 kg or more of migalastat hydrochloride.
  • Another aspect of the disclosure describes a method of purifying intermediate grade 1- deoxygalactonojirimycin compound.
  • the method comprises (i) performing a first crystallization comprising crystallizing intermediate grade 1- deoxygalactonojirimycin compound in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized 1-deoxygalactonojirimycin compound; (ii) isolating the first crystallized 1-deoxygalactonojirimycin compound from the first mixture to give an isolated first crystallized 1-deoxygalactonojirimycin compound; (iii) performing a second crystallization comprising crystallizing the isolated first crystallized 1-deoxygalactonojirimycin compound in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized 1-deoxygalactonojirimycin compound; and (iv) isolating the second crystallized 1- deoxygalactonojirimycin compound from the second mixture to give an active
  • the 1-deoxygalactonojinmycin compound comprises 1- deoxygalactonojirimycin derivatives and salts thereof.
  • the 1- deoxygalactonojirimycin derivative comprises N-alkyldeoxygalactonojirimycin.
  • the 1 -deoxy galactonojirimycin derivative comprises migalastat, N- methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N- propyldeoxygalactonojirimycin, N-butyldeoxy galactonojirimycin (lucerastat) or salt thereof.
  • the 1-deoxygalactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • the intermediate grade 1-deoxygalactonojirimycin compound, the isolated first crystallized 1-deoxygalactonojirimycin compound, or both are admixed with an amount of water which is from about 1.0 to about 1.6 times the weight of the corresponding 1- deoxy galactonoj irimycin compound.
  • the first Cl to C4 alcohol is ethanol, the second Cl to C4 alcohol is ethanol, or both the first and the second Cl to C4 alcohol are ethanol.
  • the first Cl to C4 alcohol is present in the first mixture in an amount from about 1 to about 11.4 times the weight of the intermediate 1-deoxygalactonojirimycin compound.
  • the second Cl to C4 alcohol is present in the second mixture in an amount from about 1 to about 11.4 times the weight of the isolated first crystallized 1- deoxy galactonoj irimycin compound.
  • performing the first crystallization comprises admixing the intermediate grade 1-deoxygalactonojirimycin compound in water to produce a first 1- deoxy galactonoj irimycin compound slurry or solution; adding the first Cl to C4 alcohol to the first 1-deoxygalactonojirimycin compound slurry or solution to produce a second 1- deoxy galactonoj irimycin compound slurry or solution at a first crystallization temperature for inducing crystallization; and cooling the second 1-deoxygalactonojirimycin compound slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture.
  • the first Cl to C4 alcohol is added to the first 1-deoxygalactonojirimycin compound slurry or solution in an amount from about 1 to about 11.4 times the weight of the intermediate 1-deoxygalactonojirimycin compound over a period of time ranging from about 0 to about 65 minutes.
  • the first isolation temperature is within a range from about 5°C to about 35°C, or is about 20°C.
  • the first crystallization temperature, the second crystallization temperature, or both, is within a range of from about 30°C to about 70°C.
  • isolating the first crystallized 1-deoxygalactonojirimycin compound comprises filtering the first mixture to provide the first crystallized 1- deoxygalactonojirimycin compound; washing the first crystallized 1-deoxygalactonojirimycin compound with the first Cl to C4 alcohol to provide a washed first crystallized 1- deoxygalactonojirimycin compound; and optionally, drying the washed first crystallized 1- deoxygalactonojirimycin compound to give the isolated first crystallized 1- deoxy galactonoj irimycin compound.
  • performing the second crystallization comprises admixing the isolated first crystallized 1-deoxygalactonojirimycin compound in water to produce a third 1- deoxy galactonoj irimycin compound slurry or solution; adding a first portion of the second Cl to C4 alcohol to the third 1-deoxygalactonojirimycin compound slurry or solution to produce a fourth 1-deoxygalactonojirimycin compound slurry or solution at a second crystallization temperature for inducing crystallization; adding a second portion of the second Cl to C4 alcohol to the fourth 1-deoxygalactonojirimycin compound slurry or solution after a hold time; and cooling the fourth 1-deoxygalactonojirimycin compound slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • the hold time is from about 5 minutes to about 60 minutes.
  • the first portion of the second Cl to C4 alcohol is about 1.8 to about 2.0 times the weight of the 1- deoxy galactonoj irimycin compound present in the fourth 1-deoxygalactonojirimycin compound slurry or solution.
  • the first portion of Cl to C4 alcohol is added to the third 1-deoxygalactonojirimycin compound slurry or solution over a period from about 5 minutes to about 60 minutes.
  • the second portion of the Cl to C4 alcohol is about 6.7 to about 8.4 times the weight of the 1-deoxygalactonojirimycin compound present in the fourth 1-deoxygalactonojirimycin compound slurry or solution.
  • the second isolation temperature is within a range from about 5 °C to about 35 °C, or is about 20°C.
  • isolating the second crystallized 1 -deoxy galactonojinmy cm compound comprises filtering the second mixture to isolate the second crystallized 1- deoxygalactonojirimycin compound; washing the second crystallized 1- deoxygalactonojirimycin compound with the second Cl to C4 alcohol; and drying the washed second crystallized 1-deoxygalactonojirimycin compound to give the API grade 1- deoxy galactonoj irimycin compound.
  • the method comprises (i) performing a first crystallization comprising crystallizing intermediate grade 1-deoxygalactonojirimycin compound in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized 1-deoxygalactonojirimycin compound; (ii) isolating the first crystallized 1- deoxy galactonoj irimycin compound from the first mixture to give an isolated first crystallized 1-deoxygalactonojirimycin compound; (iii) performing a second crystallization comprising crystallizing the isolated first crystallized 1-deoxygalactonojirimycin compound in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized 1- deoxy galactonoj irimycin compound; and (iv) isolating the second crystallized 1- deoxy galactonoj irimycin compound from the second mixture to
  • the active pharmaceutical ingredient (API) grade 1- deoxy galactonoj irimycin compound comprises 1-deoxygalactonojirimycin derivatives or salts thereof.
  • the 1-deoxygalactonojirimycin derivative comprises N- alkyldeoxygalactonojirimycin.
  • the 1-deoxygalactonojirimycin derivative comprises migalastat, N-methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N- propyldeoxygalactonojirimycin, N-butyldeoxy galactonoj irimycin (lucerastat) or salt thereof.
  • the active pharmaceutical ingredient (API) grade 1- deoxy galactonoj irimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • Another aspect of the disclosure describes a method of purifying intermediate grade 1- deoxygalactonojirimycin compound.
  • the method comprises: (i) admixing the intermediate grade 1-deoxygalactonojirimycin compound in water to produce a first 1-deoxygalactonojirimycin compound slurry or solution; (ii) adding a first Cl to C4 alcohol to the first 1-deoxygalactonojirimycin compound slurry or solution at a first crystallization temperature to produce a second 1-deoxygalactonojirimycin compound slurry or solution and induce crystallization; (iii) cooling the second 1-deoxygalactonojirimycin compound slurry or solution to a first isolation temperature to complete crystallization, providing a first mixture comprising a first crystallized 1-deoxygalactonojirimycin compound; (iv) filtering the first mixture to isolate an isolated first crystallized 1-deoxygalactonojirimycin compound; (v) washing the isolated first crystallized 1-de
  • the 1- deoxygalactonojirimycin compound comprises 1-deoxygalactonojirimycin derivatives and salts thereof.
  • the 1-deoxygalactonojirimycin derivative comprises N- alkyldeoxygalactonojirimycin.
  • the 1-deoxygalactonojirimycin derivative comprises migalastat, N-methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N- propyldeoxygalactonojirimycin, N-butyldeoxygalactonojirimycin (lucerastat) or salt thereof.
  • the active pharmaceutical ingredient (API) grade 1- deoxygalactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • Also provided is a method of purifying intermediate grade migalastat salt comprising: i) performing a first crystallization comprising crystallizing intermediate grade migalastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized migalastat salt; ii) isolating the first crystallized migalastat salt from the first mixture to give an isolated first crystallized migalastat salt; iii) performing a second crystallization comprising crystallizing the isolated first crystallized migalastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized migalastat salt; and iv) isolating the second crystallized migalastat salt from the second mixture to give an active pharmaceutical ingredient (API) grade migalastat salt.
  • API active pharmaceutical ingredient
  • the first crystallization comprises: admixing the intermediate grade migalastat salt in water to produce a first migalastat salt slurry or solution; adding the first Cl to C4 alcohol to the first migalastat salt slurry or solution to produce a second migalastat salt slurry or solution at a first crystallization temperature for inducing crystallization; and cooling the second migalastat salt slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture.
  • the isolating in ii) comprises: filtering the first mixture to provide the first crystallized migalastat salt; washing the first crystallized migalastat salt with the first Cl to C4 alcohol to provide a washed first crystallized migalastat salt; and optionally, drying the isolated first crystallized migalastat salt.
  • the second crystallization comprises: admixing the isolated first crystallized migalastat salt in water to produce a third migalastat salt slurry or solution; adding a portion of the Cl to C4 alcohol to the third migalastat salt slurry or solution to produce a fourth migalastat salt slurry or solution at a second crystallization temperature for inducing crystallization; adding a second portion of the Cl to C4 alcohol to the fourth migalastat salt slurry or solution after a hold time; then cooling the fourth migalastat salt slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • the isolating in iv) comprises: filtering the second mixture to isolate the second crystallized migalastat salt; washing the second crystallized migalastat salt with the second Cl to C4 alcohol; and drying the washed second crystallized migalastat salt to give the API grade migalastat salt.
  • the first Cl to C4 alcohol is ethanol. In some embodiments, the second Cl to C4 alcohol is ethanol. In some embodiments, the first and second Cl to C4 alcohol are both ethanol.
  • the intermediate grade migalastat salt, the first crystallized migalastat salt, or both is admixed in an amount of water which is from about 1.0 to about 1.6 times the weight of the corresponding migalastat salt. In some embodiments, the amount of water is from about 1.1 to about 1.4 times the weight of the corresponding migalastat salt. In some embodiments, the amount of water is about 1.3 times the weight of the corresponding migalastat salt.
  • the first crystallization temperature, the second crystallization temperature, or both is within a range from about 30°C to about 70°C. In some embodiments, the first crystallization temperature, the second crystallization temperature, or both, is within a range of from about 40°C to about 60°C. In some embodiments, the first crystallization temperature, the second crystallization temperature, or both, is about 50°C.
  • the amount of first Cl to C4 alcohol present in the first mixture is from about 1 to about 11.4 times the weight of migalastat salt present in the first mixture In some embodiments, the amount of first Cl to C4 alcohol is from about 4.8 to about 11.4 times the weight of the migalastat salt. In some embodiments, the amount of first Cl to C4 alcohol is from about 8.4 to about 10.6 times the weight of the migalastat salt, or is about 9.5 times the weight of migalastat salt.
  • a total amount of the second Cl to C4 alcohol present in the second mixture is from about 1 to about 11.4 times the weight of migalastat salt present in the second mixture. In some embodiments, the total amount of second Cl to C4 alcohol, is from about 4.8 to about 11.4 times the weight of the migalastat salt. In some embodiments, the total amount of second Cl to C4 alcohol is from about 8.4 to about 10.6 times the weight of the corresponding migalastat salt. In some embodiments, the total amount of second Cl to C4 alcohol is about 9.5 times the weight of the migalastat salt.
  • a first portion of the second Cl to C4 alcohol is added which is about 1.8 to about 2.0 times the weight of the migalastat salt present in the third migalastat salt slurry or solution. In some embodiments, the first portion of second Cl to C4 alcohol is about 1.9 times the weight of the migalastat salt present in the third migalastat salt slurry or solution. [0083] In some embodiments, a second portion of the second Cl to C4 alcohol is added which is about 6.7 to about 8.4 times the weight of the migalastat salt present in the fourth migalastat salt slurry or solution.
  • the first isolation temperature, the second isolation temperature, or both is within a range from about about 5 °C to about about 35 °C. In some embodiments, the first isolation temperature, the second isolation temperature, or both, is about 20°C.
  • the first Cl to C4 alcohol is added to the first migalastat salt slurry or solution in an amount from about 1 to about 11.4 times the weight of the intermediate migalastat salt over a period of time ranging from about 0 to about 65 minutes. In some embodiments, the first Cl to C4 alcohol is added to the first migalastat salt slurry or solution over a period of time of about 60 minutes.
  • the first portion of second Cl to C4 alcohol is added to the third migalastat salt slurry or solution over a period from about 5 minutes to about 60 minutes.
  • the hold time is from about 5 minutes to about 60 minutes.
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • a method of producing active pharmaceutical ingredient (API) grade migalastat salt comprising: i) performing a first crystallization comprising crystallizing intermediate grade migalastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized migalastat salt; 11) isolating the first crystallized migalastat salt from the first misture to give an isolated first crystallized migalastat salt; iii) performing a second crystallization comprising crystallizing the isolated first crystallized migalastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized migalastat salt; and iv) isolating the second crystallized migalastat salt from the second mixture to give active pharmaceutical ingredient (API) grade migalastat salt.
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt [0091] In another aspect is provided a method of purifying intermediate grade migalastat salt, the method comprising: i) admixing the intermediate grade migalastat salt in water to produce a first migalastat salt slurry or solution; ii).
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • Some embodiments comprise preparing the batch of migalastat salt, or a portion thereof, for commercial sale.
  • Some embodiments comprise packaging the batch of migalastat salt, or a portion thereof. Some embodiments comprise packing a portion of the migalastat salt in polyvinyl chloride (PVC)/poly chlorotrifluoroethylene (PCTFE)/PVC laminate film with aluminum foil lidding blister packs.
  • PVC polyvinyl chloride
  • PCTFE poly chlorotrifluoroethylene
  • Some embodiments comprise performing an integrity test on the packaged migalastat salt.
  • the integrity test comprises a water vapor permeation test.
  • Some embodiments comprise distributing the batch of migalastat salt, or a portion thereof.
  • Also provided are methods of distributing a commercial batch of migalastat salt comprising: (i) producing a batch of migalastat salt; (ii) validating the batch of migalastat salt by determining that the batch contains 0.15% w/w or less of Compound W, 0.15% w/w or less of Compound U, 0.15% w/w or less of Compound V, 0.15% w/w or less of Compound Y, 0.15% w/w or less of Compound BB, 0.3% w/w or less of methanol, 0.5% w/w or less of ethanol, 0.2% w/w or less of water, and 0.2% w/w or less of residue on ignition, each based on the weight of the migalastat salt, and 0.15 ppm or less of arsenic, 0.5 ppm or less of cadmium, 1.5 ppm or less of mercury, 0.5 ppm or less of lead, and 10 ppm or less
  • Some embodiments comprise tracking the distributed migalastat salt, or a portion thereof.
  • the tracking comprises scanning a barcode associated with the migalastat salt, or a portion thereof.
  • the barcode encodes information that includes one or more of a name of a product, a strength and dosage form of the product, a NDC number of the product, a container size, a number of containers, a lot number of the product, a date of a transaction, a date of the shipment, and a business name and address of a person from whom and to whom ownership of the migalastat salt, or portion thereof, is being transferred.
  • Some embodiments comprise storing the migalastat salt, or a portion thereof, at a storage temperature of from 20°C to 25 °C.
  • Also provided are methods of assessing the suitability of migalastat salt for medical use in a human subject comprising: (i) performing high performance liquid chromatography (HPLC) on the migalastat salt to determine that the migalastat salt contains 0.15% w/w or less of Compound W and 0.15% w/w or less of Compound U; (ii) performing hydrophilic interaction liquid chromatography (HILIC) on the migalastat salt to determine that the migalastat salt contains 0.15% w/w or less of Compound V, 0.15% w/w or less of Compound Y, and 0.15% w/w or less of Compound BB; (iii) performing a Karl Fischer titration on the migalastat salt to determine that the migalastat salt contains 0.2% w/w or less of water; (iv) performing gas chromatography on the migalastat salt to determine that the migalastat salt contains 0.3% w/w
  • a method of purifying intermediate grade lucerastat salt comprising: i) performing a first crystallization comprising crystallizing intermediate grade lucerastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized lucerastat salt; ii) isolating the first crystallized lucerastat salt from the first mixture; iii) performing a second crystallization comprising crystallizing the first crystallized lucerastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized lucerastat salt; and iv) isolating the second crystallized lucerastat salt from the second mixture to give active pharmaceutical ingredient (API) grade lucerastat salt.
  • API active pharmaceutical ingredient
  • the first crystallization comprises: admixing the intermediate grade lucerastat salt in water to produce a first lucerastat salt slurry or solution; adding the Cl to C4 alcohol to the first lucerastat salt slurry or solution to produce a second lucerastat salt solution or slurry at a first crystallization temperature for inducing crystallization; and cooling the second lucerastat salt slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture.
  • the isolating in ii) comprises: filtering the mixture to provide the first crystallized lucerastat salt; washing the first crystallized lucerastat salt with the first Cl to C4 alcohol to provide a washed first crystallized lucerastat salt; and optionally, drying the washed first crystallized lucerastat salt to give the isolated first crystallized lucerastat salt.
  • the second crystallization comprises: admixing the isolated first crystallized lucerastat salt in water to produce a third lucerastat salt slurry or solution; adding a first portion of the second Cl to C4 alcohol to the third lucerastat salt slurry or solution to produce a fourth lucerastat salt slurry or solution at a second crystallization temperature to induce crystallization; adding a second portion of the second Cl to C4 alcohol to the fourth lucerastat salt slurry or solution after a hold time; and cooling the fourth lucerastat salt slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • the isolating in iv) comprises: filtering the second mixture to isolate an isolated second crystallized lucerastat salt; washing the isolated second crystallized lucerastat salt with the second Cl to C4 alcohol; and drying the washed second crystallized lucerastat salt to give the API grade lucerastat salt.
  • the first Cl to C4 alcohol is ethanol.
  • the second Cl to C4 alcohol is ethanol.
  • both the first and second Cl to C4 alcohols are ethanol.
  • the lucerastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • Embodiment 1 A method of purifying intermediate grade 1-deoxygalactonojirimycin compound, the method comprising: i) performing a first crystallization comprising crystallizing intermediate grade migalastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized migalastat salt; ii) isolating the first crystallized migalastat salt from the first mixture to give an isolated first crystallized migalastat salt; iii) performing a second crystallization comprising crystallizing the isolated first crystallized migalastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized migalastat salt; and iv) isolating the second crystallized migalastat salt from the second mixture to give an active pharmaceutical ingredient (API) grade migalastat salt.
  • API active pharmaceutical ingredient
  • Embodiment 2 The method of embodiment 1, wherein the 1-deoxygalactonojirimycin compound comprises 1-deoxygalactonojirimycin derivatives and salts thereof.
  • Embodiment 3 The method of embodiment 2, wherein the 1-deoxygalactonojirimycin derivative comprises N-alkyldeoxygalactonojirimycin.
  • Embodiment 4 The method of embodiment 2 or 3, wherein the 1- deoxygalactonojirimycin derivative comprises migalastat, N-methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N-propyldeoxygalactonojirimycin, N- butyldeoxygalactonojirimycin (lucerastat) or salt thereof
  • Embodiment 5 The method of any one of embodiments 2-4, wherein the 1- deoxygalactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate.
  • Embodiment 6 The method of any one of embodiment 1-5, the first crystallization comprises: admixing the intermediate grade 1-deoxygalactonojirimycin compound in water to produce a first 1-deoxygalactonojirimycin compound slurry or solution; adding the first Cl to C4 alcohol to the first 1-deoxygalactonojirimycin compound slurry or solution to produce a second 1-deoxygalactonojirimycin compound slurry or solution at a first crystallization temperature for inducing crystallization; and cooling the second 1-deoxygalactonojirimycin compound slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture
  • Embodiment 7 The method of any one of embodiment 1-6, wherein the isolating in ii) comprises: filtering the first mixture to provide the first crystallized 1-deoxygalactonojirimycin compound; washing the first crystallized 1-deoxygalactonojirimycin compound with the first Cl to C4 alcohol to provide a washed first crystallized 1-deoxygalactonojirimycin compound; and optionally, drying the washed first crystallized 1-deoxygalactonojirimycin compound to give the isolated first crystallized 1-deoxygalactonojirimycin compound.
  • Embodiment 8 The method of any one of embodiment 1-7, wherein the second crystallization comprises: admixing the isolated first crystallized 1-deoxygalactonojirimycin compound in water to produce a third 1-deoxygalactonojirimycin compound slurry or solution; adding a first portion of the second Cl to C4 alcohol to the third 1-deoxygalactonojirimycin compound slurry or solution to produce a fourth 1-deoxygalactonojirimycin compound slurry or solution at a second crystallization temperature for inducing crystallization; adding a second portion of the second Cl to C4 alcohol to the fourth 1-deoxygalactonojirimycin compound slurry or solution after a hold time; and cooling the fourth 1-deoxygalactonojirimycin compound slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • Embodiment 9 The method of any one of embodiment 1-8, wherein the isolating in iv) comprises: filtering the second mixture to isolate the second crystallized 1- deoxygalactonojirimycin compound; washing the second crystallized 1- deoxygalactonojirimycin compound with the second Cl to C4 alcohol; and drying the washed second crystallized 1-deoxygalactonojirimycin compound to give the API grade 1- deoxy galactonoj irimycin compound.
  • Embodiment 10 The method of any one or embodiments 1-9, wherein the first Cl to C4 alcohol is ethanol, the second Cl to C4 alcohol is ethanol, or both the first and the second Cl to C4 alcohol are ethanol.
  • Embodiment 11 The method of any one of embodiments 1-10, wherein the intermediate grade 1 -deoxy galactonojirimycin compound, the isolated first crystallized 1- deoxygalactonojirimycin compound, or both, are admixed with an amount of water which is from about 1.0 to about 1.6 times the weight of the corresponding 1-deoxygalactonojirimycin compound.
  • Embodiment 12 The method of any one of embodiments 1-11, wherein the first crystallization temperature, the second crystallization temperature, or both, is within a range of from about 30°C to about 70°C.
  • Embodiment 13 The method of any one of embodiments 1-12, wherein the first Cl to C4 alcohol is present in the first mixture in an amount from about 1 to about 11.4 times the weight of the intermediate 1-deoxygalactonojirimycin compound.
  • Embodiment 14 The method of any one of embodiments 1-13, wherein the second Cl to C4 alcohol is present in the second mixture in an amount from about 1 to about 11.4 times the weight of the isolated first crystallized 1-deoxygalactonojirimycin compound.
  • Embodiment 15 The method of embodiment 8, wherein the first portion of the second Cl to C4 alcohol is about 1.8 to about 2.0 times the weight of the 1-deoxygalactonojirimycin compound present in the fourth 1-deoxygalactonojirimycin compound slurry or solution.
  • Embodiment 16 The method of embodiment 8 or 15, wherein the second portion of the Cl to C4 alcohol is about 6.7 to about 8.4 times the weight of the 1-deoxygalactonojirimycin compound present in the fourth 1-deoxygalactonojirimycin compound slurry or solution.
  • Embodiment 17 The method of embodiment 6, wherein the first isolation temperature is within a range from about 5 °C to about 35 °C, or is about 20°C.
  • Embodiment 18 The method of embodiment 8, wherein the second isolation temperature is within a range from about 5 °C to about 35 °C, or is about 20°C.
  • Embodiment 19 The method of embodiment 6, wherein the first Cl to C4 alcohol is added to the first 1-deoxygalactonojirimycin compound slurry or solution in an amount from about 1 to about 11.4 times the weight of the intermediate 1-deoxygalactonojirimycin compound over a period of time ranging from about 0 to about 65 minutes.
  • Embodiment 20 The method of embodiment 8 or 15, wherein the first portion of Cl to C4 alcohol is added to the third 1 -deoxy galactonojirimycin compound slurry or solution over a period from about 5 minutes to about 60 minutes.
  • Embodiment 21 The method of embodiment 8, wherein the hold time is from about 5 minutes to about 60 minutes.
  • Embodiment 22 A method of producing active pharmaceutical ingredient (API) grade 1-deoxygalactonojirimycin compound, the method comprising: i) performing a first crystallization comprising crystallizing intermediate grade 1- deoxy galactonojirimycin compound in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized 1-deoxygalactonojirimycin compound; ii) isolating the first crystallized 1-deoxygalactonojirimycin compound from the first mixture to give an isolated first crystallized 1-deoxygalactonojirimycin compound; iii) performing a second crystallization comprising crystallizing the isolated first crystallized 1-deoxygalactonojirimycin compound in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized 1-deoxygalactonojirimycin compound; and iv) isolating the second crystallized 1-deoxygalactonojirimycin compound from the second mixture to give active
  • Embodiment 23 The method of embodiment 22, wherein 1-deoxygalactonojirimycin compound comprises 1-deoxygalactonojirimycin derivatives and salts thereof.
  • Embodiment 24 The method of embodiment 23, wherein the 1-deoxygalactonojirimycin derivative comprises N-alkyldeoxygalactonojirimycin.
  • Embodiment 25 The method of embodiment 23 or 24 , wherein the 1- deoxy galactonojirimycin derivative comprises migalastat, N-methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N-propyldeoxygalactonojirimycin, N- butyldeoxygalactonojirimycin (lucerastat) or salt thereof.
  • Embodiment 26 The method of any one of embodiments 23-25, wherein 1- deoxy galactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • 1- deoxy galactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate,
  • Embodiment 27 A method of purifying intermediate grade 1-deoxygalactonojirimycin compound, the method comprising: i) admixing the intermediate grade 1-deoxygalactonojirimycin compound in water to produce a first 1-deoxygalactonojirimycin compound slurry or solution; ii).
  • Embodiment 28 The method of embodiment 27, wherein 1-deoxygalactonojirimycin compound comprises 1-deoxygalactonojirimycin derivatives and salts thereof.
  • Embodiment 29 The method of embodiment 28, wherein the 1-deoxygalactonojirimycin derivative comprises N-alkyldeoxygalactonojirimycin.
  • Embodiment 30 The method of embodiment 28 or 29, wherein the 1- deoxygalactonojirimycin derivative comprises migalastat, N-methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N-propyldeoxygalactonojirimycin, N- butyldeoxygalactonojirimycin (lucerastat) or salt thereof.
  • Embodiment 31 The method of any one of embodiments 28-30, wherein 1- deoxygalactonojirimycin derivatives comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p- sulphonate salt.
  • Embodiment 32 A method of purifying intermediate grade migalastat salt, the method comprising: i) performing a first crystallization comprising crystallizing intermediate grade migalastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized migalastat salt; ii) isolating the first crystallized migalastat salt from the first mixture to give an isolated first crystallized migalastat salt; iii) performing a second crystallization comprising crystallizing the isolated first crystallized migalastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized migalastat salt; and iv) isolating the second crystallized migalastat salt from the second mixture to give an active pharmaceutical ingredient (API) grade migalastat salt.
  • API active pharmaceutical ingredient
  • Embodiment 33 The method of embodiment 32, wherein the first crystallization comprises: admixing the intermediate grade migalastat salt in water to produce a first migalastat salt slurry or solution; adding the first Cl to C4 alcohol to the first migalastat salt slurry or solution to produce a second migalastat salt slurry or solution at a first crystallization temperature for inducing crystallization; and cooling the second migalastat salt slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture.
  • Embodiment 34 The method of embodiment 32 or 33, wherein the isolating in ii) comprises: filtering the first mixture to provide the first crystallized migalastat salt; washing the first crystallized migalastat salt with the first Cl to C4 alcohol to provide a washed first crystallized migalastat salt; and optionally, drying the washed first crystallized migalastat salt to give the isolated first crystallized migalastat salt.
  • Embodiment 35 The method of any one of embodiments 32-34, wherein the second crystallization comprises: admixing the isolated first crystallized migalastat salt in water to produce a third migalastat salt slurry or solution; adding a first portion of the second Cl to C4 alcohol to the third migalastat salt slurry or solution to produce a fourth migalastat salt slurry or solution at a second crystallization temperature for inducing crystallization; adding a second portion of the second Cl to C4 alcohol to the fourth migalastat salt slurry or solution after a hold time; and cooling the fourth migalastat salt slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • Embodiment 36 The method of any one of embodiments 32-35, wherein the isolating in iv) comprises: filtering the second mixture to isolate the second crystallized migalastat salt; washing the second crystallized migalastat salt with the second Cl to C4 alcohol; and drying the washed second crystallized migalastat salt to give the API grade migalastat salt.
  • Embodiment 37 The method of any one of embodiments 32-36, wherein the first Cl to C4 alcohol is ethanol, the second Cl to C4 alcohol is ethanol, or both the first and the second Cl to C4 alcohol is ethanol.
  • Embodiment 38 The method of any one of embodiments 32-37, wherein the intermediate grade migalastat salt, the isolated first crystallized migalastat salt, or both, is admixed in an amount of water which is from 1.0 to 1.6 times the weight of the corresponding migalastat salt.
  • Embodiment 39 The method of any one of embodiments 32-38, wherein the amount of water is from 1.1 to 1.4 times the weight of the corresponding migalastat salt.
  • Embodiment 40 The method of any one of embodiments 32-39, wherein the amount of water is 1.3 times the weight of the corresponding migalastat salt.
  • Embodiment 41 The method of any one of embodiments 32-40, wherein the first crystallization temperature, the second crystallization temperature, or both, is within a range from about 30°C to about 70°C.
  • Embodiment 42 The method of any one of embodiments 32-41, wherein the first crystallization temperature, the second crystallization temperature, or both, is within a range of from 40°C to 60°C.
  • Embodiment 43 The method of any one of embodiments 32-42, wherein the first crystallization temperature, the second crystallization temperature, or both, is about 50°C.
  • Embodiment 44 The method of any one of embodiments 32-43, wherein the first Cl to C4 alcohol is present in the first mixture in an amount from about 1 to about 11.4 times the weight of the intermediate migalastat salt.
  • Embodiment 45 The method of embodiment 44, wherein the first Cl to C4 alcohol is present in an amount from about 4.8 to about 11.4 times the weight of the corresponding migalastat salt.
  • Embodiment 46 The method of embodiment 44, wherein the first Cl to C4 alcohol is present in an amount from about 8.4 to about 10.6 times the weight of the corresponding migalastat salt.
  • Embodiment 47 The method of embodiment 44, wherein the first Cl to C4 alcohol is used in a total amount of about 9.5 times the weight of the corresponding migalastat salt.
  • Embodiment 48 The method of any one of embodiments 32-47, wherein the second Cl to C4 alcohol is present in the second mixture in an amount from about 1 to about 11.4 times the weight of the isolated first crystallized migalastat salt.
  • Embodiment 49 The method of any one of embodiments 32-48, wherein the second Cl to C4 alcohol is present in an amount from about 4.8 to about 11.4 times the weight of the corresponding migalastat salt.
  • Embodiment 50 The method of any one of embodiments 32-49, wherein the second Cl to C4 alcohol is present in an amount from about 8.4 to about 10.6 times the weight of the corresponding migalastat salt.
  • Embodiment 51 The method of any one of embodiments 32-50, wherein the second Cl to C4 alcohol is used in a total amount of about 9.5 times the weight of the corresponding migalastat salt.
  • Embodiment 52 The method of any one of embodiments 32-51, wherein the first portion of the second Cl to C4 alcohol is about 1.8 to about 2.0 times the weight of the migalastat salt present in the third migalastat salt slurry or solution.
  • Embodiment 53 The method of any one of embodiments 32-52, wherein the first portion of the Cl to C4 alcohol is about 1.9 times the weight of the migalastat salt present in the third migalastat salt slurry or solution.
  • Embodiment 54 The method of any one of embodiments 32-53, wherein the second portion of the Cl to C4 alcohol is about 6.7 to about 8.4 times the weight of the migalastat salt present in the second migalastat salt solution.
  • Embodiment 55 The method of any one of embodiments 32-54, wherein the first isolation temperature is within a range from about 5 °C to about 35 °C, or is about 20°C.
  • Embodiment 56 The method of any one of embodiments 32-55, wherein the second isolation temperature is within a range from about 5 °C to about 35 °C, or is about 20°C.
  • Embodiment 57 The method of any one of embodiments 32-56, wherein the first Cl to C4 alcohol is added to the first migalastat salt slurry or solution in an amount from about 1 to about 11.4 times the weight of the intermediate migalastat salt over a period of time ranging from about 0 to about 65 minutes.
  • Embodiment 58 The method of any one of embodiments 32-57, wherein the first Cl to C4 alcohol is added to the first migalastat salt slurry or solution over a period of time of about 60 minutes.
  • Embodiment 59 The method of any one of embodiments 32-58, wherein the first portion of the second Cl to C4 alcohol is added to the third migalastat salt slurry or solution over a period from about 5 minutes to about 60 minutes.
  • Embodiment 60 The method of any one of embodiments 32-59, wherein the hold time is from about about 5 minutes to about about 60 minutes.
  • Embodiment 61 The method of any one of embodiments 32-60, wherein the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane- sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt.
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate,
  • Embodiment 62 A method of producing active pharmaceutical ingredient (API) grade migalastat salt, the method comprising: i) performing a first crystallization comprising crystallizing intermediate grade migalastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized migalastat salt; ii) isolating the first crystallized migalastat salt from the first mixture to give an isolated first crystallized migalastat salt; iii) performing a second crystallization comprising crystallizing the isolated first crystallized migalastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized migalastat salt; and iv) isolating the second crystallized migalastat salt from the second mixture to give active pharmaceutical ingredient (API) grade migalastat salt.
  • Embodiment 63 The method of embodiment 62, wherein the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene- p-sulphonate salt.
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate,
  • Embodiment 64 A method of purifying intermediate grade migalastat salt, the method comprising: i) admixing the intermediate grade migalastat salt in water to produce a first migalastat salt slurry or solution; ii).
  • Embodiment 65 The method of embodiment 64, wherein the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene- p-sulphonate salt.
  • the migalastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, c
  • Embodiment 66 A method of purifying intermediate grade lucerastat salt, the method comprising: i) performing a first crystallization comprising crystallizing intermediate grade lucerastat salt in a first mixture comprising water and a first Cl to C4 alcohol to give a first crystallized lucerastat salt; ii) isolating the first crystallized lucerastat salt from the first mixture; 111) performing a second crystallization comprising crystallizing the first crystallized lucerastat salt in a second mixture comprising water and a second Cl to C4 alcohol to give a second crystallized lucerastat salt; and iv) isolating the second crystallized lucerastat salt from the second mixture to give active pharmaceutical ingredient (API) grade lucerastat salt.
  • API active pharmaceutical ingredient
  • Embodiment 67 The method of embodiment 66, wherein the first crystallization comprises: admixing the intermediate grade lucerastat salt in water to produce a first lucerastat salt slurry or solution; adding the Cl to C4 alcohol to the first lucerastat salt slurry or solution to produce a second lucerastat salt slurry or solution at a first crystallization temperature for inducing crystallization; and cooling the second lucerastat salt slurry or solution to a first isolation temperature to complete crystallization, providing the first mixture.
  • Embodiment 68 The method of embodiment 66 or 67, wherein the isolating in ii) comprises: filtering the first mixture to provide the first crystallized lucerastat salt; washing the first crystallized lucerastat salt with the first Cl to C4 alcohol to provide a washed first crystallized lucerastat salt; and optionally, drying the washed first crystallized lucerastat salt to give the isolated first crystallized lucerastat salt.
  • Embodiment 69 The method of any one of embodiments 66-68, wherein the second crystallization comprises: admixing the isolated first crystallized lucerastat salt in water to produce a third lucerastat salt slurry or solution; adding a first portion of the second Cl to C4 alcohol to the third lucerastat salt slurry or solution to produce a fourth lucerastat salt slurry or solution at a second crystallization temperature for inducing crystallization; adding a second portion of the second Cl to C4 alcohol to the fourth lucerastat salt slurry or solution after a hold time; and cooling the fourth lucerastat salt slurry or solution to a second isolation temperature to complete crystallization, providing the second mixture.
  • Embodiment 70 The method of any one of embodiments 66-69, wherein the isolating in iv) comprises: filtering the second mixture to isolate an isolated second crystallized lucerastat salt; washing the isolated second crystallized lucerastat salt with the second Cl to C4 alcohol; and drying the washed second crystallized lucerastat salt to give the API grade lucerastat salt.
  • Embodiment 71 The method of embodiment 66, wherein the first Cl to C4 alcohol, the second Cl to C4 alcohol, or both the first and second Cl to C4 alcohol is ethanol.
  • Embodiment 72 The method of embodiment 67, wherein the first Cl to C4 alcohol, the second Cl to C4 alcohol, or both the first and second Cl to C4 alcohol is ethanol.
  • Embodiment 73 The method of embodiment 68, wherein the first Cl to C4 alcohol, the second Cl to C4 alcohol, or both the first and second Cl to C4 alcohol is ethanol.
  • Embodiment 74 The method of embodiment 69, wherein the first Cl to C4 alcohol, the second Cl to C4 alcohol, or both the first and second Cl to C4 alcohol is ethanol.
  • Embodiment 75 The method of embodiment 70, wherein the first Cl to C4 alcohol, the second Cl to C4 alcohol, or both the first and second Cl to C4 alcohol is ethanol.
  • Embodiment 76 The method of any one of embodiments 66-75, wherein the lucerastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt.
  • the lucerastat salt comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzo
  • FIG. 1 sets forth a diagram showing an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 2 depicts Stage 1 of an exemplary migalastat hydrochloride synthesis scheme, and shows an impurity that can result from Stage 1.
  • Fig. 3 depicts Stage 2 of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 4 also depicts Stage 2 of an exemplary migalastat hydrochloride synthesis scheme, and shows impurities that can result from Stage 2.
  • Fig. 5 depicts Stage 3 of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 6 also depicts Stage 3 of an exemplary migalastat hydrochloride synthesis scheme, and shows impurities that can result from Stage 3.
  • Fig. 7 depicts Stages 3a and 3b of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 8 depicts Stages 3a and 3b of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 9 depicts formation of impurities during Stage 3 of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 10 shows a half-normal effects plot identifying the effects of individual parameters and interactions between parameters on critical quality attributes.
  • Fig. 11 shows an effects plot illustrating the effect of palladium catalyst quantity on levels of Compound V.
  • Fig. 12 shows a half-normal effects plot showing how experimental parameters influence Compound U formation.
  • Fig. 13 shows an interaction plot showing the impact of temperature and palladium catalyst quantity on Compound U formation.
  • Fig. 14 shows a reaction profile for Stage 3a at various production scales.
  • Fig. 15 depicts Stages 3b and 3c of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 16 shows a schematic of an exemplary Stage 3b process in which temperature is varied after addition of hydrochloric acid.
  • Fig. 17 shows a half normal plot showing the impact of filtration temperature on residue on ignition in intermediate grade migalastat hydrochloride.
  • Fig. 18 provides a graphical representation of solubility data associated with sodium chloride across a range of temperatures in a reaction mixture of hydrochloric acid and methanol.
  • Fig. 19 depicts Stages 3b and 3c of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 20 shows a half normal plot showing the impact of various production parameters on the levels of Compound X.
  • Fig. 21 depicts a process for purging Compound X during Stages 3b and 3c of an exemplary migalastat hydrochloride synthesis scheme.
  • Fig. 22 shows a half-normal plot showing the impact of ethanol addition time and temperature during Stage 3c on levels of Compound U.
  • Fig. 23 shows an effects plot illustrating the impact of temperature on levels of Compound U.
  • Fig. 24 depicts Stage 4 of an exemplary migalastat hydrochloride synthesis scheme, and shows impurities that can result from Stage 4.
  • Fig. 25 provides graphical representation of the impact of total quantities of water (left graph) and ethanol (right graph) on the relative concentration of sodium chloride solubilized in a crystallization mixture.
  • Fig. 26 depicts a flow diagram showing exemplary process controls that can be used for commercial production of migalastat hydrochloride.
  • Intermediate grade means that a substance does not comply with regulatory requirements for a finished pharmaceutical product, e.g., because it does not meet specification criteria for one or more of drug identity, strength, quality, and purity.
  • “Pharmaceutical grade” or "Active Pharmaceutical Ingredient (API) grade” as used herein means that a substance (e.g., an API) complies with regulatory requirements (e.g., FDA, EMA, and/or PMDA requirements) for incorporation into a finished drug product, e.g., related to identity, strength, quality, and purity.
  • regulatory requirements e.g., FDA, EMA, and/or PMDA requirements
  • a “critical quality attribute” is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
  • CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release, and/or stability.
  • the CQAs can additionally include those properties (e.g., particle size distribution, bulk density) that affect drug product CQAs.
  • a “critical process parameter” is process parameter whose variability has an impact on a critical quality attribute.
  • Fabry disease refers to an X-linked inborn error of glycosphingolipid catabolism due to deficient lysosomal a-Gal A activity. This defect causes accumulation of the substrate globotriaosylceramide (“GE-3”, also known as Gb or ceramide trihexoside) and related glycosphingolipids in vascular endothelial lysosomes of the heart, kidneys, skin, and/or other tissues.
  • GE-3 substrate globotriaosylceramide
  • Another substrate of the enzyme is plasma globotriaosylsphingosine (“plasma lyso- Gb 3 ”).
  • a “carrier” is a female who has one X chromosome with a defective a-Gal A gene and one X chromosome with the normal gene and in whom X chromosome inactivation of the normal allele is present in one or more cell types.
  • a carrier can be diagnosed with Fabry disease.
  • a “patient” refers to a subject who has been diagnosed with or is suspected of having a particular disease.
  • the patient may be human or animal.
  • a “Fabry patient refers to an individual who has been diagnosed with or suspected of having Fabry disease and has a mutated a-Gal A as defined further below. Characteristic markers of Fabry disease can occur in male hemizygotes and female carriers with the same prevalence, although females typically are less severely affected.
  • ERT-naive patient refers to a Fabry patient that has never received enzyme replacement therapy (ERT) or has not received ERT for at least 6 months prior to initiating migalastat therapy.
  • ERT-experienced patient refers to a Fabry patient that was receiving ERT immediately prior to initiating migalastat therapy. In some embodiments, the ERT-experienced patient has received at least 12 months of ERT immediately prior to initiating migalastat therapy.
  • Human a-galactosidase A refers to an enzyme encoded by the human GLA gene.
  • the full DNA sequence of a-Gal A, including introns and exons, is available in GenBank Accession No. X14448.1.
  • the human a-Gal A enzyme consists of 429 amino acids and is available in GenBank Accession Nos. X14448.1 and U78027.1.
  • mutant protein includes a protein which has a mutation in the gene encoding the protein which results in the inability of the protein to achieve a stable conformation under the conditions normally present in the endoplasmic reticulum (ER). The failure to achieve a stable conformation result in a substantial amount of the enzyme being degraded, rather than being transported to the lysosome. Such a mutation is sometimes called a “conformational mutant.” Such mutations include, but are not limited to, missense mutations, and in-frame small deletions and insertions.
  • mutant a-Gal A includes an a-Gal A which has a mutation in the gene encoding a-Gal A which results in the inability of the enzyme to achieve a stable conformation under the conditions normally present in the ER. The failure to achieve a stable conformation result in a substantial amount of the enzyme being degraded, rather than being transported to the lysosome.
  • a-Gal A activity refers to a-Gal A activity in cells from a patient which is below the normal range as compared (using the same methods) to the activity in cells from normal individuals not having Fabry.
  • the term “a-Gal A activity refers to the normal physiological function of a wild-type a- Gal A in a cell.
  • a-Gal A activity includes hydrolysis of GL-3.
  • the terms “enhance a-Gal A activity” or “increase a-Gal A activity” refer to increasing the amount of a-Gal A that adopts a stable conformation in a cell contacted with a pharmacological chaperone specific for the a-Gal A, relative to the amount in a cell (preferably of the same cell-type or the same cell, e.g., at an earlier time) not contacted with the pharmacological chaperone specific for the a-Gal A.
  • This term also refers to increasing the trafficking of a-Gal A to the lysosome in a cell contacted with a pharmacological chaperone specific for the a-Gal A, relative to the trafficking of a-Gal A not contacted with the pharmacological chaperone specific for the protein. These terms refer to both wild-type and mutant a-Gal A.
  • the increase in the amount of a-Gal A in the cell is measured by measuring the hydrolysis of an artificial substrate in lysates from cells that have been treated with the PC. An increase in hydrolysis is indicative of increased a-Gal A activity.
  • a “responder” is an individual diagnosed with or suspected of having a lysosomal storage disorder, such as Fabry disease, whose cells exhibit sufficiently increased a-Gal A activity, respectively, and/or amelioration of symptoms or enhancement in surrogate markers, in response to contact with a pharmaceutical chaperone.
  • a lysosomal storage disorder such as Fabry disease
  • Non-limiting examples of enhancements in surrogate markers for Fabry are lyso-GN and those disclosed in U.S. Patent Application Publication No. US 2010/0113517, which is hereby incorporated by reference in its entirety.
  • Weights is referred to as a relative amount of a component or compound, and it is defined relative to a reference material. For instance, for 1 g of a reference material, 2 weights of a compound means 2 g of the compound. Other relative amounts, such as “molar equivalents” and “volumes” are also determined with reference to a reference material.
  • the production of migalastat hydrochloride can result in a plurality of impurities, especially when produced at a large scale (bulk) quantity.
  • methods of producing intermediates used in the production of migalastat hydrochloride are also provided.
  • methods of purifying intermediate grade migalastat hydrochloride are also useful for validating, releasing, and or distributing a batch of an intermediate of migalastat hydrochloride, or a portion thereof.
  • 1 -deoxy galactonojirimycin (MzgaZas/a/)l-deoxygalactonojirimycin, also known as migalastat or (2R,3S,4R,5S)-2-(hydroxymethyl) piperdine-3,4,5-triol, refers to a compound having the following free base structures:
  • 1-deoxygalactonojirimycin compound refers to 1- deoxygalactonojirimycin and derivatives thereof in both the free base form and any pharmaceutically acceptable salt forms.
  • 1- deoxygalactonojirimycin derivative comprises N-alkyl derivatives of 1- deoxygalactonojorimycin such as C1-C4 N-alkyl derivatives.
  • N- alkyldeoxygalactonojirimycin comprises N-methyldeoxygalactonojirimycin, N- ethyldeoxygalactonojirimycin, N-propyldeoxygalactonojirimycin and N- butyldeoxygalactonojirimycin.
  • N-butyldeoxygalactonojirimycin is also known as lucerasate.
  • 1-deoxygalactonojirimycin compound comprises migalastat, N- methyldeoxygalactonojirimycin, N-ethyldeoxygalactonojirimycin, N- propyldeoxygalactonojirimycin, N-butyldeoxygalactonojirimycin (lucerastat) or salt thereof.
  • the 1-deoxygalactonojirimycin compound refers to migalastat or a salt thereof.
  • the 1-deoxygalactonojirimycin compound comprises hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene -p- sulphonate, and the like salts of 1-deoxygalactonojirimycin compounds.
  • migalastat generally encompasses both the free base form and any pharmaceutically acceptable salt forms of unsubstituted 1-deoxygalactonojirimycin (DGJ).
  • DGJ unsubstituted 1-deoxygalactonojirimycin
  • migalastat hydrochloride hydrochloride salt of unsubstituted 1-deoxygalactonojirimycin is known as migalastat hydrochloride.
  • Migalastat hydrochloride has the following structure:
  • the term “free base equivalent” or “FBE” refers to the amount of DGJ present in the DGJ or salt thereof.
  • FBE means either an amount of DGJ free base, or the equivalent amount of DGJ free base that is provided by a salt of DGJ.
  • 150 mg of DGJ HCI provides as much DGJ as 123 mg of the free base form of DGJ.
  • Other salts will have different conversion factors, depending on the molecular weight of the counter ion.
  • migalastat hydrochloride is referenced throughout, also provided are methods and compositions that instead use other salts, such as hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene- 2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p- sulphonate, and the like.
  • salts such as hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnam
  • 1-deoxygalactonojirimycin compound encompasses pharmaceutical grade 1- deoxygalactonojirimycin compound, intermediate grade 1-deoxygalactonojirimycin compound, and pre-intermediate grade 1-deoxygalactonojirimycin compound (e.g., in aqueous solution).
  • intermediate grade 1-deoxygalactonojirimycin compound or unless it would be apparent to the person skilled in the art to refer to intermediate grade 1-deoxygalactonojirimycin compound or pre-intermediate grade 1- deoxygalactonojirimycin compound based on context, the term 1-deoxygalactonojirimycin compound will implicate a degree of purity sufficient for pharmaceutical use.
  • 1-deoxygalactonojirimycin compound is purified according to a first purification method.
  • the first purification method can be any of the method known to the person skilled in the art.
  • the purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ion-exchange chromatography, affinity chromatography, normal-phase liquid chromatography and reversephase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the 1 -deoxy galactonojirimycin compound is optionally treated to protect one or more chemical groups.
  • 1-deoxygalactonojirimycin compound with one or more protected chemical groups provide better purification.
  • 1-deoxygalactonojirimycin compound is converted into a pharmaceutically acceptable salt according to any of the known methods.
  • the pharmaceutically acceptable salt provides better purification.
  • the term migalastat hydrochloride encompasses pharmaceutical grade migalastat hydrochloride, intermediate grade migalastat hydrochloride, and pre-intermediate grade migalastat hydrochloride (e.g., in aqueous solution).
  • intermediate grade migalastat hydrochloride or unless it would be apparent to the person skilled in the art to refer to intermediate grade migalastat hydrochloride or pre-intermediate grade migalastat hydrochloride based on context, the term migalastat hydrochloride will implicate a degree of purity sufficient for pharmaceutical use.
  • Migalastat hydrochloride generally has a white to almost white appearance and is in solid form.
  • 1-deoxygalactonojirimycin compound can be produced in four general stages, each of which are discussed below. Compounds formed throughout Stages 1-3 of the process can be considered to be intermediates of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the stage 4 process can produce pharmaceutical grade drug substance.
  • Stage 1 of 1-deoxygalactonojirimycin compound production can be performed by reacting pivaloyl imidazole with D-(+)-galactose to give 1,2,3,6-tetrapivaloyl-D- galactofuranoside.
  • Stage 1 components are described using relative terms (e.g., weights or molar equivalents), those amounts are relative to D-(+)-galactose unless indicated otherwise.
  • D-(+)-galactose is dissolved by heating in N,N- Dimethylformamide (DMF).
  • the D-(+)-galactose is dissolved in at least about 12 weights (expressed relative to D-(+)-galactose) of DMF, such as about 12 weights to about 18 weights, about 12.10 to about 17.08 weights, about 12 weights, about 13 weights, about 14 weights, about 15 weights, about 16 weights, or about 17 weights of DMF.
  • the D-(+)-galactose is dissolved at least 12 weights of DMF, such as 12 weights to 18 weights, 12.10 to 17.08 weights, 12 weights, 13 weights, 14 weights, 15 weights, 16 weights, or 17 weights of DMF.
  • the galactose is dissolved in DMF at a temperature of from about 80°C to about 100°C, about 85°C to about 90°C, about 88°C to about 92°C, about 88°C, about 89°C, about 90°C, about 91 °C, or about 92°C. In some embodiments, the galactose is dissolved in DMF at a temperature of from 80°C to 100°C, 85°C to 90°C, 88°C to 92°C, 88°C, 89°C, 90°C, 91°C, or 92°C.
  • a solution of pivaloyl imidazole in toluene is added to the solution of D-(+)-galactose, and then the mixture is treated with methanol.
  • the solution of pivaloyl imidazole contains about 15 to about 35% w/w pivaloyl imidazole, about 18 to about 30% w/w, about 18.4 to about 28.3% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, or about 28% w/w pivaloyl imidazole, based on the total weight of the solution.
  • the solution of pivaloyl imidazole contains 15 to 35% w/w pivaloyl imidazole, 18 to 30% w/w, 18.4 to 28.3% w/w, 19% w/w, 20% w/w, 21% w/w, 22% w/w, 23% w/w, 24% w/w, 25% w/w, 26% w/w, 27% w/w, or 28% w/w pivaloyl imidazole, based on the total weight of the solution.
  • about 3.5 to about 5.5 molar equivalents of pivaloyl imidazole is added to the solution of D-(+)-galactose, such as about 4 to about 5 molar equivalents, about 4.5 to about 5 molar equivalents, about 4.6 to about 4.8 molar equivalents, about 4.6 molar equivalents, about 4.7 molar equivalents, or about 4.8 molar equivalents of pivaloyl imidazole.
  • 3.5 to 5.5 molar equivalents of pivaloyl imidazole is added to the solution of D-(+)-galactose, such as 4 to 5 molar equivalents, 4.5 to 5 molar equivalents, 4.6 to 4.8 molar equivalents, 4.6 molar equivalents, 4.7 molar equivalents, or 4.8 molar equivalents of pivaloyl imidazole.
  • the pivaloyl imidazole is reacted with the D-(+)-galactose at a temperature of from about 70°C to about 90°C, such as from about 75°C to about 85°C, about 77°C to about 85°C, about 77°C, about 78°C, about 79°C, about 80°C, about 81°C, about 82°C, about 83°C, about 84°C, or about 85°C.
  • the pivaloyl imidazole is reacted with the D-(+)-galactose at a temperature of from 70°C to 90°C, such as from 75°C to 85°C, 77°C to 85°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, or 85°C.
  • the mixture of pivaloyl imidazole and D-(+)-galactose is treated with methanol.
  • the mixture is treated with from about 0.25 to about 5 weights of methanol, such as about 0.5 to about 4 weights, about 0.5 to about 3 weights, about 0.5 weights, about 1 weight, about 2 weights, or about 3 weights of methanol.
  • the mixture is treated with from 0.25 to 5 weights of methanol, such as 0.5 to 4 weights, 0.5 to 3 weights, 0.5 weights, 1 weight, 2 weights, or 3 weights of methanol.
  • the resultant mixture is washed with water and the organic layer is separated.
  • the solution is concentrated and heptane is added and then the mixture is seeded and cooled.
  • about 5 to about 10 weights of heptane is added, such as about 6 to about 9.5 weights, about 6.27 to about 9.4 weights, about 6.27 weights, about 7 weights, about 8 weights, about 9 weights, or about 9.4 weights of heptane is added.
  • 5 to 10 weights of heptane are added, such as 6 to 9.5 weights, 6.27 to 9.4 weights, 6.27 weights, 7 weights, 8 weights, 9 weights, or 9.4 weights of heptane.
  • the solution is crystallized at a temperature of from about -60° to about -5°C, such as about -55°C to about -10°C, about -50°C to about -15°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, or about -15°C.
  • the solution is crystallized at a temperature of from -60° to -5 °C, such as - 55°C to -10°C, -50°C to -15°C, -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, or -15°C.
  • the yield of 1,2,3,6-tetrapivaloyl-D-galactofuranoside is about 15% or more, such as about 20% or more, about 23% or more, about 25% or more, about 30% or more, about 33% or more, about 15% to about 40%, about 20% to about 35%, about 23% to about 33%, about 23%, about 25%, about 30%, or about 33%.
  • the yield of 1,2,3,6-tetrapivaloyl-D-galactofuranoside is 15% or more, such as 20% or more, 23% or more, 25% or more, 30% or more, 33% or more, 15% to 40%, 20% to 35%, 23% to 33%, 23%, 25%, 30%, or 33%.
  • Purity of 1,2,3,6-tetrapivaloyl-D-galactofuranoside can be expressed using an amount of total or specific impurities. Amounts can be calculated, inter alia, using % w/w (e.g., based on the weight of the 1,2,3,6-tetrapivaloyl-D-galactofuranoside) or % area (e.g., based on the area under a chromatograph peak, such as an HPLC peak, of the impurity or impurities as compared to the total area under chromatographic peaks).
  • a particularly disclosed impurity percentage is meant to encompass amounts as calculated based on % w/w and/or % area.
  • the % impurity is calculated based on % w/w; in some embodiments the % impurity is calculated based on % area; in some embodiments the % impurity is calculated based on % w/w and % area.
  • the produced 1,2,3,6-tetrapivaloyl-D-galactofuranoside has about 5% or less of total impurities, such as about 4% or less, about 3% or less, about 2.9% or less, about 2% or less, about 1% or less, or about 1.5% to about 2.5% of total impurities. In some embodiments, the produced 1,2,3,6-tetrapivaloyl-D-galactofuranoside has 5% or less total impurities, such as 4% or less, 3% or less, 2.9% or less, 2% or less, 1% or less, or 1.5% to 2.5% of total impurities.
  • the produced 1,2,3,6-tetrapivaloyl-D- galactofuranoside has about 5% or less of Compound B, such as about 4% or less, about 3% or less, about 2.9% or less, about 2% or less, about 1% or less, or about 1.5% to about 2.5% of Compound B. In some embodiments, the produced 1,2,3,6-tetrapivaloyl-D-galactofuranoside has 5% or less of Compound B, such as 4% or less, 3% or less, 2.9% or less, 2% or less, 1% or less, or 1.5% to 2.5% of Compound B.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside is purified according to a second purification method.
  • the second purification method can be any of the method known to the person skilled in the art.
  • the second purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ion-exchange chromatography, affinity chromatography, normal-phase liquid chromatography and reversephase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the second purification removes impurity comprising Compound B.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside is converted into a pharmaceutically acceptable salt according to any of the known methods.
  • the pharmaceutically acceptable salt provides better purification.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside is optionally treated to protect one or more chemical groups. In some embodiments, 1,2,3,6-tetrapivaloyl-D- galactofuranoside with one or more protected chemical groups provide better purification.
  • Stage 2 of 1-deoxygalactonojirimycin compound production can be performed by activating 1,2,3,6-tetrapivaloyl-D-galactofuranoside with trifluoromethanesulfonic acid anhydride and then reacting it with water to give 1,2,3,6-tetrapivaloyl-a-L-altrofuranoside.
  • the resulting intermediate can be activated with trifluoromethanesulfonic acid anhydride and then reacted with sodium azide to give 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside.
  • Stage 2 components are described using relative terms (e.g., weights or molar equivalents), those amounts are relative to 1,2,3,6-tetrapivaloyl-D-galactofuranoside unless indicated otherwise.
  • the trifluoromethanesulfonic acid anhydride in either of the above-mentioned steps is independently from about 0.5 to about 3 molar equivalents, such as from about 0.75 to about 2 molar equivalents, about 1 to about 1.6 molar equivalents, about 1 molar equivalent, about 1.5 molar equivalents, or about 1.6 molar equivalents.
  • the trifluoromethanesulfonic acid anhydride in either of the above-mentioned steps is independently from 0.5 to 3 molar equivalents, such as from 0.75 to 2 molar equivalents, 1 to 1.6 molar equivalents, 1 molar equivalent, 1.5 molar equivalents, or 1.6 molar equivalents.
  • Some embodiments comprise adding trifluoromethanesulfonic acid anhydride and pyridine to a solution of 1,2,3,6-tetrapivaloyl-D-galactofuranoside in isopropyl acetate (IP Ac).
  • IP Ac isopropyl acetate
  • about 0.75 to about 3 weights of pyridine is added to the solution, such as about 1 weight to about 2 weights, about 1.15 weights to about 1.73 weights, about 1.15 weights, about 1.25 weights, about 1.5 weights, or about 1.73 weights.
  • 0.75 to 3 weights of pyridine are added to the solution, such as 1 weight to 2 weights, 1.15 weights to 1.73 weights, 1.15 weights, 1.25 weights, 1.5 weights, or 1.73 weights of pyridine.
  • water is added to the mixture of trifluoromethanesulfonic acid anhydride, pyridine, 1,2,3,6-tetrapivaloyl-D-galactofuranoside, and IP Ac.
  • the mixture is then heated, e.g., to a temperature of from about 45 °C to about 70°C, such as from about 50°C to about 65°C, about 55°C to about 60°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C.
  • the mixture is heated to a temperature of from 45°C to 70°C, such as from 50°C to 65°C, 55°C to 60°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C.
  • the aqueous layer is separated and the organic layer is dried by azeotropic distillation before adding IPAc and then l,8-diazabicycloundec-7-ene (DBU) to produce Compound E.
  • DBU l,8-diazabicycloundec-7-ene
  • Some embodiments comprise adding from about 0.02 to about 0.08 weights of DBU, such as from about 0.03 to about 0.07, from about 0.033 to about 0.066, about 0.033, about 0.04, about 0.05, about 0.06, or about 0.066 weights of DBU.
  • Some embodiments comprise adding from 0.02 to 0.08 weights of DBU, such as from 0.03 to 0.07, from 0.033 to 0.066, 0.033, 0.04, 0.05, 0.06, or 0.066 weights of DBU.
  • Some embodiments comprise washing the IPAc solution of Compound E with aqueous acid, such as aqueous hydrochloric acid (HC1), and then with aqueous pyridine.
  • aqueous acid such as aqueous hydrochloric acid (HC1)
  • aqueous pyridine comprises about 0.75 to about 3 weights of pyridine, such as about 1 weight to about 2 weights, about 1.15 weights to about 1.73 weights, about 1.15 weights, about 1.25 weights, about 1.5 weights, or about 1.73 weights of pyridine.
  • 0.75 to 3 weights of pyridine are added to the solution, such as 1 weight to 2 weights, 1.15 weights to 1.73 weights, 1.15 weights, 1.25 weights, 1.5 weights, or 1.73 weights of pyridine.
  • the resulting solution is dried by azeotropic distillation and diluted with IPAc addition.
  • trifluoromethanesulfonic acid anhydride and pyridine are added (e.g., at amounts previously mentioned) to the distilled and diluted solution.
  • an IPAc solution of Compound F is washed with water and added to sodium azide and N,N-diisopropylethylamine (DIPEA) in dimethylsulfoxide (DMSO).
  • DIPEA N,N-diisopropylethylamine
  • DMSO dimethylsulfoxide
  • Some embodiments comprise adding the solution to about 0.05 to about 0.3 weights of sodium azide, such as from about 0.1 to about 0.2, about 0.13 to about 0.19, about 0.13, about 0.15, about 0.17, or about 0.19 weights of sodium azide.
  • Some embodiments comprise adding the solution to 0.05 to 0.3 weights of sodium azide, such as from 0.1 to 0.2, 0.13 to 0.19, 0.13, 0.15, 0.17, or 0.19 weights of sodium azide.
  • Some embodiments comprise adding the solution to about 0.1 to about 0.7 weights of DIPEA, such as about 0.2 to about 0.6 weights, about 0.25 to about 0.5 weights, about 0.28 to about 0.4 weights, about 0.28 weights, about 0.35 weights, or about 0.4 weights of DIPEA. Some embodiments comprise adding the solution to 0.1 to 0.7 weights of DIPEA, such as 0.2 to 0.6 weights, 0.25 to 0.5 weights, 0.28 to 0.4 weights, 0.28 weights, 0.35 weights, or 0.4 weights of DIPEA.
  • Some embodiments comprise stirring the mixture of Compound F, sodium azide, and DIPEA. In some embodiments, the mixture is stirred for at least about 30 minutes, at least about 45 minutes, or at least about 1 hour. In some embodiments, the mixture is stirred for at least 30 minutes, at least 45 minutes, or at least 1 hour.
  • a 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside mixture is washed with water and the organic layer is concentrated by distillation.
  • the concentrated mixture is treated with ethanol and water.
  • the concentrated mixture is treated with from about 3 to about 12 weights of ethanol, such as from about 4 to about 11 weights, about 5 to about 10 weights, about 5.5 to about 9 weights, about 5.64 to about 8.45 weights, about 5.64 weights, about 6 weights, about 7 weights, about 8 weights, or about 8.45 weights of ethanol.
  • the concentrated mixture is treated with from 3 to 12 weights of ethanol, such as from 4 to 11 weights, 5 to 10 weights, 5.5 to 9 weights, 5.64 to 8.45 weights, 5.64 weights, 6 weights, 7 weights, 8 weights, or 8.45 weights of ethanol.
  • the concentrated mixture is treated with from about 2 to about 11 weights of water, such as from about 3 to about 10 weights, about 4 to about 9 weights, about 4.5 to about 8 weights, about 4.78 to about 7.17 weights, about 4.78 weights, about 5 weights, about 6 weights, about 7 weights, or about 7.17 weights of water.
  • the concentrated mixture is treated with from 2 to 11 weights of water, such as from 3 to 10 weights, 4 to 9 weights, 4.5 to 8 weights, 4.78 to 7.17 weights, 4.78 weights, 5 weights, 6 weights, 7 weights, or 7.17 weights of water.
  • solid 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside is isolated by filtration.
  • the filtration is at a temperature of from about 5 C to about 35 C, such as from about 10 C to about 30 C, about 10 C to about 25 C, about 10°C, about 15 °C, about 20°C, or about 25 °C.
  • the filtration is at a temperature of from 5°C to 35°C, such as from 10°C to 30°C, 10°C to 25°C, 10°C, 15°C, 20°C, or 25 °C.
  • Some embodiments comprise washing solid 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside in methanol.
  • the solid 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside is washed in from about 0.5 to about 4 weights of methanol, such as from about 0.6 to about 3 weights, about 0.7 to about 2.5 weights, about 0.79 to about 2.38 weights, about 0.79 weights, about 1 weight, about 1.5 weights, about 2 weights, or about 2.38 weights of methanol.
  • the solid 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside is washed in from 0.5 to 4 weights of methanol, such as from 0.6 to 3 weights, 0.7 to 2.5 weights, 0.79 to 2.38 weights, 0.79 weights, 1 weight, 1.5 weights, 2 weights, or 2.38 weights of methanol.
  • Some embodiments comprise drying the washed 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl- D-galactofuranoside.
  • the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside is dried under vacuum.
  • the 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside is dried under vacuum with heating.
  • the heating is at about 50°C or less, such as about 45°C or less, or about 40°C or less.
  • the heating is at 50°C or less, such as 45°C or less, or 40°C or less.
  • the yield of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside is about 45% or more, such as about 50% or more, about 53% or more, about 55% or more, about 60% or more, about 65% or more, about 73% or more, about 75% or more, about 50% to about 75%, about 53% to about 73%, about 53%, about 60%, about 65%, or about 73%.
  • the yield of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside is 45% or more, such as 50% or more, 53% or more, 55% or more, 60% or more, 65% or more, 73% or more, 75% or more, 50% to 75%, 53% to 73%, 53%, 60%, 65%, or 73%.
  • Purity of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside can be expressed using an amount of total or specific impurities. Amounts can be calculated, inter alia, using % w/w (e.g., based on the weight of the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside) or % area (e.g., based on the area under a chromatograph peak, such as an HPLC peak, of the impurity or impurities as compared to the total area under chromatographic peaks).
  • % w/w e.g., based on the weight of the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside
  • % area e.g., based on the area under a chromatograph peak, such as an HPLC peak, of
  • a particularly disclosed impurity percentage is meant to encompass amounts as calculated based on % w/w and/or % area.
  • the % impurity is calculated based on % w/w; in some embodiments the % impurity is calculated based on % area; in some embodiments the % impurity is calculated based on % w/w and % area.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 4% or less of 1,2,3,6-tetrapivaloyl-D-galactofuranoside, such as about 3% or less, about 2.6% or less, about 2% or less, about 1.5% or less, about 1% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.36% or less, about 0.25% or less, about 0.16% or less, about 0.1% or less, or about 0.16 to about 0.36% of 1, 2,3,6- tetrapivaloyl-D-galactofuranoside.
  • the produced 5-azido-5-deoxy- 1,2,3,6-tetrapivaloyl-D-galactofuranoside has 4% or less of 1,2,3,6-tetrapivaloyl-D- galactofuranoside, such as 3% or less, 2.6% or less, 2% or less, 1.5% or less, 1% or less, 0.75% or less, 0.6% or less, 0.5% or less, 0.36% or less, 0.25% or less, 0.16% or less, 0.1% or less, or 0.16 to 0.36% of 1,2,3,6-tetrapivaloyl-D-galactofuranoside.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound E, such as about 2% or less, about 1.5% or less, about 1.3% or less, about 1% or less, about 0.75% or less, about 0.5% or less, about 0.3% or less, about 0.1% or less, about 0.06% or less, or about 0.05% or less.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound E, such as 2% or less, 1.5% or less, 1.3% or less, 1% or less, 0.75% or less, 0.5% or less, 0.3% or less, 0.1% or less, 0.06% or less, or 0.05% or less. In some embodiments, the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has no detectable amount of Compound E.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound G, such as about 2% or less, about 1.5% or less, about 1.3% or less, about 1% or less, about 0.75% or less, about 0.5% or less, about 0.3% or less, about 0.1% or less, about 0.06% or less, about 0.05% or less, or about 0.03% or less.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound G, such as 2% or less, 1.5% or less, 1.3% or less, 1% or less, 0.75% or less, 0.5% or less, 0.3% or less, 0.1% or less, 0.06% or less, 0.05% or less, or 0.03% or less.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has no detectable amount of Compound G.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 7% or less of Compound J, such as about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.86% to about 1.67% of Compound J.
  • the produced 5-azido-5- deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 7% or less of Compound J, such as 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.86% to 1.67% of Compound J.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound I, such as about 2% or less, about 1.5% or less, about 1.3% or less, about 1% or less, about 0.9% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.35% or less, about 0.3% or less, about 0.1% or less, about 0.06% or less, about 0.05% or less, or about 0.03% or less.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound I, such as 2% or less, 1.5% or less, 1.3% or less, 1% or less, 0.9% or less, 0.75% or less, 0.6% or less, 0.5% or less, 0.35% or less, 0.3% or less, 0.1% or less, 0.06% or less, 0.05% or less, or 0.03% or less.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has no detectable amount of Compound I.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound K, such as about 2% or less, about 1.5% or less, about 1.3% or less, about 1% or less, about 0.9% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.35% or less, about 0.3% or less, about 0.11% or less, about 0.1% or less, about 0.08% or less, about 0.06% or less, about 0.05% or less, about 0.03% or less, or about 0.08% to about 0.11% of Compound K.
  • Compound K such as about 2% or less, about 1.5% or less, about 1.3% or less, about 1% or less, about 0.9% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.35% or less, about 0.3% or less, about 0.11% or less, about 0.1% or less, about 0.08% or less
  • the produced 5-azido- 5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound K, such as 2% or less, 1.5% or less, 1.3% or less, 1% or less, 0.9% or less, 0.75% or less, 0.6% or less, 0.5% or less, 0.35% or less, 0.3% or less, 0.11% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.05% or less, 0.03% or less, or 0.08% to 0.11% of Compound K.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound N, such as about 2% or less, about 1.5% or less, about 1% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.28% or less, about 0.25% or less, about 0.2% or less, about 0.1% or less, about 0.06% or less, or about 0.06% to about 0.28% of Compound N.
  • the produced 5-azido- 5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound N, such as 2% or less, 1.5% or less, 1% or less, 0.75% or less, 0.6% or less, 0.5% or less, 0.28% or less, 0.25% or less, 0.2% or less, 0.1% or less, 0.06% or less, or 0.06% to about 0.28% of Compound N.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 3% or less of Compound O, such as about 2% or less, about 1.5% or less, about 1% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.3% or less, about 0.17% or less, about 0.12% or less, about 0.1% or less, about 0.05% or less, or about 0.12% to about 0.17% of Compound O.
  • the produced 5-azido-5- deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% or less of Compound O, such as 2% or less, 1.5% or less, 1% or less, 0.75% or less, 0.6% or less, 0.5% or less, 0.3% or less, 0.17% or less, 0.12% or less, 0.1% or less, 0.05% or less, or 0.12% to 0.17% of Compound O.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has about 5% or less of total impurities, such as about 4% or less, about 3% or less, about 2.9% or less, about 2% or less, about 1% or less, or about 1.5% to about 2.5% of total impurities.
  • the produced 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside has 5% or less total impurities, such as 4% or less, 3% or less, 2.9% or less, 2% or less, 1% or less, or 1.5% to 2.5% of total impurities.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside, Compound D, Compound E, Compound F, 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside, 1,2,3,6-tetrapivaloyl-a-L-altrofuranoside and/or derivatives thereof are independently purified according to a third purification method.
  • the third purification method can be any of the method known to the person skilled in the art.
  • the third purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ionexchange chromatography, affinity chromatography, normal-phase liquid chromatography and reverse-phase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the third purification removes one or more impurities, the impurities comprises
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside Compound D, Compound E, Compound F, 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside,
  • 1.2.3.6-tetrapivaloyl-a-L-altrofuranoside and/or derivatives thereof are independently converted into a pharmaceutically acceptable salt according to any of the known methods.
  • the pharmaceutically acceptable salt provides better purification.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside Compound D, Compound E, Compound F, 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside,
  • 1.2.3.6-tetrapivaloyl-a-L-altrofuranoside and/or derivatives thereof are independently treated to protect one or more chemical group of for further purification.
  • 1.2.3.6-tetrapivaloyl-D-galactofuranoside, 1 ,2,3 ,6-tetrapivaloyl-a-L-altrofuranoside and/or derivatives thereof with one or more protected chemical groups independently provide better purification.
  • Stage 3 of 1-deoxygalactonojirimycin compound production can be performed by reducing 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside using hydrogen and a palladium catalyst.
  • sodium methoxide is added to remove pivaloyl groups.
  • the product is treated to make N-alkyl substituted intermediate grade 1-deoxygalactonojirimycin compound.
  • alkylation of the piperidine nitrogen atom with an appropriate alkylating agent forms N-alkyl substituted 1-deoxygalactonojirimycin compound.
  • alkylation is performed by reductive alkylation of 1-deoxygalactonojirimycin compound with alkylaldehyde in the presence of a reducing agent.
  • suitable reducing agents include hydrogen and a catalyst, sodium cyanoborohydride, and sodium triacetoxyborohydnde.
  • the product is treated with acid and isolated to give salt of intermediate grade 1-deoxygalactonojirimycin compound.
  • intermediate grade migalastat can be treated with hydrochloric acid to make migalastat hydrochloride.
  • Stage 3 of 1-deoxygalactonojirimycin compound production can be separated into 3 sub-steps, termed Stages 3a, 3b, and 3c.
  • Stages 3a, 3b, and 3c 3 sub-steps
  • relative terms e.g., weights, molar equivalents, or volumes
  • 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside and a palladium catalyst on carbon are stirred in methanol under a hydrogen atmosphere.
  • the palladium catalyst is a 10% palladium catalyst on carbon.
  • Some embodiments comprise using about 0.005 to about 0.05 molar equivalents of the palladium catalyst, such as about 0.006 to about 0.04 molar equivalents, about 0.007 to about 0.03 molar equivalents, about 0.007 to about 0.02 molar equivalents, about 0.007 to about 0.013 molar equivalents, about 0.007 molar equivalents, about 0.008 molar equivalents, about 0.009 molar equivalents, about 0.01 molar equivalents, about 0.011 molar equivalents, about 0.012 molar equivalents, or about 0.013 molar equivalents of palladium catalyst.
  • Some embodiments comprise using 0.005 to 0.05 molar equivalents of the palladium catalyst, such as 0.006 to 0.04 molar equivalents, 0.007 to 0.03 molar equivalents, 0.007 to 0.02 molar equivalents, 0.007 to 0.013 molar equivalents, 0.007 molar equivalents, 0.008 molar equivalents, 0.009 molar equivalents, 0.01 molar equivalents, 0.011 molar equivalents, 0.012 molar equivalents, or 0.013 molar equivalents of palladium catalyst.
  • 0.005 to 0.05 molar equivalents of the palladium catalyst such as 0.006 to 0.04 molar equivalents, 0.007 to 0.03 molar equivalents, 0.007 to 0.02 molar equivalents, 0.007 to 0.013 molar equivalents, 0.007 molar equivalents, 0.008 molar equivalents, 0.009 molar equivalents, 0.01 molar equivalents, 0.011 molar equivalent
  • the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside and a palladium catalyst on carbon are stirred in about 3 to about 9 weights of methanol, such as about 4 to about 8 weights, about 5 to about 7.5 weights, about 5.54 to about 7.13 weights, about 5.54 weights, about 6 weights, about 6.5 weights, about 7 weights, or about 7.13 weights of methanol.
  • the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside and a palladium catalyst on carbon are stirred in 3 to 9 weights of methanol, such as 4 to 8 weights, 5 to 7.5 weights, 5.54 to 7.13 weights, 5.54 weights, 6 weights, 6.5 weights, 7 weights, or 7.13 weights of methanol.
  • the process of stirring the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl- D-galactofuranoside and the palladium catalyst on carbon in methanol under a hydrogen atmosphere is vented several times (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times) to release nitrogen, and hydrogen pressure is reapplied each time.
  • the mixture is stirred (e.g., after venting) at a temperature of from about 30°C to about 60°C, such as from about 35°C to about 55°C, about 40°C to about 50°C, about 40°C, about 45°C, or about 50°C.
  • the mixture is stirred at a temperature of from 30°C to 60°C, such as from 35°C to 55°C, 40°C to 50°C, 40°C, 45°C, or 50°C.
  • the hydrogen pressure is from about 5 bar (absolute) to about 13 bar (absolute), such as from about 6 bar to about 12 bar, about 7 bar to about 11 bar, about 8 bar to about 10 bar, about 8 bar, about 9 bar, or about 10 bar. In some embodiments, the hydrogen pressure is from 5 bar (absolute) to 13 bar (absolute), such as from 6 bar to 12 bar, 7 bar to 11 bar, 8 bar to 10 bar, 8 bar, 9 bar, or 10 bar.
  • the stirring is for a time period of about 30 minutes or more, such as about 35 minutes or more, about 40 minutes or more, about 44 minutes or more, about 50 minutes or more, about 55 minutes or more, about 60 minutes or more, about 65 minutes or more, about 68 minutes or more, about 75 minutes or more, about 30 minutes to about 80 minutes, about 35 minutes to about 75 minutes, about 40 minutes to about 70 minutes, about 44 minutes to about 68 minutes, about 44 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, or about 68 minutes.
  • the stirring is for a time period of 30 minutes or more, such as 35 minutes or more, 40 minutes or more, 44 minutes or more, 50 minutes or more, 55 minutes or more, 60 minutes or more, 65 minutes or more, 68 minutes or more, 75 minutes or more, 30 minutes to 80 minutes, 35 minutes to 75 minutes, 40 minutes to 70 minutes, 44 minutes to 68 minutes, 44 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, or 68 minutes.
  • a sodium methoxide solution (e.g., 30% sodium methoxide) in methanol is added to a solution of Compound S.
  • the sodium methoxide solution contains from about 0.5 to about 2 equivalents of methanol, such as from about 0.7 to about 1.5 equivalents, about 0.8 to about 1.2 equivalents, about 0.8 equivalents, about 0.9 equivalents, about 1 equivalent, about 1.1 equivalents, or about 1.2 equivalents of methanol.
  • the sodium methoxide solution contains from 0.5 to 2 equivalents of methanol, such as from 0.7 to 1.5 equivalents, 0.8 to 1.2 equivalents, 0.8 equivalents, 0.9 equivalents, 1 equivalent, 1.1 equivalents, or 1.2 equivalents of methanol.
  • the sodium methoxide I Compound S mixture is concentrated, e.g., by distillation.
  • the mixture is concentrated to about 0.3 weights, about 0.4 weights, about 0.5 weights, about 0.6 weights, about 0.7 weights, or about 0.8 weights (by volume marker).
  • the mixture is concentrated to 0.3 weights, 0.4 weights, 0.5 weights, 0.6 weights, 0.7 weights, or 0.8 weights (by volume marker).
  • an acid such as hydrochloric acid, is added to the concentrated mixture.
  • the acid is at a concentration of from about 30% to about 45% acid, such as from about 33% to about 40%, about 35% to about 37%, about 35%, about 36%, or about 37% acid. In some embodiments, the acid is at a concentration of from 30% to 45% acid, such as from 33% to 40%, 35% to 37%, 35%, 36%, or 37% acid.
  • about 1.5 to about 4 volumes of the acid, such as hydrochloric acid is added to the mixture, such as from about 2 to about 3.5 volumes, about 2.9 to about 3.2 volumes, about 2.9 volumes, about 3 volumes, about 3.1 volumes, or about 3.2 volumes.
  • 1.5 to 4 volumes of the acid, such as hydrochloric acid are added to the mixture, such as from 2 to 3.5 volumes, 2.9 to 3.2 volumes, 2.9 volumes, 3 volumes, 3.1 volumes, or 3.2 volumes.
  • the acid such as hydrochloric acid
  • the acid can function as an antisolvent for the by-product sodium salt (e.g., which precipitates out after adding sodium salt, such as sodium chloride, and agitating a batch), which can then be removed by filtration.
  • the acid such as hydrochloric acid
  • the acid is added at a temperature of from about 10°C to about 60°C, such as from about 15°C to about 55°C, about 20°C to about 50°C, about 20°C to about 45°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C.
  • the acid, such as hydrochloric acid is added at a temperature of from 10°C to 60°C, such as from 15°C to 55°C, 20°C to 50°C, 20°C to 45°C, 20°C, 25°C, 30°C, 35°C, 40°C, or 45°C.
  • the mixture is aged for an age time following addition of the acid, such as hydrochloric acid, to allow precipitation of sodium salt, such as sodium chloride.
  • the age time is about 15 hours or less, such as about 12 hours or less, about 10 hours or less, about 9 hours or less, about 8 hours or less, about 7 hours or less, about 6 hours of less, or about 5 hours or less.
  • the age time is 15 hours or less, such as 12 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours of less, or 5 hours or less.
  • the mixture is aged at a temperature of from about 25 °C to about 70°C, such as from about 30°C to about 65°C, about 35°C to about 60°C, about 40°C to about 55°C, about 40°C, about 45°C, about 50°C, or about 55°C.
  • the mixture is aged at a temperature of from 25°C to 70°C, such as from 30°C to 65°C, 35°C to 60°C, 40°C to 55°C, 40°C, 45°C, 50°C, or 55°C.
  • the suspension formed from aging the mixture is cooled to a filtration temperature and then the sodium salt, such as sodium chloride, is filtered.
  • the filtration temperature is from about 15°C to about 50°C, such as from about 20°C to about 45°C, about 25°C to about 40°C, about 25°C, about 30°C, about 35°C, or about 40°C.
  • the filtration temperature is from 15°C to 50°C, such as from 20°C to 45°C, 25 °C to 40°C, 25°C, 30°C, 35°C, or 40°C.
  • ethanol is added to the product of Stage 3b.
  • the ethanol is added over a period of about 15 minutes or more, such as about 20 minutes or more, about 25 minutes or more, about 30 minutes or more, about 35 minutes or more, about 40 minutes or more, about 45 minutes or more, about 50 minutes or more, about 55 minutes or more, about 60 minutes or more, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, or about 60 minutes.
  • the ethanol is added over a period of 15 minutes or more, such as 20 minutes or more, 25 minutes or more, 30 minutes or more, 35 minutes or more, 40 minutes or more, 45 minutes or more, 50 minutes or more, 55 minutes or more, 60 minutes or more, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes.
  • intermediate grade 1-deoxygalactonojirimycin compound is isolated.
  • the intermediate grade 1-deoxygalactonojirimycin compound is isolated at a temperature of about 5 C or more, such as about 10 C or more, about 15 C or more, about 20°C or more, about 25°C or more, about 30°C or more, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.
  • the intermediate grade 1- deoxygalactonojirimycin compound is isolated at a temperature of 5 °C or more, such as 10°C or more, 15°C or more, 20°C or more, 25°C or more, 30°C or more, 5°C, 10°C, 15°C, 20°C, 25°C, or 30°C.
  • the isolated intermediate grade 1-deoxygalactonojirimycin compound is washed, e.g., with ethanol. In some embodiments, the washed intermediate grade 1-deoxygalactonojirimycin compound is dried.
  • the yield of intermediate grade 1-deoxygalactonojirimycin compound is about 50% or more, such as about 60% or more, about 65% or more, about 70% or more, about 72% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 92% or more, about 95% or more, about 70% to about 95%, or about 72% to about 92%.
  • the yield of intermediate grade 1-deoxygalactonojirimycin compound is 50% or more, such as 60% or more, 65% or more, 70% or more, 72% or more, 75% or more, 80% or more, 85% or more, 90% or more, 92% or more, 95% or more, 70% to 95%, or 72% to 92%.
  • Purity of intermediate grade 1-deoxygalactonojirimycin compound can be expressed using an amount of total or specific impurities. Amounts can be calculated, inter alia, using % w/w (e.g., based on the weight of the intermediate grade 1-deoxygalactonojirimycin compound) or % area (e.g., based on the area under a chromatograph peak, such as an HPLC peak, of the impurity or impurities as compared to the total area under chromatographic peaks). A particularly disclosed impurity percentage is meant to encompass amounts as calculated based on % w/w and/or % area.
  • the % impurity is calculated based on % w/w; in some embodiments the % impurity is calculated based on % area; in some embodiments the % impurity is calculated based on % w/w and % area. If an impurity amount is specifically tied to a type of calculation (e.g., % w/w), it is understood that such a calculation is not limiting on the scope of the disclosure, and so the impurity amount additionally or alternatively can be determined using other calculations (e.g., % area) if desired.
  • Compound R, Compound S, 1-deoxygalactonojinmycin compound, 1-deoxygalactonojirimycin salt, intermediate grade 1 -deoxy galactonojirimycin compound and/or derivatives thereof are independently purified according to a fourth purification method.
  • the fourth purification method can be any of the method known to the person skilled in the art.
  • the fourth purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ion-exchange chromatography, affinity chromatography, normal-phase liquid chromatography and reversephase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the fourth purification removes one or more impurities, the impurities comprises Compound U, Compound V, Compound Y, Compound W, Compound BB, Compound Z, Compound AA, Compound X and/or derivatives thereof.
  • Compound R, Compound S, 1-deoxygalactonojirimycin compound, intermediate grade 1-deoxygalactonojirimycin compound and/or derivatives thereof are independently converted into a pharmaceutically acceptable salt according to any of the known methods.
  • the pharmaceutically acceptable salt provides better purification.
  • Compound R, Compound S, 1-deoxygalactonojirimycin compound, 1-deoxygalactonojirimycin salt, intermediate grade 1-deoxygalactonojirimycin compound and/or derivatives thereof are independently treated to protect one or more chemical groups for further purification.
  • one or more of Compound R, Compound S, 1-deoxygalactonojirimycin compound, 1-deoxygalactonojirimycin salt, intermediate grade 1- deoxy galactonojirimycin compound and/or derivatives thereof with one or more protected chemical groups provides better purification.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound U, such as about 1% w/w or less, about 0.75% w/w or less, about 0.67% w/w or less, about 0.5% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, or about 0.1% w/w or less of Compound U.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound U, such as 1% w/w or less, 0.75% w/w or less, 0.67% w/w or less, 0.5% w/w or less, 0.4% w/w or less, 0.25% w/w or less, or 0.1% w/w or less of Compound U. In some embodiments, the intermediate grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound U.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound V, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.42% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, about 0.13% w/w or less, or about 0.1% w/w or less of Compound V.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound V, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.42% w/w or less, 0.4% w/w or less, 0.25% w/w or less, 0.13% w/w or less, or 0.1% w/w or less of Compound V.
  • the intermediate grade 1- deoxygalactonojirimycin compound has no detectable amount of Compound V.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound Y, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.41% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, or about 0.1% w/w or less of Compound Y.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound Y, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.41% w/w or less, 0.4% w/w or less, 0.25% w/w or less, or 0.1% w/w or less of Compound Y.
  • the intermediate grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound Y.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound W, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.25% w/w or less, about 0.15% or less, about 0.1% w/w or less, about 0.04% or less, or about 0.01% or less of Compound W.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound W, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.25% w/w or less, 0.15% or less, 0.1% w/w or less, 0.04% or less, or 0.01% or less of Compound W.
  • the intermediate grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound W.
  • the produced intermediate grade 1-deoxygalactonojinmycin compound has about 2% w/w or less of Compound BB, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.4% w/w or less, about 0.39% w/w or less, about 0.3% or less, about 0.25% w/w or less, about 0.15% or less, or about 0.1% w/w or less of Compound BB.
  • the produced intermediate grade 1- deoxygalactonojirimycin compound has 2% w/w or less of Compound BB, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.4% w/w or less, 0.39% w/w or less, 0.3% or less, 0.25% w/w or less, 0.15% or less, or 0.1% w/w or less of Compound BB.
  • the intermediate grade 1 -deoxy galactonojirimycin compound has no detectable amount of Compound BB.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound Z, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.44% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, about 0.15% or less, or about 0.1% w/w or less of Compound Z.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound Z, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.44% w/w or less, 0.4% w/w or less, 0.25% w/w or less, 0.15% or less, or 0.1% w/w or less of Compound Z.
  • the intermediate grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound Z.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has about 2% w/w or less of Compound AA, such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.41% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, about 0.15% or less, about 0.1% w/w or less, about 0.09% or less, or about 0.05% or less of Compound AA.
  • Compound AA such as about 1% w/w or less, about 0.75% w/w or less, about 0.5% w/w or less, about 0.41% w/w or less, about 0.4% w/w or less, about 0.25% w/w or less, about 0.15% or less, about 0.1% w/w or less, about 0.09% or less, or about 0.05% or less of Compound AA.
  • the produced intermediate grade 1-deoxygalactonojirimycin compound has 2% w/w or less of Compound AA, such as 1% w/w or less, 0.75% w/w or less, 0.5% w/w or less, 0.41% w/w or less, 0.4% w/w or less, 0.25% w/w or less, 0.15% or less, 0.1% w/w or less, 0.09% or less, or 0.05% or less of Compound AA.
  • the intermediate grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound AA.
  • the intermediate grade 1-deoxygalactonojirimycin compound contains about 1.2% area or less of Compound CC, such as about 1% or less, about 0.7% or less, about 0.5% or less, about 0.2% or less, or about 0.1% or less of Compound CC. In some embodiments, the intermediate grade 1-deoxygalactonojirimycin compound contains 1.2% area or less of Compound CC, such as 1% or less, 0.7% or less, 0.5% or less, 0.2% or less, or 0.1% or less of Compound CC.
  • the intermediate grade 1-deoxygalactonojirimycin compound contains about 1.4% area or less of Compound A, such as about 1.2% or less, about 1% or less, about 0.7% or less, about 0.5% or less, about 0.2% or less, or about 0.1% or less of Compound A. In some embodiments, the intermediate grade 1-deoxygalactonojirimycin compound contains 1.4% area or less of Compound A, such as 1.2% or less, 1% or less, 0.7% or less, 0.5% or less, 0.2% or less, or 0.1% or less of Compound A.
  • the intermediate grade 1-deoxygalactonojirimycin compound contains about 0.6% area or less of Compound EE, such as about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less of Compound EE. In some embodiments, the intermediate grade 1-deoxygalactonojirimycin compound contains 0.6% area or less of Compound EE, such as 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less of Compound EE.
  • the intermediate grade 1-deoxygalactonojirimycin compound contains about 4.1% area or less of Compound DD, such as about 3% or less, about 2% or less, about 1% or less, about 0.7% or less, about 0.5% or less, about 0.2% or less, or about 0.1% or less of Compound DD. In some embodiments, the intermediate grade 1-deoxygalactonojirimycin compound contains 4.1% area or less of Compound DD, such as 3% or less, 2% or less, 1% or less, 0.7% or less, 0.5% or less, 0.2% or less, or 0.1% or less of Compound DD.
  • the intermediate grade 1-deoxygalactonojirimycin compound has about 5% or less of total impurities, such as about 4% or less, about 3% or less, about 2% or less, about 1.5% or less, about 1% or less, about 0.67% or less, about 0.61% or less, about 0.5% or less, about 0.32% or less, about 0.31% or less, or about 0.25% or less of total impurities.
  • the intermediate grade 1-deoxygalactonojirimycin compound has 5% or less of total impurities, such as 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.67% or less, 0.61% or less, 0.5% or less, 0.32% or less, 0.31% or less, or 0.25% or less of total impurities.
  • Stage 4 Preparation of pharmaceutical grade 1-deoxygalactonojirimycin compound
  • intermediate grade 1-deoxygalactonojirimycin compound is crystallized to form pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • intermediate 1-deoxygalactonojirimycin compound is crystallized twice or more (e.g., two times, three times, four times, or more) to form pharmaceutical grade 1- deoxy galactonoj irimycin compound.
  • intermediate grade 1-deoxygalactonojirimycin compound is optionally purified according to a fifth purification method before crystallization.
  • the fifth purification method can be any of the method known to the person skilled in the art.
  • the fifth purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ion-exchange chromatography, affinity chromatography, normal-phase liquid chromatography and reverse-phase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • intermediate grade 1-deoxygalactonojirimycin compound is converted into a pharmaceutically acceptable salt according to any of the known methods.
  • the pharmaceutically acceptable salt provides better purification.
  • intermediate grade 1-deoxygalactonojirimycin compound is independently treated to protect one or more chemical groups for further purification.
  • the intermediate grade 1-deoxygalactonojirimycin compound with one or more protected chemical groups provide better purification.
  • Stage 4a components are described using relative terms (e.g., weights), those amounts are relative to intermediate grade 1-deoxygalactonojirimycin compound unless indicated otherwise
  • the crystallization is in a mixture of water and a lower alcohol, for example, a C1-C4 alcohol.
  • a lower alcohol for example, a C1-C4 alcohol.
  • examples of such alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and n-butanol.
  • the lower alcohol is ethanol. Accordingly, in some embodiments, the crystallization is in a mixture of water and ethanol.
  • the intermediate grade 1-deoxygalactonojirimycin compound is admixed with water to provide a first slurry or solution of the intermediate grade 1- deoxygalactonojirimycin compound.
  • the intermediate grade 1- deoxygalactonojirimycin compound is admixed with from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about 1.1 to about 1.4 weights, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the intermediate grade 1-deoxygalactonojirimycin compound is admixed with from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about 1.1 to about 1.4, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the temperature both during and after the addition may vary.
  • the temperature is adjusted after the intermediate grade 1-deoxygalactonojirimycin compound is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60 °C.
  • the temperature is adjusted after the intermediate grade 1- deoxygalactonojirimycin compound is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35 °C to about 65 °C, about 40°C to about 60°C, about 40°C, about 45 °C, about 50°C, about 55 °C, or about 60°C.
  • the intermediate grade 1- deoxygalactonojirimycin compound is admixed with water at a temperature from about 30 °C to about 70 °C, and the temperature is maintained or is adjusted, either up or down, to the first crystallization temperature.
  • a C1-C4 alcohol is added to the first slurry or solution of intermediate grade 1- deoxygalactonojirimycin compound to produce a second slurry or solution of 1- deoxygalactonojirimycin compound and induce crystallization.
  • the Cl- C4 alcohol is ethanol.
  • the amount of the C1-C4 alcohol added may vary, and is generally based on weight, relative to the weight of the intermediate grade 1-deoxygalactonojirimycin compound. In some embodiments, from about 1 to about 15 weights of C1-C4 alcohol, such as ethanol, is added.
  • from about 1 to about 11.4 weights of C1-C4 alcohol, such as ethanol, is added to the first slurry or solution of 1-deoxygalactonojirimycin compound.
  • from about 4.8 to about 11.4 weights of C1-C4 alcohol, such as ethanol is added to the first slurry or solution of 1 -deoxy galactonojirimycin compound.
  • from about 8.4 to about 10.6 weights of C1-C4 alcohol, such as ethanol is added to the first slurry or solution of 1-deoxygalactonojirimycin compound.
  • C1-C4 alcohol such as ethanol
  • 1-deoxygalactonojirimycin compound such as from about 7 to about 12 weights, about 8 to about 11 weights, about 8.5 to about 10.4 weights, about 8.5 weights, about 9 weights, about 9.5 weights, about 10 weights, or about 10.4 weights of C1-C4 alcohol.
  • weights of C1-C4 alcohol such as ethanol
  • 1-deoxygalactonojirimycin compound such as from 7 to 12 weights, 8 to 11 weights, 8.5 to 10.4 weights, 8.5 weights, 9 weights, 9.5 weights, 10 weights, or 10.4 weights of C1-C4 alcohol.
  • the first 1-deoxygalactonojirimycin compound is cooled to a first isolation temperature to complete crystallization, providing a first mixture comprising a crystallized 1-deoxygalactonojirimycin compound.
  • the second slurry or solution is cooled to an isolation temperature, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25 °C, about 30°C, or about 35°C.
  • the isolation temperature is from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the Stage 4a product i.e., the first crystallized 1- deoxy galactonojirimycin compound
  • the isolated Stage 4a product is washed with the Cl to C4 alcohol, e.g., with ethanol.
  • the Cl to C4 alcohol wash can be conducted with about 0.5 weights of Cl to C4 alcohol (relative to the weight of the isolated Stage 4a product) or more, such as about 1 or more weights, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the Cl to C4 alcohol wash is conducted with about 0.5 weights of Cl to C4 alcohol or more, such as 1 or more weights, 2 or more weights, 3 or more weights, 5 or more weights, or 10 or more weights.
  • the Stage 4a product i.e., the first crystallized 1- deoxygalactonojirimycin compound
  • the Stage 4a product is dried, e.g., under vacuum.
  • the Stage 4a product is dried at a temperature of about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C.
  • Stage 4a product is dried at a temperature or 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C.
  • the Stage 4a product is optionally purified according to a sixth purification method before crystallization.
  • the sixth purification method can be any of the method known to the person skilled in the art.
  • the purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ionexchange chromatography, affinity chromatography, normal-phase liquid chromatography and reverse-phase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the Stage 4a product is optionally treated to protect one or more chemical groups for further purification. In some embodiments, the Stage 4a product with one or more protected chemical groups provide better purification.
  • the Stage 4a product is converted into a pharmaceutically acceptable salt according to any of the known methods. In some embodiments, the Stage 4a product provides better purification.
  • Stage 4b components are described using relative terms (e.g., weights), those amounts are relative to the Stage 4a product unless indicated otherwise
  • the Stage 4a product i.e., the first crystallized 1- deoxygalactonojirimycin compound
  • the second crystallization comprises crystallizing the first crystallized 1- deoxygalactonojirimycin compound in a second mixture comprising water and a Cl to C4 alcohol to give a second crystallized 1-deoxygalactonojirimycin compound; and isolating the second crystallized 1-deoxygalactonojinmycin compound from the second mixture to give active pharmaceutical ingredient (API) grade 1-deoxygalactonojirimycin compound.
  • API active pharmaceutical ingredient
  • the Stage 4a product i.e., the first crystallized 1- deoxygalactonojirimycin compound
  • water is admixed with water to produce a third 1- deoxygalactonojirimycin compound slurry or solution.
  • the Stage 4a product is admixed with from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about 1.1 to about 1.4 weights, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the Stage 4a product is admixed with from 0.5 to 4 weights of water, such as from about 0.5 to about 3 weights, 1 to 2 weights, about 1.1 to about 1.4, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the temperature both during and after the addition may vary.
  • the temperature is adjusted after the Stage 4a product is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35°C to about 65 °C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the temperature is adjusted after the Stage 4a product is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35°C to about 65 °C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the first crystallized 1-deoxygalactonojirimycin compound is admixed with water at a temperature from about 30°C to about 70°C, and the temperature is maintained or is adjusted, either up or down, to the second crystallization temperature.
  • a first quantity of a C1-C4 alcohol is added to the Stage 4a product, the third 1-deoxygalactonojirimycin compound slurry or solution, to produce a fourth 1-deoxygalactonojirimycin compound slurry or solution and induce crystallization.
  • the C1-C4 alcohol is ethanol.
  • the first quantity of C1-C4 alcohol, such as ethanol is from about 0.5 to about 4 weights of C1-C4 alcohol, such as from about 0.75 to about 3 weights, about 1 to about 2.5 weights, about 1.8 to about 2 weights, about 1.8 weights, about 1.9 weights, or about 2 weights of C1-C4 alcohol.
  • the first quantity of C1-C4 alcohol is from about 0.5 to about 4 weights of C1-C4 alcohol, such as from about 0.75 to about 3 weights, about 1 to about 2.5 weights, about 1.8 to about 2 weights, about 1.8 weights, about 1.9 weights, or about 2 weights of C1-C4 alcohol.
  • the first quantity of C1-C4 alcohol, such as ethanol is added over a period of about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the first quantity of C1-C4 alcohol such as ethanol
  • the first quantity of C1-C4 alcohol is added over a period of about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the first quantity of C1-C4 alcohol, such as ethanol is added over a period from about 5 minutes to about 60 minutes.
  • a second quantity of the C1-C4 alcohol (e.g., ethanol) is added to the mixture following a hold time.
  • the hold time can be about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the hold time is a period of about 3 minutes or more, such as 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the hold time is a period of time from about 5 minutes to about 60 minutes.
  • the second quantity of the C1-C4 alcohol comprises about 4 to about 15 weights of the C1-C4 alcohol (e.g., ethanol), such as from about 5 to about 12 weights, about 6 to about 10 weights, about 6.5 to about 9 weights, about 6.7 to about 8.4 weights, about 6.8 weights, about 7 weights, about 7.5 weights, about 8 weights, or about 8.4 weights.
  • the second quantity of the C1-C4 alcohol comprises about 4 to 15 weights of the C1-C4 alcohol (e.g., ethanol), such as from about 5 to about 12 weights, about 6 to about 10 weights, about 6.5 to about 9 weights, about 6.8 to about 8.4 weights, about 6.8 weights, about 7 weights, about 7.5 weights, about 8 weights, or about 8.4 weights.
  • the C1-C4 alcohol e.g., ethanol
  • the second quantity of the C1-C4 alcohol (e.g., ethanol) is added over a period of about 10 minutes or more, such as about 15 minutes or more, about 20 minutes or more, about 30 minutes or more, about 45 minutes or more, or about 60 minutes or more. In some embodiments, the second quantity of the C1-C4 alcohol (e.g., ethanol) is added over a period of about 10 minutes or more, such as about 15 minutes or more, about 20 minutes or more, about 30 minutes or more, about 45 minutes or more, or about 60 minutes or more.
  • the total amount of the C1-C4 alcohol (e.g., ethanol) added may vary, and is generally based on weight, relative to the weight of the intermediate grade 1 -deoxy galactonojirimycin compound.
  • the amount of the C1-C4 alcohol (e.g., ethanol) used in Stage 4b i.e., the first quantity + the second quantity of the C1-C4 alcohol
  • the amount of Cl- C4 alcohol used in Stage 4b is different from the amount of C1-C4 alcohol used in Stage 4a.
  • Some embodiments comprise cooling the Stage 4b slurry or solution in which crystallization has at least partially proceed to a second isolation temperature in order to complete the crystallization, providing the second mixture comprising crystallized 1- deoxygalactonojirimycin compound.
  • the second isolation temperature is, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5 °C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the second isolation temperature is about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the Stage 4b product i.e., the second crystallized 1- deoxygalactonojirimycin compound
  • the isolated Stage 4b product is washed with the Cl to C4 alcohol, e.g. , with ethanol.
  • the wash can be conducted with about 0.5 weights of Cl to C4 alcohol or more, such as about 1 or more weight, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the wash is conducted with about 0.5 weights of ethanol or more, such as about 1 or more weight, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights of ethanol.
  • the Stage 4b product is dried, e.g., under vacuum. In some embodiments, the Stage 4b product is dried at a temperature of about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60 C. In some embodiments, Stage 4b product is dried at a temperature of 90 C or less, such as 80°C or less, 70°C or less, 60°C or less, 50°C or less, 80°C, 70°C, or 60°C.
  • the yield of pharmaceutical grade 1-deoxygalactonojirimycin compound is about 40% or more, such as about 50% or more, about 56% or more, about 60% or more, about 65% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 100% or more, about 102% or more, about 50% to about 105%, or about 56% to about 102%.
  • the yield of pharmaceutical grade 1-deoxygalactonojirimycin compound is 40% or more, such as 50% or more, 56% or more, 60% or more, 65% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 100% or more, 102% or more, 50% to 105%, or 56% to 102%.
  • the Stage 4b product is optionally purified according to a seventh purification method before crystallization.
  • the seventh purification method can be any of the method known to the person skilled in the art.
  • the purification method comprises chromatography, sublimation, crystallization, fractional extraction and distillation.
  • the chromatography comprises size exclusion chromatography, ionexchange chromatography, affinity chromatography, normal-phase liquid chromatography and reverse-phase liquid chromatography.
  • the ion-exchange chromatography comprises anion exchange chromatography and cation exchange chromatography.
  • the Stage 4b product is optionally treated to protect one or more chemical group for further purification. In some embodiments, the Stage 4b product with one or more protected chemical groups provide better purification.
  • the Stage 4b product is converted into a pharmaceutically acceptable salt according to any of the known methods. In some embodiments, the Stage 4b product provides better purification.
  • the purity of 1-deoxygalactonojirimycin compound produced by the methods disclosed herein may vary.
  • the purity of 1-deoxygalactonojirimycin compound can be expressed using an amount of total or specific impurities. Amounts can be calculated, inter alia, using % w/w (e.g., based on the weight of the 1-deoxygalactonojirimycin compound), % area (e.g., based on the area under a chromatograph peak, such as an HPLC peak, of the impurity or impurities as compared to the 1 -deoxy galactonojirimycin compound), parts per million (ppm), etc.
  • a particularly disclosed impurity percentage is meant to encompass amounts as calculated based on % w/w and/or % area.
  • the % impurity is calculated based on % w/w; in some embodiments the % impurity is calculated based on % area; in some embodiments the % impurity is calculated based on % w/w and % area. If an impurity amount is specifically tied to a type of calculation e.g., % w/w), it is understood that such a calculation is not limiting on the scope of the disclosure, and so the impurity amount additionally or alternatively can be determined using other calculations (e.g., % area) if desired.
  • API grade 1-deoxygalactonojirimycin compound provides active pharmaceutical ingredient (API) grade 1-deoxygalactonojirimycin compound.
  • providing API grade 1-deoxygalactonojirimycin compound comprises purifying an intermediate grade 1-deoxygalactonojirimycin compound as described herein (e.g., by performing one or more crystallizations as described herein above).
  • the impurity profile of the pharmaceutical grade 1-deoxygalactonojirimycin compound i.e., the impurity profile of any given batch thereof
  • the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.15% w/w or less of Compound W, such as about 0.1% w/w or less, about 0.05 w/w or less, or about 0.025% w/w or less of Compound W. In some embodiments, the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15% w/w or less of Compound W, such as 0.1% w/w or less, 0.05 w/w or less, or 0.025% w/w or less of Compound W. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound W.
  • the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.15% w/w or less of Compound U, such as about 0.1% w/w or less, about 0.05 w/w or less, or about 0.025% w/w or less of Compound U. In some embodiments, the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15% w/w or less of Compound U, such as 0.1% w/w or less, 0.05 w/w or less, or 0.025% w/w or less of Compound U. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound U.
  • the produced pharmaceutical grade 1-deoxygalactonojinmycin compound has about 0.15% w/w or less of Compound V, such as about 0.1% w/w or less, about 0.05 w/w or less, or about 0.025% w/w or less of Compound V. In some embodiments, the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15% w/w or less of Compound V, such as 0.1% w/w or less, 0.05 w/w or less, or 0.025% w/w or less of Compound V. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound V.
  • the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.15% w/w or less of Compound Y, such as about 0.1% w/w or less, about 0.05 w/w or less, or about 0.025% w/w or less of Compound Y. In some embodiments, the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15% w/w or less of Compound Y, such as 0.1% w/w or less, 0.05 w/w or less, or 0.025% w/w or less of Compound Y. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound Y.
  • the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.15% w/w or less of Compound BB, such as about 0.1% w/w or less, about 0.05 w/w or less, or about 0.025% w/w or less of Compound BB. In some embodiments, the produced pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15% w/w or less of Compound BB, such as 0.1% w/w or less, 0.05 w/w or less, or 0.025% w/w or less of Compound BB. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of Compound BB.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.3% w/w or less of the C1-C4 alcohol (e.g., methanol), such as about 0.2% w/w or less, about 0.1% w/w or less, or about 0.05% w/w or less of the C1-C4 alcohol (e.g., methanol).
  • the C1-C4 alcohol e.g., methanol
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.3% w/w or less of the C1-C4 alcohol (e.g., methanol), such as 0.2% w/w or less, 0.1% w/w or less, or 0.05% w/w or less of the C1-C4 alcohol (e.g., methanol). In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of the Cl- C4 alcohol (e.g., methanol).
  • the pharmaceutical grade 1-deoxygalactonojinmycin compound has about 0.5% w/w or less of the C1-C4 alcohol (e.g., ethanol), such as about 0.4% w/w or less, about 0.3% w/w, about 0.2% w/w or less, about 0.1% w/w or less, or about 0.05% w/w or less of the C1-C4 alcohol (e.g., ethanol).
  • the C1-C4 alcohol e.g., ethanol
  • the C1-C4 alcohol e.g., ethanol
  • the pharmaceutical grade 1- deoxygalactonojirimycin compound has 0.5% w/w or less of the C1-C4 alcohol (e.g., ethanol), such as 0.4% w/w or less, 0.3% w/w, 0.2% w/w or less, 0.1% w/w or less, or 0.05% w/w or less of the C1-C4 alcohol (e.g., ethanol). In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound has no detectable amount of the C1-C4 alcohol (e.g., ethanol).
  • the C1-C4 alcohol e.g., ethanol
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.2% w/w or less of water, such as about 0.1% w/w or less, or about 0.05% w/w or less of water. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.2% w/w or less of water, such as 0.1% w/w or less, or 0.05% w/w or less of water. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of water.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.2% w/w or less of residue on ignition, such as about 0.1% w/w or less, or about 0.05% w/w or less of residue on ignition. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound has 0.2% w/w or less of residue on ignition, such as 0.1% w/w or less, or 0.05% w/w or less of residue on ignition. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of residue on ignition.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.15 ppm or less of arsenic, such as about 0.1 ppm or less, or about 0.05 ppm or less of arsenic. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.15 ppm or less of arsenic, such as 0.1 ppm or less, or 0.05 ppm or less of arsenic. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of arsenic.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.5 ppm or less of cadmium, such as about 0.4 ppm or less, about 0.3 ppm or less, about 0.2 ppm or less, about 0.1 ppm or less, or about 0.05 ppm or less of cadmium. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.5 ppm or less of cadmium, such as 0.4 ppm or less, 0.3 ppm or less, 0.2 ppm or less, 0.1 ppm or less, or 0.05 ppm or less of cadmium. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound has no detectable amount of cadmium.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 1.5 ppm or less of mercury, such as about 1 ppm or less, about 0.9 ppm or less, about 0.8 ppm or less, about 0.7 ppm or less, about 0.6 ppm or less, about 0.5 ppm or less, about 0.4 ppm or less, about 0.3 ppm or less, about 0.2 ppm or less, about 0.1 ppm or less, or about 0.05 ppm or less of mercury.
  • mercury such as about 1 ppm or less, about 0.9 ppm or less, about 0.8 ppm or less, about 0.7 ppm or less, about 0.6 ppm or less, about 0.5 ppm or less, about 0.4 ppm or less, about 0.3 ppm or less, about 0.2 ppm or less, about 0.1 ppm or less, or about 0.05 ppm or less of mercury.
  • the pharmaceutical grade 1- deoxygalactonojirimycin compound has 1.5 ppm or less of mercury, such as 1 ppm or less, 0.9 ppm or less, 0.8 ppm or les, 0.7 ppm or less, 0.6 ppm or less, 0.5 ppm or less, 0.4 ppm or less, 0.3 ppm or less, 0.2 ppm or less, 0.1 ppm or less, or 0.05 ppm or less of mercury. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of mercury.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.5 ppm or less of lead, such as about 0.4 ppm or less, about 0.3 ppm or less, about 0.2 ppm or less, about 0.1 ppm or less, or about 0.05 ppm or less of lead. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.5 ppm or less of lead, such as 0.4 ppm or less, 0.3 ppm or less, 0.2 ppm or less, 0.1 ppm or less, or 0.05 ppm or less of lead. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of lead.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 10 ppm or less of palladium, such as about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, about 5 ppm or less, about 4 ppm or less, about 3 ppm or less, about 2 ppm or less, about 1 ppm or less, or about 0.5 ppm or less of palladium.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has 10 ppm or less of palladium, such as 9 ppm or less, 8 ppm or less, 7 ppm or less, 6 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, 1 ppm or less, or 0.5 ppm or less of palladium. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has no detectable amount of palladium.
  • the pharmaceutical grade 1-deoxygalactonojinmycin compound contains about 0.1% or less of Compound CC, such as about 0.05% or less, or about 0.2% or less of Compound CC. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound contains 0.1% or less of Compound CC, such as 0.05% or less, or 0.2% or less of Compound CC. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound contains no detectable amount of Compound CC.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 0.1% or less of Compound A, such as about 0.05% or less, or about 0.2% or less of Compound A. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 0.1% or less of Compound A, such as 0.05% or less, or 0.2% or less of Compound A. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound A.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 0.1% or less of Compound EE, such as about 0.05% or less, or about 0.2% or less of Compound EE. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 0.1% or less of Compound EE, such as 0.05% or less, or 0.2% or less of Compound EE. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound EE.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 0.1% or less of Compound DD, such as about 0.05% or less, or about 0.2% or less of Compound DD. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound contains 0.1% or less of Compound DD, such as 0.05% or less, or 0.2% or less of Compound DD. In some embodiments, the pharmaceutical grade 1- deoxygalactonojirimycin compound contains no detectable amount of Compound DD.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound D per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound D per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of Compound D per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound D per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound D per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound F per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound F per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of Compound F per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound F per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound F per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of 5-azido-5- deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1- deoxygalactonojirimycin compound contains no detectable amount of 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside per gram of pharmaceutical grade 1 -deoxy galactonojinmycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound N per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound N per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of Compound N per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound N per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound N per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound Q per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound Q per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of Compound Q per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound Q per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound Q per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound P per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound P per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojinmycin compound contains 12 pg or less of Compound P per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound P per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound P per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of Compound X per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of Compound X per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of Compound X per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of Compound X per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of Compound X per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains about 12 pg or less of ethyl chloride per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of ethyl chloride per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of ethyl chloride per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of ethyl chloride per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of ethyl chloride per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojinmycin compound contains about 12 pg or less of methyl chloride per gram of pharmaceutical grade 1- deoxygalactonojirimycin compound, such as about 10 pg or less, about 8 pg or less, about 5 pg or less, about 4 pg or less, about 3 pg or less, about 2 pg or less, about 1 pg or less, or about 0.5 pg or less of methyl chloride per gram of pharmaceutical grade 1 -deoxy galactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 12 pg or less of methyl chloride per gram of pharmaceutical grade 1- deoxy galactonojirimycin compound, such as 10 pg or less, 8 pg or less, 5 pg or less, 4 pg or less, 3 pg or less, 2 pg or less, 1 pg or less, or 0.5 pg or less of methyl chloride per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains no detectable amount of methyl chloride per gram of pharmaceutical grade 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.1% or less of any unspecified impurity, such as about 0.05% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less of unspecified impurity. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.1% or less of any unspecified impurity, such as 0.05% or less, 0.03% or less, 0.02% or less, or 0.01% or less of unspecified impurity.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound has about 0.5% or less of total impurities, such as about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, or about 0.05% or less of total impurities. In some embodiments, the pharmaceutical grade 1-deoxygalactonojirimycin compound has 0.5% or less of total impurities, such as 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, or 0.05% or less of total impurities.
  • 1,2,3,6-tetrapivaloyl- D-galactofuranoside is produced from about 1 kg or more of D-(+)-galactose, such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 29 kg or more, about 30 kg or more, about 40 kg or more, about 50 kg or more, about 55 kg or more, about 60 kg or more, about 70 kg or more, about 80 kg or more, about 90 kg or more, about 100 kg or more, about 5 kg to about 75 kg, about 10 kg to about 70 kg, about 15 kg to about 65 kg, about 15 kg to about 60 kg, about 20 kg to about 55 kg, about 22 kg to about 55 kg, about 22 kg, about 25 kg, about 30 kg, about 35 kg, about 40 kg, about 45 kg, about 50 kg, or about 55 kg of D-(+)-galactose.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside is produced from 1 kg or more of D-(+)- galactose, such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg or more, 100 kg or more, 5 kg to 75 kg, 10 kg to 70 kg, 15 kg to 65 kg, 15 kg to 60 kg, 20 kg to 55 kg, 22 kg to 55 kg, 22 kg, 25 kg, 30 kg, 35 kg, 40 kg, 45 kg, 50 kg, or 55 kg of D-(+)- galactose.
  • D-(+)- galactose such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg
  • 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside is produced from about 1 kg or more of 1,2,3,6-tetrapivaloyl-D-galactofuranoside, such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 30 kg or more, about 36 kg or more, about 40 kg or more, about 50 kg or more, about 60 kg or more, about 70 kg or more, about 80 kg or more, about 84 kg or more, about 90 kg or more, about 100 kg or more, about 5 kg to about 100 kg, about 15 kg to about 95 kg, about 25 kg to about 90 kg, about 36 kg to about 84 kg, about 36 kg, about 45 kg, about 55 kg, about 65 kg, about 75 kg, or about 84 kg of 1, 2,3,6- tetrapivaloyl-D-galactofuranoside.
  • 5-azido-5-deoxy-l,2,3,6- tetrapivaloyl-D-galactofuranoside is produced from 1 kg or more of 1,2,3,6-tetrapivaloyl-D- galactofuranoside, such as 5 kg or more, 10 kg or more, 20 kg or more, 30 kg or more, 36 kg or more, 40 kg or more, 50 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 84 kg or more, 90 kg or more, 100 kg or more, 5 kg to about 100 kg, 15 kg to 95 kg, 25 kg to 90 kg, 36 kg to 84 kg, 36 kg, 45 kg, 55 kg, 65 kg, 75 kg, or 84 kg of 1,2,3,6-tetrapivaloyl-D- galactofuranoside.
  • intermediate grade 1-deoxygalactonojirimycin compound is produced from about 1 kg or more of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside, such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 29 kg or more, about 30 kg or more, about 40 kg or more, about 50 kg or more, about 55 kg or more, about 60 kg or more, about 70 kg or more, about 80 kg or more, about 90 kg or more, about 100 kg or more, about 5 kg to about 50 kg, about 10 kg to about 45 kg, about 15 kg to about 40 kg, about 20 kg to about 35 kg, about 25 kg to about 31 kg, about 25 kg, about 26 kg, about 27 kg, about 28 kg, about 29 kg, about 30 kg, or about 31 kg of 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside.
  • intermediate grade 1- deoxygalactonojirimycin compound is produced from 1 kg or more of 5-azido-5-deoxy-l,2,3,6- tetrapivaloyl-D-galactofuranoside, such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg or more, 100 kg or more, 5 kg to 50 kg, 10 kg to 45 kg, 15 kg to 40 kg, 20 kg to 35 kg, 25 kg to 31 kg, 25 kg, 26 kg, 27 kg, 28 kg, 29 kg, 30 kg, or 31 kg of 5-azido- 5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound is produced from about 1 kg or more of intermediate grade 1-deoxygalactonojirimycin compound, such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 29 kg or more, about 30 kg or more, about 40 kg or more, about 50 kg or more, about 55 kg or more, about 60 kg or more, about 70 kg or more, about 80 kg or more, about 90 kg or more, about 100 kg or more, about 5 kg to about 50 kg, about 6 kg to about 40 kg, about 7 kg to about 30 kg, about 8 kg to about 35 kg, about 10 kg to about 20 kg, about 11.5 kg to about 17.3 kg, about 11.5 kg, about 12 kg, about 13 kg, about 14 kg, about 15 kg, about 16 kg, or about 17.3 kg of intermediate grade 1-deoxygalactonojirimycin compound.
  • intermediate grade 1-deoxygalactonojirimycin compound such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 29 kg or more, about
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound is produced from 1 kg or more of intermediate grade 1-deoxygalactonojirimycin compound, such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg or more, 100 kg or more, 5 kg to 50 kg, 6 kg to 40 kg, 7 kg to 30 kg, 8 kg to 35 kg, 10 kg to 20 kg, 11.5 kg to 17.3 kg, 11.5 kg, 12 kg, 13 kg, 14 kg, 15 kg, 16 kg, or 17.3 kg of intermediate grade 1-deoxygalactonojirimycin compound.
  • intermediate grade 1-deoxygalactonojirimycin compound such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg or
  • the produced batch of pharmaceutical grade 1- deoxygalactonojirimycin compound is from about 1 kg or more, such as about 5 kg or more, about 10 kg or more, about 20 kg or more, about 29 kg or more, about 30 kg or more, about 40 kg or more, about 50 kg or more, about 55 kg or more, about 60 kg or more, about 70 kg or more, about 80 kg or more, about 90 kg or more, about 100 kg or more, about 5 kg to about 50 kg, about 6 kg to about 40 kg, about 7 kg to about 30 kg, about 8 kg to about 35 kg, about 10 kg to about 20 kg, about 11.5 kg to about 17.3 kg, about 11.5 kg, about 12 kg, about 13 kg, about 14 kg, about 15 kg, about 16 kg, or about 17.3 kg.
  • the produced batch of pharmaceutical grade 1-deoxygalactonojirimycin compound is 1 kg or more, such as 5 kg or more, 10 kg or more, 20 kg or more, 29 kg or more, 30 kg or more, 40 kg or more, 50 kg or more, 55 kg or more, 60 kg or more, 70 kg or more, 80 kg or more, 90 kg or more, 100 kg or more, 5 kg to 50 kg, 6 kg to 40 kg, 7 kg to 30 kg, 8 kg to 35 kg, 10 kg to 20 kg, 11.5 kg to 17.3 kg, 11.5 kg, 12 kg, 13 kg, 14 kg, 15 kg, 16 kg, or 17.3 kg.
  • Impurities can be determined by any suitable method, such as infrared spectroscopy, high performance liquid chromatography (HPLC), hydrophilic interaction liquid chromatography (HILIC), gas chromatography, nuclear magnetic resonance (NMR), mass spectrometry (MS), inductively coupled plasma mass spectroscopy (ICP-MS), Karl Fischer titration, and/or residue on ignition.
  • HPLC high performance liquid chromatography
  • HILIC hydrophilic interaction liquid chromatography
  • MS nuclear magnetic resonance
  • MS mass spectrometry
  • ICP-MS inductively coupled plasma mass spectroscopy
  • Karl Fischer titration Karl Fischer titration, and/or residue on ignition.
  • Some embodiments comprise using an impurity or a salt thereof as a reference standard to detect amounts (e.g., trace amounts) of the impurity in a batch of 1-deoxygalactonojirimycin compound, or an intermediate thereof. Some embodiments comprise producing the reference standard.
  • Some embodiments comprise obtaining a sample from a batch of 1- deoxy galactonojirimycin compound, or an intermediate thereof, and determining an amount of one or more impurities in the sample.
  • impurities are set forth based on %w/w (e.g., based on the weight of the 1-deoxygalactonojirimycin compound or intermediate in which the impurity is measured).
  • the impurities are set forth based on % area (e.g., based on the area under an HPLC peak associated with the impurity as compared to the total area under HPLC chromatographic peaks, which can be detected, e.g., using HILIC or UV detection).
  • % area can be calculated as set forth in NORMAN DYSON, CHROMATOGRAPHIC INTEGRATION METHODS (The Royal Society of Chemistry, 2d ed.
  • impurities are set forth based on an amount or based on ppm. Unless otherwise specified, a particularly disclosed impurity percentage is meant to encompass amounts as calculated based on % w/w and/or % area. In other words: in some embodiments, the % impurity is calculated based on % w/w; in some embodiments the % impurity is calculated based on % area. If an impurity amount is specifically tied to a type of calculation (e.g., % w/w), it is understood that such a calculation is not limiting on the scope of the disclosure, and so the impurity amount can be determined using alternative calculations (e.g. , % area) if desired. While exemplary validation components and values are discussed below for particular impurities, other components and values (e.g. , provided in preceding paragraphs or in the working examples) can also be used for batch validation.
  • a batch of 1,2,3,6-tetrapivaloyl-D-galactofuranoside is validated by determining the amount of Compound B in the batch. In some embodiments, the batch of 1,2,3,6-tetrapivaloyl-D-galactofuranoside has 3% area or less of Compound B.
  • a batch of 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside is validated by determining the amount of one or more (or all) of 1, 2,3,6- tetrapivaloyl-D-galactofuranoside, Compound E, Compound G, Compound J, Compound I, Compound K, Compound N, and Compound O in the batch.
  • the batch contains 0.6% area or less of 1,2,3,6-tetrapivaloyl-D-galactofuranoside, 0.3% area or less of Compound E, 0.3% area or less of Compound G, 3% area or less of Compound J, 0.6% area or less of Compound I, 0.3% area or less of Compound K, 1% area or less of Compound N, and 0.3% area of less of Compound O.
  • a batch of intermediate grade 1-deoxygalactonojirimycin compound is validated by determining the amounts of one or more (or all) of Compound U, Compound V, Compound Y, Compound W, and Compound BB in the batch of intermediate grade 1-deoxygalactonojirimycin compound.
  • the batch contains 0.4% w/w or less of Compound U, 0.4% w/w or less of Compound V, 0.25% w/w or less of Compound Y, 0.15% w/w or less of Compound W, and 0.3% w/w or less of Compound BB.
  • the batch contains 0.4% area or less of Compound U, 0.4% area or less of Compound V, 0.25% area or less of Compound Y, 0.15% area or less of Compound W, and 0.3% area or less of Compound BB.
  • a batch of pharmaceutical grade 1-deoxygalactonojinmycin compound is validated by determining the amounts of one or more (or all) of Compound W, Compound U, Compound V, Compound Y, Compound BB, C1-C4 alcohol(s) (e.g., methanol and/or ethanol), water, residue on ignition, arsenic, cadmium, mercury, lead, and palladium in the batch of 1-deoxygalactonojirimycin compound.
  • the pharmaceutical grade 1-deoxygalactonojirimycin compound contains 0.15% w/w or less of Compound W, 0.15% w/w or less of Compound U, 0.15% w/w or less of Compound V, 0.15% w/w or less of Compound Y, 0.15% w/w or less of Compound BB, 0.3% w/w or less of the C1-C4 alcohol (e.g., methanol), 0.5% w/w or less of the C1-C4 alcohol (e.g., ethanol), 0.2% w/w or less of water, and 0.2% w/w or less of residue on ignition, each based on the weight of the 1- deoxygalactonojirimycin compound, and 0.15 ppm or less of arsenic, 0.5 ppm or less of cadmium, 1.5 ppm or less of mercury, 0.5 ppm or less of lead, and 10 ppm or less of palladium.
  • a validated batch of pharmaceutical grade 1- deoxygalactonojirimycin compound is assessed as suitable for medical use in a subject.
  • the validated batch of 1-deoxygalactonojirimycin compound is a commercial batch of 1-deoxygalactonojirimycin compound.
  • the validated batch is distributed.
  • a batch that does not meet validation standards is not distributed.
  • a batch that does not meet validation standards is reprocessed until standards are met.
  • a pregelatinized starch is added to validated 1- deoxygalactonojirimycin compound and the mixture is screened, e.g. using a rotating impeller screening mill. In some embodiments, the screening is performed using an about a 457-micron screen, such as a 457-micron screen.
  • the validated 1-deoxygalactonojirimycin compound is blended.
  • the blending can comprise pre-lubrication and/or lubrication blending steps.
  • Exemplary prelubrication blending steps involve blending 1-deoxygalactonojirimycin compound and pregelatinized starch, e.g., using a diffusion mixer.
  • Exemplary 1-deoxygalactonojirimycin compound: pregelatinized starch ratios include about 1:1 to about 5:1, such as about 2:1 to about 4:1, about 3:1 to about 3.5:1, about 3:1, about 3.1:1.
  • Exemplary ratios also include 1:1 to 5:1, such as 2:1 to 4:1, 3:1 to 3.5:1, 3:1, 3.1:1. 3.2:1, 3.3:1, 3.4:1, or 3.5:1.
  • the diffusion mixing is performed at about 100-300 revolutions for about 5 to 15 minutes at a speed of about 20 rpm.
  • Exemplary lubrication blending steps include adding magnesium stearate to a prelubrication mix.
  • Example 1-deoxygalactonojirimycin compound : magnesium stearate ratios include about 100:1 to about 200:1, such as about 125:1 to about 175:1, about 145:1 to about 155:1, about 150:1, about 152:1, about 153:1, about 154:1, or about 155:1.
  • Example 1- deoxygalactonojirimycin compound : magnesium stearate ratios also include 100:1 to 200:1, such as 125:1 to 175:1, 145:1 to 155:1, 150:1, 152:1, 153:1, 154:1, or 155:1.
  • the lubrication blending step is conducted using a diffusion mixer, e.g., at about 60 revolutions for about 3 minutes at about 20 rpm.
  • the validated 1-deoxygalactonojirimycin compound is divided in whole or in part into portions, such as for migalastat hydrochloride with 123 mg portions FBE of migalastat (e.g., 150 mg migalastat hydrochloride).
  • the portions of 1- deoxygalactonojirimycin compound are encapsulated, e.g., in a capsule.
  • the encapsulation is with an encapsulation machine.
  • the encapsulation machine targets a capsule fill weight of about 196 mg.
  • the encapsulated 1-deoxygalactonojirimycin compound is packaged, e.g., in a container closure system.
  • the container closure system can be flexible or semirigid, and can be composed entirely, primarily, or partially of plastic.
  • the 1-deoxygalactonojirimycin compound is packaged in a paperboard package, a flexible pouch, a plastic container (e.g., cup or tray) having a heat-sealed flexible lid, or a plastic container (e.g., can) with double-seamed metal ends.
  • the container closure system can comprise one or more hermetic seals that prevent contamination of the migalastat, oxidation of the migalastat, and/or exposure of the 1-deoxygalactonojirimycin compound to external environmental conditions.
  • the container closure system comprises primary packaging (the immediate packaging that comes into contact with the consumable 1- deoxygalactonojirimycin compound product).
  • the container closure system comprises secondary packaging, which comprises an exterior packaging of the primary packaging.
  • Some embodiments comprise packaging one or more units of migalastat. Packaging can comprise inserting one or more units of 1-deoxygalactonojirimycin compound (e.g., one or more capsules) into a container closure system.
  • the secondary packaging may be the smallest sellable unit for commerce.
  • the packaging comprises polyvinyl chloride (PVC)/poly chlorotrifluoroethylene (PCTFE)/PVC laminate film with aluminum foil lidding blister packs.
  • PVC polyvinyl chloride
  • PCTFE poly chlorotrifluoroethylene
  • Some embodiments comprise sealing the packaging (e.g., forming a hermetic seal on the primary packaging). Some embodiments comprise physical or chemical testing of the packaging integrity. The testing can be performed on packaged migalastat. Integrity testing can be performed, for example, via one or more of air leak testing, biotesting, burst testing, chemical etching, compression, squeeze testing, distribution (abuse) testing, dye penetration, electester, electrolytic testing, gas leak detection, incubation, light testing, machine vision, proximity tester, seam scope projection, sound testing, tensile (peel) testing, or vacuum testing. Some embodiments comprise testing the light transmission of the packaging. Some embodiments comprise testing water vapor permeation of the packaging. Exemplary testing protocols are set forth in the US Pharmacopeia sections ⁇ 661> and ⁇ 671>, which are incorporated herein by reference in their entireties.
  • Manufacturing 1-deoxygalactonojirimycin compound can comprise repackaging 1- deoxygalactonojirimycin compound (e.g., by distributors).
  • Repackaging can comprise removing 1-deoxygalactonojirimycin compound from an original container closure system (e.g., from primary packaging and/or secondary packaging).
  • Repackaging can comprise placing 1- deoxygalactonojirimycin compound into a new container closure system (e.g., placing unpacked 1-deoxygalactonojirimycin compound into a new primary packaging and/or placing packaged 1-deoxygalactonojirimycin compound into a secondary container closure system) and optionally hermetically sealing the new container closure system.
  • repackaging comprises placing unpacked 1-deoxygalactonojirimycin compound into a new primary container closure system
  • the amount of 1-deoxygalactonojirimycin compound in each primary container may be the same as or different from the amount in the original packaging.
  • repackaging comprises packaging 1-deoxygalactonojirimycin compound in unit dose container closure systems. If repackaging comprises placing 1-deoxygalactonojirimycin compound removed from a secondary container closure system into a new secondary container closure system, the amount of 1-deoxygalactonojirimycin compound (e.g., the number of primary containers) in the new secondary container closure system may be the same as or different from the amount in the original secondary packaging.
  • Package integrity testing and/or inspection may be performed after the original packaging, after the repackaging, or after both packaging and repackaging.
  • Packaging and/or repackaging may be performed according to Current Good Manufacturing Practices (CGMP).
  • Testing may comprise stability testing on packaged 1-deoxygalactonojirimycin compound used to determine the expiration date of the 1- deoxygalactonojirimycin compound when stored in a specific type of primary container closure system.
  • NDC National Drug Code
  • bar code e.g., a bar code
  • product identifier e.g., a unique serial number, an expiration date, and a lot number
  • the NDC is a 10-digit basic identifier for pharmaceutical products.
  • the product identifier may comprise a standardized graphic.
  • the product identifier may be in a human-readable format and/or on a machine-readable data carrier that conforms to the standards developed by an international standards development organization.
  • the product identifier can comprise the standardized numerical identifier (SNI), lot number, and/or expiration date of the product.
  • the standardized numerical identifier can comprise a set of numbers or characters used to uniquely identify each package or homogeneous case (i.e. a sealed case containing only product that has a single NDC number belonging to a single lot) that is composed of the NDC that corresponds to the specific product (including the particular package configuration) combined with a unique alphanumeric serial number (e.g., of up to 20 characters).
  • an encoded, standardized bar code e.g., a linear bar code
  • the bar code can comprise the NDC number.
  • the bar code comprises the NDC and/or any other information.
  • globally accepted GS1 system data structures and/or symbologies are be used to convey the NDC, a unique serial number, expiration date and lot number, as well as optional quantity information.
  • a bar code or other machine readable data carrier can be scanned or read by a machine (e.g., by a distributor upon receiving 1-deoxygalactonojirimycin compound from a manufacturer) for processing the transport of the 1 -deoxy galactonojinmycin compound through the chain of commerce and/or manufacturing process or for inventorying the migalastat.
  • Some embodiments comprise tracing or tracking the manufactured 1- deoxygalactonojirimycin compound, e.g., at a batch level, lot level, or package level. In some embodiments, the tracing is performed electronically.
  • dispensers in a drug supply chain exchange information about a drug and who handled it each time it is sold (e.g., in the US market). In some embodiments, such information comprises transaction information and/or a transaction history. Transaction information can comprise proprietary or established name or names of the product, strength and dosage form of the product, NDC number of the product, container size, number of containers, lot number of the product, date of the transaction, date of the shipment, and/or business name and address of the person from whom and to whom ownership is being transferred.
  • Tracing can be performed using any suitable system or process.
  • tracing is performed using paper-based methods.
  • tracing is performed using electronic-based methods. Examples of tracing methods include paper or electronic versions of invoices, paper versions or packing slips, electronic data interchange (El) standards, such as advance ship notice (ASN), and electronic product code information services (EPCIS).
  • El electronic data interchange
  • ASN advance ship notice
  • EPCIS electronic product code information services
  • email or other web-based platforms are used.
  • the tracing is performed by scanning a barcode, e.g., that carries transaction information.
  • the 1-deoxygalactonojirimycin compound is stored at a temperature of from about 20°C to about 25 °C, such as about 20°C, about 21 °C, about 22°C, about 23 °C, about 24°C, or about 25°C.
  • the 1-deoxygalactonojirimycin compound is stored at a temperature of from 20°C to 25°C, such as 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C. In some embodiments, excursions are permitted between about 15° and about 30 °C, such as from 15 °C to 30°C.
  • packaged 1-deoxygalactonojirimycin compound is stored under such conditions for approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, packaged 1-deoxygalactonojirimycin compound is stored under these conditions for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • packaged 1- deoxygalactonojirimycin compound is stored under these conditions for no longer than 12, 24, 36, 48, or 60 months.
  • 1-deoxygalactonojirimycin compound is received from a manufacturer by a distributor and possession can be transferred to a third party (e.g., a pharmacy, hospital, or patient) by the distributor.
  • the distributor may store the 1- deoxygalactonojirimycin compound under controlled conditions (e.g., the temperature described above) for a period of time before transferring possession to the third party.
  • the distributor may package, repackage, or label the packages (e.g., affix to or imprint on the information described elsewhere herein) prior to transferring possession (distributing) to a third party.
  • an effective dose of 1-deoxygalactonojirimycin compound is administered to the patient in need thereof.
  • some embodiments comprise administering migalastat or salt thereof in a range of from about 100 mg FBE to about 150 mg FBE.
  • Exemplary doses include about 100 mg FBE, about 105 mg FBE, about 110 mg FBE, about 115 mg FBE, about 120 mg FBE, about 123 mg FBE, about 125 mg FBE, about 130 mg FBE, about 135 mg FBE, about 140 mg FBE, about 145 mg FBE or about 150 mg FBE.
  • the dose is 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt, administered at a frequency of once every other day.
  • 1-deoxygalactonojirimycin compound is administered at a frequency of once every other day.
  • the migalastat is administered at a frequency of once every other day.
  • a dose of 123 mg of the migalastat free base can be administered at a frequency of once every other day.
  • 1-deoxygalactonojirimycin compound is administered for a certain period of time.
  • 1-deoxygalactonojirimycin compound, migalastat or salt thereof is administered for a duration of at least 28 days, such as at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30 or 36 months, or at least 1, 2, 3, 4 or 5 years.
  • the 1-deoxygalactonojirimycin compound therapy such as migalastat therapy, is long-term therapy of at least 6 months, such as at least 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30 or 36 months or at least 1, 2, 3, 4 or 5 years.
  • 1 -deoxy galactonojirimycin compound is administered in a formulation suitable for any route of administration.
  • administration of 1-deoxygalactonojirimycin compound, such as migalastat or salt thereof may be in a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule or solution.
  • the patient is orally administered capsules each containing 150 mg migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt.
  • Some embodiments comprise administering 1-deoxygalactonojirimycin compound to a subject having an HEK assay amenable a-galactosidase A mutation.
  • An a-galactosidase A variant can be categorized as amenable if the resultant mutant a-Gal A activity (measured in the cell lysates) meets two criteria in an in vitro HEK assay: 1) it shows a relative increase of at least 20% compared to the pre-treatment a-Gal A activity, and 2) it shows an absolute increase of at least 3% of the wild-type (normal) a-Gal A activity.
  • the in vitro HEK assay comprises transfecting Human Embryonic Kidney (HEK-293) cell lines with specific a- galactosidase A variants (mutations) which produce mutant a-Gal A proteins.
  • HEK-293 Human Embryonic Kidney
  • amenability of the GLA variants can be assessed after a 5-day incubation with 1- deoxy galactonojirimycin compound, such as 10 micromol/L migalastat.
  • 1- deoxy galactonojirimycin compound such as 10 micromol/L migalastat.
  • Migalastat also known as 1-deoxygalactonojirimycin or (2R,3S,4R,5S)-2- (hydroxymethyl) piperdine-3,4,5-triol, refers to a compound having the following free base structures:
  • Migalastat hydrochloride is a compound having the following structure:
  • Migalastat salt such as migalastat hydrochloride
  • migalastat hydrochloride may be prepared by contacting free base migalastat (e.g., migalastat as provided according to the prior paragraph) in solution with at least a molar equivalent of an aqueous solution of acid, such as hydrochloric acid, or a solution of acid gas, such as solution of hydrogen chloride gas, in an appropriate solvent, for example, an alcohol or ether.
  • the migalastat salt can be isolated by removal of the solvent, for example, by evaporation.
  • intermediate grade migalastat salt such as intermediate grade migalastat hydrochloride
  • intermediate grade migalastat salt is crystallized twice or more (e.g., two times, three times, four times, or more) to form pharmaceutical grade migalastat salt.
  • the crystallization is in a mixture of water and a lower alcohol, for example, a C1-C4 alcohol.
  • a lower alcohol for example, a C1-C4 alcohol.
  • examples of such alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and n-butanol.
  • the lower alcohol is ethanol.
  • the intermediate grade migalastat salt is admixed with water. In some embodiments, the intermediate grade migalastat salt is admixed in from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about
  • the intermediate grade migalastat salt is admixed in from 0.5 to 4 weights of water, such as from 0.5 to 3 weights, 1 to
  • the first crystallized migalastat salt is admixed with about 1, 1.1 weights, 1.2 weights, 1.3 weights, 1.4 weights, 1.5 weights or 1.6 weights of water.
  • the temperature during the mixing and crystallization may vary.
  • the temperature is adjusted to a first crystallization temperature after the intermediate grade migalastat salt is admixed with water, e.g., to a temperature from about 30°C to about 70°C, about 35 °C to about 65 °C, about 40°C to about 60°C, about 40°C, about 45 °C, about 50°C, about 55°C, or about 60°C.
  • the temperature is adjusted after the intermediate grade migalastat salt is admixed with water, e.g., to a temperature of from 30°C to 70°C, 35°C to 65°C, 40°C to 60°C, 40°C, 45°C, 50°C, 55°C, or 60°C.
  • the migalastat salt is admixed with water, at a temperature from about 30°C to about 70°C, and the temperature is maintained or is adjusted, either up or down, to the first crystallization temperature.
  • the C1-C4 alcohol e.g., ethanol
  • the C1-C4 alcohol is added to the intermediate grade migalastat mixture at the first crystallization temperature to induce crystallization.
  • from about 1 to about 15 weights of C1-C4 alcohol e.g., ethanol
  • is added such as from about 1 to about 12 weights, about 1 to about 11.4 weights, about 4.8 to about 11.4 weights, about 7 to about 12 weights, about 8 to about 11 weights, about 8.4 to about 10.6 weights, about 8.5 to about 10.4 weights, about 8.5 weights, about 9 weights, about 9.5 weights, about 10 weights, or about 10.4 weights of C1-C4 alcohol (e.g., ethanol).
  • weights of C1-C4 alcohol e.g., ethanol
  • C1-C4 alcohol e.g., ethanol
  • weights of C1-C4 alcohol e.g., ethanol
  • C1-C4 alcohol e.g., ethanol
  • C1-C4 alcohol e.g., ethanol
  • C1-C4 alcohol is added to the first migalastat salt slurry or solution over a period of time ranging from about 0 to about 65 minutes. In some embodiments, C1-C4 alcohol (e.g., ethanol) is added to the first migalastat salt slurry or solution over a period of time of about 60 minutes.
  • the resulting slurry or solution is cooled to an isolation temperature, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the isolation temperature is from 3°C to 50°C, 5 C to 45 C, 5 C to 40 C, 5°C to 35°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, or 35°C in order to complete the crystallization.
  • the cooling comprises an active cooling step (e.g. removal of heat by contact with ice, refrigerant, etc).
  • the cooling comprises a passive cooling step by allowing the slurry or solution to reach the ambient temperature of its surroundings.
  • the first crystallized migalastat salt is isolated from the slurry or solution via filtration (e.g., conducted at the isolation temperature).
  • the first crystallized migalastat salt is washed, e.g., with a C1-C4 alcohol (e.g., ethanol) following isolation.
  • the wash can be conducted with about 0.5 weights of C1-C4 alcohol (e.g., ethanol; relative to the weight of the isolated Stage 4a product) or more, such as about 1 or more weights, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the wash is conducted with 0.5 weights of C1-C4 alcohol (e.g., ethanol) or more, such as 1 or more weights, 2 or more weights, 3 or more weights, 5 or more weights, or 10 or more weights.
  • C1-C4 alcohol e.g., ethanol
  • the first crystallized migalastat salt is dried, e.g., under vacuum. In some embodiments, the first crystallized migalastat salt is dried at a temperature or about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C. In some embodiments, the first crystallized migalastat salt is dried at a temperature or 90°C or less, such as 80°C or less, 70°C or less, 60°C or less, 50°C or less, including, e.g., a temperature of 80°C, 70°C, or 60°C.
  • the first crystallized migalastat salt is further purified by a second crystallization.
  • the first crystallized migalastat salt is admixed with water.
  • the first crystallized migalastat salt is admixed in from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about
  • the first crystallized migalastat salt is admixed in from 0.5 to 4 weights of water, such as from 0.5 to 3 weights, 1 to
  • the first crystallized migalastat salt is admixed with about 1, 1.1 weights, 1.2 weights, 1.3 weights, 1.4 weights, 1.5 weights or 1.6 weights of water.
  • the temperature is adjusted to a second crystallization temperature after the first crystallized migalastat salt is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the temperature is adjusted after the first crystallized migalastat salt is admixed with water, e.g., to a temperature of from 30°C to 70°C, 35°C to 65°C, 40°C to 60°C, 40°C, 45°C, 50°C, 55°C, or 60°C.
  • the migalastat salt is admixed with water, at a temperature from about 30°C to about 70°C, and the temperature is maintained or is adjusted, either up or down, to the second crystallization temperature.
  • a first quantity of C1-C4 alcohol (e.g., ethanol) is added to the first crystallized migalastat salt mixture at the first crystallization temperature to induce crystallization.
  • the first quantity of C1-C4 alcohol e.g., ethanol
  • the first quantity of C1-C4 alcohol is from about 0.5 to about 4 weights of ethanol relative to the weight of migalastat salt, such as from about 0.75 to about 3 weights, about 1 to about 2.5 weights, about 1.8 to about 2 weights, about 1.8 weights, about 1.9 weights, or about 2 weights of C1-C4 alcohol (e.g., ethanol), relative to the weight of migalastat salt.
  • the first quantity of C1-C4 alcohol (e.g., ethanol) is from 0.5 to 4 weights, such as from 0.75 to 3 weights, 1 to 2.5 weights, 1.8 to 2 weights, 1.8 weights, 1.9 weights, or 2 weights of C1-C4 alcohol (e.g., ethanol), relative to the weight of migalastat salt.
  • the first quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more. In some embodiments, the first quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of 3 minutes or more, such as 4 minutes or more, 5 minutes or more, 10 minutes or more, or 15 minutes or more. In some embodiments, the first quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of from about 5 to about 65 minutes.
  • a second quantity of C1-C4 alcohol (e.g., ethanol) is added to the mixture following a hold time.
  • the hold time can be about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the hold time is a period of 3 minutes or more, such as 4 minutes or more, 5 minutes or more, 10 minutes or more, or 15 minutes or more.
  • the second quantity of C1-C4 alcohol (e.g., ethanol) comprises about 4 to about 15 weights of C1-C4 alcohol (e.g., ethanol) relative to the weight of migalastat salt, such as from about 5 to about 12 weights, about 6 to about 10 weights, about 6.5 to about 9 weights, about 6.7 to about 8.4 weights, about 6.8 to about 8.4 weights, about 6.8 weights, about
  • the second quantity of C1-C4 alcohol (e.g., ethanol) comprises 4 to 15 weights, such as from 5 to 12 weights, 6 to 10 weights, 6.5 to 9 weights, 6.8 to 8.4 weights, 6.8 weights, 7 weights, 7.5 weights,
  • C1-C4 alcohol e.g., ethanol
  • the second quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of about 5 minutes or more, such as about 10 minutes or more, about 15 minutes or more, about 20 minutes or more, about 30 minutes or more, about 45 minutes or more, or about 60 minutes or more.
  • the second quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of 5 minutes or more, such as 10 minutes of more, 15 minutes or more, 20 minutes or more, 30 minutes or more, 45 minutes or more, or 60 minutes or more.
  • the amount of C1-C4 alcohol (e.g., ethanol) used in the second crystallization is the same as the amount of C1-C4 alcohol (e.g., ethanol) used in the first crystallization.
  • the amount of Cl- C4 alcohol (e.g., ethanol) used is different from the amount of C1-C4 alcohol (e.g., ethanol) used in the first crystallization.
  • Some embodiments comprise cooling the resulting slurry or solution (e.g., that contains both the first and second quantities of C1-C4 alcohol (e.g., ethanol)) to an isolation temperature in order to complete the second crystallization.
  • the slurry or solution is cooled to an isolation temperature, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the isolation temperature is 3 °C to 50°C, 5 °C to 45 °C, 5 °C to 40°C, 5 °C to 35 °C, 5 °C, 10°C, 15 °C, 20°C, 25°C, 30°C, or 35°C.
  • the cooling comprises an active cooling step (e.g. removal of heat by contact with ice, refrigerant, etc). In other embodiments, the cooling comprises a passive cooling step by allowing the slurry or solution to reach the ambient temperature of its surroundings. [0439] In some embodiments, the second crystallized migalastat salt is isolated from the slurry or solution via filtration e.g., conducted at the isolation temperature).
  • the second crystallized migalastat salt is washed, e.g., with a C1-C4 alcohol (e.g., ethanol).
  • the wash can be conducted with about 0.5 weights of C1-C4 alcohol (e.g., ethanol) or more, such as about 1 or more weight, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the wash is conducted with 0.5 weights or more, such as 1 or more weight, 2 or more weights, 3 or more weights, 5 or more weights, or 10 or more weights of C1-C4 alcohol (e.g., ethanol).
  • the second crystallized migalastat salt is dried, e.g., under vacuum.
  • the second crystallized migalastat salt is dried at a temperature of about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C.
  • the second crystallized migalastat salt product is dried at a temperature of 90°C or less, such as 80°C or less, 70°C or less, 60°C or less, 50°C or less, 80°C, 70°C, or 60°C.
  • Lucerastat also known as N-butyldeoxygalactonojirimycin or (2R,3S,4R,5S)-l-buthyl- 2-(hydroxymethyl)piperdine-3,4,5-triol, refers to a compound having the following free base structures:
  • Lucerastat can be produced from migalastat by butylation of the piperidine nitrogen atom with an appropriate alkylating agent.
  • butylation may be performed by reductive alkylation of migalastat with butyraldehyde in the presence of a reducing agent.
  • suitable reducing agents include hydrogen and a catalyst, sodium cyanoborohydride, and sodium triacetoxyborohydride.
  • Lucerastat hydrochloride is a compound having the following structure:
  • Lucerastat salt such as lucerastat hydrochloride
  • free base lucerastat e.g., lucerastat as provided according to the prior paragraph
  • acid such as hydrochloric acid
  • acid gas such as solution of hydrogen chloride gas
  • the lucerastat salt, such as lucerastat hydrochloride is isolated by removal of the solvent, for example, by evaporation.
  • intermediate grade lucerastat salt such as intermediate grade lucerastat hydrochloride
  • intermediate grade lucerastat salt is crystallized twice or more (e.g., two times, three times, four times, or more) to form pharmaceutical grade lucerastat salt.
  • the crystallization is in a mixture of water and a lower alcohol, for example, a C1-C4 alcohol.
  • a lower alcohol for example, a C1-C4 alcohol.
  • examples of such alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and n-butanol.
  • the lower alcohol is ethanol.
  • the intermediate grade lucerastat salt is admixed with water.
  • the intermediate grade lucerastat salt is admixed in from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about 1.1 to about 1.4 weights, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the intermediate grade lucerastat salt is admixed in from 0.5 to 4 weights of water, such as from 0.5 to 3 weights, 1 to 2 weights, 1.1 to about 1.4, 1.1 weights, 1.2 weights, 1.3 weights, or 1.4 weights of water.
  • the temperature during the mixing and crystallization may vary.
  • the temperature is adjusted to a first crystallization temperature after the intermediate grade lucerastat salt is admixed with water, e.g. , to a temperature from about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the temperature is adjusted after the intermediate grade lucerastat salt is admixed with water, e.g., to a temperature of from 30°C to 70°C, 35°C to 65°C, 40°C to 60°C, 40°C, 45°C, 50°C, 55°C, or 60°C.
  • the lucerastat salt is admixed with water, at a temperature from about 30°C to about 70°C, and the temperature is maintained or is adjusted, either up or down, to the first crystallization temperature.
  • the C1-C4 alcohol e.g., ethanol
  • the C1-C4 alcohol is added to the intermediate grade lucerastat mixture at the first crystallization temperature to induce crystallization.
  • from about 6 to about 15 weights of C1-C4 alcohol e.g., ethanol
  • is added such as from about 7 to about 12 weights, about 8 to about 11 weights, about 8.5 to about 10.4 weights, about 8.5 weights, about 9 weights, about 9.5 weights, about 10 weights, or about 10.4 weights of C1-C4 alcohol (e.g., ethanol).
  • weights of C1-C4 alcohol e.g., ethanol
  • C1-C4 alcohol e.g., ethanol
  • weights of C1-C4 alcohol e.g., ethanol
  • the resulting slurry or solution is cooled to an isolation temperature, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the isolation temperature is from 3°C to 50°C, 5°C to 45°C, 5°C to 40°C, 5°C to 35°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, or 35°C in order to complete the crystallization.
  • the first crystallized lucerastat salt is isolated from the slurry or solution via filtration (e.g., conducted at the isolation temperature).
  • the first crystallized lucerastat salt is washed, e.g., with a C1-C4 alcohol (e.g., ethanol) following isolation.
  • the wash can be conducted with about 0.5 weights of C1-C4 alcohol (e.g., ethanol; relative to the weight of the isolated Stage 4a product) or more, such as about 1 or more weights, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the wash is conducted with .5 weights of C1-C4 alcohol (e.g., ethanol) or more, such as 1 or more weights, 2 or more weights, 3 or more weights, 5 or more weights, or 10 or more weights.
  • C1-C4 alcohol e.g., ethanol
  • the first crystallized lucerastat salt is dried, e.g., under vacuum. In some embodiments, the first crystallized lucerastat salt is dried at a temperature or about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C. In some embodiments, the first crystallized lucerastat salt is dried at a temperature or 90°C or less, such as 80°C or less, 70°C or less, 60°C or less, 50°C or less, including, e.g., a temperature of 80°C, 70°C, or 60°C.
  • the first crystallized lucerastat salt is further purified by a second crystallization.
  • the first crystallized lucerastat salt is admixed with water.
  • the first crystallized lucerastat salt is admixed in from about 0.5 to about 4 weights of water, such as from about 0.5 to about 3 weights, about 1 to about 2 weights, about 1.1 to about 1.4 weights, about 1.1 weights, about 1.2 weights, about 1.3 weights, or about 1.4 weights of water.
  • the first crystallized lucerastat salt is admixed in from 0.5 to 4 weights of water, such as from 0.5 to 3 weights, 1 to 2 weights, 1.1 to about 1.4, 1.1 weights, 1.2 weights, 1.3 weights, or 1.4 weights of water.
  • the temperature is adjusted to a second crystallization temperature after the first crystallized lucerastat salt is admixed with water, e.g., to a temperature of from about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the temperature is adjusted after the first crystallized lucerastat salt is admixed with water, e.g., to a temperature of from 30°C to 70°C, 35°C to 65°C, 40°C to 60°C, 40°C, 45°C, 50°C, 55°C, or 60°C.
  • the lucerastat salt is admixed with water, at a temperature from about 30°C to about 70°C, and the temperature is maintained or is adjusted, either up or down, to the second crystallization temperature.
  • a first quantity of C1-C4 alcohol is added to the first crystallized lucerastat salt mixture at the first crystallization temperature to induce crystallization.
  • the first quantity of C1-C4 alcohol e.g., ethanol
  • the first quantity of C1-C4 alcohol is from about 0.5 to about 4 weights of the C1-C4 alcohol (e.g., ethanol) relative to the weight of lucerastat salt, such as from about 0.75 to about 3 weights, about 1 to about 2.5 weights, about 1.8 to about 2 weights, about 1.8 weights, about 1.9 weights, or about 2 weights of C1-C4 alcohol (e.g., ethanol), relative to the weight of lucerastat salt.
  • the first quantity of C1-C4 alcohol e.g., ethanol
  • the first quantity of C1-C4 alcohol is from 0.5 to 4 weights, such as from 0.75 to 3 weights, 1 to
  • the first quantity of C1-C4 alcohol e.g., ethanol
  • the first quantity of C1-C4 alcohol is added over a period of about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the first quantity of C1-C4 alcohol e.g., ethanol
  • a second quantity of C1-C4 alcohol (e.g., ethanol) is added to the mixture following a hold time.
  • the hold time can be about 3 minutes or more, such as about 4 minutes or more, about 5 minutes or more, about 10 minutes or more, or about 15 minutes or more.
  • the hold time is a period of 3 minutes or more, such as 4 minutes or more, 5 minutes or more, 10 minutes or more, or 15 minutes or more.
  • the second quantity of C1-C4 alcohol comprises about 4 to about 15 weights of C1-C4 alcohol (e.g., ethanol) relative to the weight of lucerastat salt, such as from about 5 to about 12 weights, about 6 to about 10 weights, about 6.5 to about 9 weights, about 6.8 to about 8.4 weights, about 6.8 weights, about 7 weights, about 7.5 weights, about 8 weights, or about 8.4 weights.
  • the second quantity of C1-C4 alcohol comprises 4 to 15 weights, such as from 5 to 12 weights, 6 to 10 weights,
  • the second quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of about 10 minutes or more, such as about 15 minutes or more, about 20 minutes or more, about 30 minutes or more, about 45 minutes or more, or about 60 minutes or more.
  • the second quantity of C1-C4 alcohol (e.g., ethanol) is added over a period of 10 minutes or more, such as 15 minutes or more, 20 minutes or more, 30 minutes or more, 45 minutes or more, or 60 minutes or more.
  • the amount of C1-C4 alcohol (e.g., ethanol) used in the second crystallization is the same as the amount of C1-C4 alcohol (e.g., ethanol) used in the first crystallization.
  • the amount of Cl- C4 alcohol (e.g., ethanol) used is different from the amount of C1-C4 alcohol (e.g., ethanol) used in the first crystallization.
  • Some embodiments comprise cooling the resulting slurry or solution (e.g., that contains both the first and second quantities of C1-C4 alcohol (e.g., ethanol)) to an isolation temperature in order to complete the second crystallization.
  • the slurry or solution is cooled to an isolation temperature, e.g., of from about 3°C to about 50°C, about 5°C to about 45°C, about 5°C to about 40°C, about 5°C to about 35°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C.
  • the isolation temperature is 3°C to 50°C, 5°C to 45°C, 5°C to 40°C, 5°C to 35°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, or 35°C.
  • the second crystallized lucerastat salt is isolated from the slurry or solution via filtration (e.g., conducted at the isolation temperature).
  • the second crystallized lucerastat salt is washed, e.g., with a C1-C4 alcohol (e.g., ethanol).
  • the wash can be conducted with about 0.5 weights of C1-C4 alcohol (e.g., ethanol) or more, such as about 1 or more weight, about 2 or more weights, about 3 or more weights, about 5 or more weights, or about 10 or more weights.
  • the wash is conducted with 0.5 weights or more, such as 1 or more weight, 2 or more weights, 3 or more weights, 5 or more weights, or 10 or more weights of C1-C4 alcohol (e.g., ethanol).
  • C1-C4 alcohol e.g., ethanol
  • the second crystallized lucerastat salt is dried, e.g., under vacuum. In some embodiments, the second crystallized lucerastat salt is dried at a temperature of about 90°C or less, such as about 80°C or less, about 70°C or less, about 60°C or less, about 50°C or less, about 80°C, about 70°C, or about 60°C. In some embodiments, the second crystallized lucerastat salt product is dried at a temperature of 90°C or less, such as 80°C or less, 70°C or less, 60°C or less, 50°C or less, 80°C, 70°C, or 60°C.
  • HPLC High performance liquid chromatography
  • HILIC Hydrophilic interaction liquid chromatography
  • GC gas chromatography
  • ICP-MS Inductively coupled plasma mass spectroscopy
  • Migalastat hydrochloride was produced using the tolerances set forth in Table 3 unless otherwise defined: Table 3: Tolerances used during production of migalastat hydrochloride
  • Equipment Reactors were glass, glass-lined steel, stainless steel, or Hastelloy C and were equipped with appropriate stirring and temperature controls. Filtrations for the purpose of isolating crystalline products were performed using a Hastelloy Nutsche type filter with a metal filter fabric. Other solid materials, like inorganic salts, were separated from product-containing solutions by use of lens-shaped or GAF-filters (Hastelloy, ECTFE coated or stainless steel) with paper or textile inserts.
  • lens-shaped or GAF-filters Hastelloy, ECTFE coated or stainless steel
  • FIG. 1 A flow diagram for the synthesis of a batch migalastat hydrochloride is shown in Fig. 1.
  • Diazabicycloundec-7-ene NaOMe - Sodium methoxide; NaN - Sodium azide; EtOH - Ethanol; DIPEA - N,N-Diisopropylethylamine; PivCl - Pivaloyl chloride; HC1 - Hydrochloric acid; Tf2O - Trifluoromethanesulfonic acid; Pd/C Palladium on carbon anhydride.
  • the synthesis involved 4 Stages. Batches were produced using the input scale set forth in Table 4 for each of the 4 Stages:
  • Stage 1 of migalastat hydrochloride production was performed as shown in Fig. 2, which also demonstrates an impurity formed during Stage 1.
  • Pivaloyl imidazole was reacted with D- (+)-galactose to give 1,2,3,6-tetrapivaloyl-D-galactofuranoside.
  • Pivaloyl imidazole was prepared by mixing pivaloyl chloride and imidazole in toluene. The slurry or solution was filtered and washed with toluene to give a solution of pivaloyl imidazole in toluene (18.4%- 28.3% w/w).
  • Stage 2 of migalastat hydrochloride production was performed as shown in Fig. 3.
  • 1,2,3,6-tetrapivaloyl-D-galactofuranoside was activated with trifluoromethanesulfonic acid anhydride and then reacted with water to give 1,2,3,6-tetrapivaloyl-a-L-altrofuranoside.
  • the resulting intermediate was again activated with trifluoromethanesulfonic acid anhydride and then reacted with sodium azide to give 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside which was isolated.
  • the aqueous layer was separated and the organic layer dried by azeotropic distillation before adding IP Ac and then l,8-diazabicycloundec-7-ene (DBU) (0.033-0.066 weights).
  • IP Ac IP Ac
  • DBU l,8-diazabicycloundec-7-ene
  • the resulting IP Ac solution of Compound E was washed with aqueous hydrochloric acid (HC1) and then with aqueous pyridine.
  • the solution was dried by azeotropic distillation and diluted with IP Ac addition.
  • Trifluoromethanesulfonic acid anhydride 1.0-1.6 molar equiv.
  • pyridine 1.15-1.73 weights
  • the resulting IP Ac solution of Compound F was washed with water and added to sodium azide (0.13-0.19 weights) and N,N- diisopropylethylamine (DIPEA) (0.28-0.40 weights) in dimethylsulfoxide (DMSO). The mixture was stirred for at least 1 hour. The resulting 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D- galactofuranoside mixture was washed with water and the organic layer was concentrated by distillation. The mixture was treated with ethanol (5.64-8.45 weights) and water (4.78-7.17 weights).
  • DIPEA N,N- diisopropylethylamine
  • the solid 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside was isolated by filtration at 10-25°C, washed with methanol (0.79-2.38 weights), and dried under vacuum with heating at ⁇ 40°C.
  • Stage 3 of migalastat hydrochloride production was performed as shown in Fig. 5. Impurities that are present following Stage 3 are shown in Fig. 6. Specific production steps or parameters associated with steps 3a, b, and/or c are shown in Fig. 7-9, which are discussed in greater detail below.
  • Stage 3a 5 -azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside (1 weight) and 10% palladium catalyst on carbon (0.007-0.013 molar equivalents of palladium) were stirred in methanol (5.54-7.13 weights) under a hydrogen atmosphere. The process was vented several times to release nitrogen, and hydrogen pressure was reapplied each time. After venting, the mixture was stirred at a temperature of 40-50°C under a hydrogen pressure of 8-10 bar (absolute) for a time of not less than 44 hours. The reaction mixture was filtered to remove the catalyst.
  • Stage 3b 30% Sodium methoxide solution in methanol (0.8-1.2 equivalents) was added to the solution of Compound S. The mixture was concentrated by distillation to about 0.5 weights (by volume marker) and 37% hydrochloric acid (2.9-3.2 volumes) was added at 20-45 °C before the mixture was aged at a temperature of 40- 55 °C for not more than 10 hours to allow precipitation of the sodium chloride. The suspension was cooled to the filtration temperature of 25-40°C and the sodium chloride was filtered. [0480] Stage 3c: Ethanol was added over not less than 30 minutes. The intermediate grade migalastat hydrochloride was isolated at a temperature of not less than 15°C, washed with ethanol, and dried.
  • Table 9 shows batch analysis data from batches of intermediate grade migalastat hydrochloride manufactured at a range of scales. These data demonstrate that the control of the CQAs in intermediate grade migalastat hydrochloride across a range of scales.
  • Table 9 Impurities Data from Stage 3 at Different Scales
  • Stage 4 of migalastat hydrochloride production was performed as shown in Fig. 24, which also shows potential impurities that are present following Stage 4. More particularly, intermediate grade migalastat hydrochloride was recrystallized twice from a mixture of water and ethanol to give migalastat hydrochloride.
  • Stage 4a quantities are expressed relative to intermediate grade migalastat hydrochloride.
  • Stage 4a 11.5-17.3 kg of intermediate grade migalastat hydrochloride (1 weight) was dissolved in water (1.1 - 1.4 weights). The temperature was adjusted to 40-60°C, ethanol (8.5 - 10.4 weights) was added, and the slurry or solution cooled to an isolation temperature of 5-35 °C. The product was filtered, washed with ethanol (not less than 1 weight), and dried under vacuum at not more than 80 °C.
  • Stage 4b The first stage of the Stage 4b product.
  • Stage 4a product (1 weight) was dissolved in water.
  • the solution was clarified by filtration and water was added to give a total water quantity of (1.1 - 1.4 weights).
  • the temperature was adjusted to 40-60°C and ethanol 1 quantity (1.8 - 2.0 weights) added over not less than 5 minutes to induce crystallization.
  • ethanol 2 quantity (6.8 - 8.4 weights) was added over not less than 20 minutes and the mixture was cooled to an isolation temperature of 5 -35 °C.
  • the migalastat hydrochloride was filtered, washed with ethanol
  • NLT Not less than; 'Weights expressed relative to input amounts for each Stage
  • Stage 3 produces intermediate grade migalastat hydrochloride.
  • Stage 4 recrystallization is a distinct purification process for the final drug substance migalastat hydrochloride. If intermediate grade migalastat hydrochloride does not conform to Stage 3 specifications, it may be processed through the Stage 4a or Stage 4b recrystallization process. The isolated product can be analyzed against both the intermediate grade migalastat hydrochloride and migalastat hydrochloride (API) specifications. The final recrystallization may not have to be repeated if the isolated product from the recrystallization meets the migalastat hydrochloride specification.
  • API migalastat hydrochloride
  • migalastat hydrochloride does not conform to the migalastat hydrochloride specifications, it may be recrystallized by performing the Stage 4b recrystallization process.
  • Heel of migalastat hydrochloride recovered from the filter drier may be collected in Stage 4a or 4b and reprocessed using the Stage 4b process for the recrystallization of migalastat hydrochloride.
  • Fig. 26 sets forth a flow diagram identifying process controls in place for each unit operation of a commercial process.
  • the controls are a combination of manufacturing operating parameters and in-process control tests.
  • the typical time of manufacture for the drug product is one day for screening and blending of encapsulation blend and two days for encapsulation. Hold time of filled capsules prior to packaging is up to 30 days.
  • Migalastat hydrochloride and pregelatinized starch were screened using a rotating impeller screening mill (Comil), through a 457 micron screen.
  • Step 2 Blending of Encapsulation Mix (Pre-lubrication and Lubrication)
  • Pre-lubrication 4590 g of migalastat hydrochloride and 1380 g of pregelatinized starch were blended using a suitable diffusion mixer, such as 100-300 revolutions, for example 5 to 15 minutes at a speed of 20 rpm.
  • Lubrication 30 g of magnesium stearate was added to the pre-lubrication mix and blended for typically 60 revolutions, for example 3 minutes at 20 rpm using a suitable diffusion mixer.
  • the blend obtained at Step 2 was encapsulated using a suitable encapsulation machine to the target capsule fill weight of 196 mg.
  • In-process control tests for filled capsule weight (individual and mean), closed capsule length, and description were applied at regular intervals throughout the encapsulation run.
  • Step 4 Primary Packaging and Testing
  • the capsules from Step 3 were filled into polyvinyl chloride (PVC)/ polychlorotrifluoroethylene (PCTFE)/PVC laminate film with aluminum foil lidding blister packs using suitable automated blister packaging equipment. A seal integrity test was performed at the start of packaging and at appropriate intervals for the duration of the packaging process.
  • PVC polyvinyl chloride
  • PCTFE polychlorotrifluoroethylene
  • Capsules from blisters failing the seal integrity test may be reprocessed in Step 4.
  • B is an intermediate in the conversion of D-(+)-galactose to 1,2,3,6-tetrapivaloyl-D- galactofuranoside.
  • Table 15 Impurity standards used for setting specification limits in 1,2,3,6-tetrapivaloyl-D- galactofuranoside
  • Table 16 Data used for setting impurity specification limits in 5-azido-5-deoxy-l, 2,3,6- tetrapivaloyl-D-galactofuranoside
  • Table 17 Data used for setting impurity specification limits in 5-azido-5-deoxy- 1,2,3,6-tetrapivaloyl-D-galactofuranoside
  • Table 18 Impurity standards used for setting specification limits in 5-azido-5-deoxy-l,2,3,6- tetrapivaloyl-D-galactofuranoside
  • Example 7 Controlling Pharmaceutical Grade Migalastat Hydrochloride Impurities
  • Migalastat hydrochloride contains four stereocenters, which raise the possibility of impurities related to epimerization. Levels of four epimers were measured in batches of intermediate grade migalastat hydrochloride manufactured at the commercial scale, and the levels were less than 0.1% w/w in all batches. [0511] Compound A, Compound EE, and Compound DD were spiked into the intermediate grade migalastat hydrochloride input to the Stage 4b recrystallization. Levels of each impurity were confirmed to be below 0.1% w/w in the migalastat hydrochloride produced.
  • Table 23 Summary of genotoxic / potentially genotoxic impurities in migalastat hydrochloride
  • Compound Q, Compound P, and Compound X were confirmed as genotoxins (Ames positive).
  • Compound D and Compound F were not sufficiently stable for Ames testing and, therefore, were also designated as genotoxins.
  • Impurities designated as genotoxins were screened-for using limit tests in suitable intermediates or migalastat hydrochloride drug substance itself. All the designated genotoxins were demonstrated to be below the TTC. Furthermore, confirmatory spiking experiments were completed for each of the designated genotoxins, except for Compound D and Compound F, to demonstrate that the commercial manufacturing process efficiently purges these impurities.
  • Compound D is transformed in Stage 2 to Compound F.
  • TTC Threshold of Toxicological Concern
  • Fig. 7 It was established that there was a potential risk of formation of increased levels of the critical quality attribute (CQA) Compound W through oxidation in the presence of the palladium on carbon catalyst (Fig. 7). Compound W does not purge in the Stage 4 recrystallization. An alteration in the order of the unit operations in Stage 3a was implemented to mitigate this risk and improve control of Compound W. Earlier filtration of the palladium on carbon catalyst suppresses formation of Compound W and this modification was therefore introduced into the commercial process to provide additional process robustness.
  • Fig. 8 illustrates the commercial process with the catalyst removed at the end of Stage 3a. This is exemplified by the data summarized in Table 27, which shows levels of Compound W from a direct comparison experiment.
  • Compound W was present at 0.6% area in intermediate grade migalastat hydrochloride following manufacture via the process in which the palladium catalyst is present at Stage 3b. In contrast, Compound W was not detected in intermediate grade migalastat hydrochloride produced via the process in which the palladium catalyst is removed before Stage 3b.
  • Table 27 Levels of Compound W in Intermediate Grade Migalastat Hydrochloride Produced via Laboratory Scale Clinical/Stability and Commercial Processes
  • Stage 3a Compound U is formed as a result of incomplete reduction of the intermediate Compound T (see Fig. 9).
  • Compound Y, Compound BB, and Compound V are formed from by-products of Stage 3a.
  • Stage 3a 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside is reduced quickly to the first intermediate Compound R.
  • Compound R is then transformed in a slower process via Compound T to the intermediate Compound S.
  • the extent of the Stage 3 a reduction is related to the reaction time, and time was identified as a CPP for the control of Compound U derived from residual Compound R and Compound T.
  • Stage 3a A detailed risk assessment of Stage 3a was undertaken. Through this process, additional parameters in Stage 3 a were identified as potentially impacting the drug -related impurity CQAs Compound Y, Compound U, Compound BB, and Compound V. These parameters were then investigated in a series of multifactorial experiments.
  • Fig. 11 illustrates the effect on Compound V of the palladium catalyst quantity.
  • Error bars represent least significant differences (ESD) at 95% confidence levels. If the response ranges indicated by the LSD bars for two points do not overlap, the points are statistically different.
  • Experimental values run in the design are represented on the effect plot as circles.
  • the specific effect plot is conditional on the level of factors not explicitly displayed (the conditional levels are listed as text to the left of the graphics with a label “Actual Factors”), hence, demonstrating the size of the relationship and not the precise location. Effect plots such as Fig.
  • Heterogeneous hydrogenation processes can be sensitive to vessel configuration and impeller speed, which strongly influence the gas/liquid mass transfer properties of the system. For this reason, the design of these reactors usually includes a high speed turbine impeller positioned low in the vessel.
  • the impeller shafts may be ‘gas entrainment’ type, i.e., shaft of hollow construction with apertures at the top and bottom extremities which cause gas to be drawn down from the head-space and expelled via the turbine into the liquid vortex causing maximum dispersion and gas transfer.
  • Fig. 14 shows the reaction profile for Stage 3a in a 70 g laboratory scale experiment, at 0.8 kg (20 liter) scale and at 31 kg production scale. Zero hours was defined as the time following completion of the venting to release the nitrogen generated during reduction of the 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-D-galactofuranoside to Compound R. Each of the batches met the reaction endpoint after an equivalent amount of time, and the overall reaction profile at the three scales was comparable. Notably, the plant scale hydrogenator outperformed the lab scale equipment.
  • Residue on ignition is a CQA and a measure of inorganic impurity levels.
  • Sodium chloride is an inorganic by-product impurity of Stage 3b that is detected in intermediate grade migalastat hydrochloride. No further inorganic impurities are introduced after this Stage, and the residue on ignition of drug substance is impacted by the levels of sodium chloride in intermediate grade migalastat hydrochloride.
  • Sodium chloride is formed following the addition of 37% hydrochloric acid to the concentrated mixture of migalastat free base and sodium alkoxides. The sodium chloride, which has only partial solubility in the 37% hydrochloric acid solution of migalastat, is then mostly removed by filtration.
  • Fig. 15 is a schematic of the Stage 3b process, showing how the temperature is varied after the addition of the 37 % hydrochloric acid.
  • Compound X is a genotoxic impurity which can form in Stage 3, as shown in Fig. 19.
  • Compound X was well controlled in batches of drug substance, being not greater than 2.0 mcg/g, well below the threshold of toxicological concern (TTC) of 12 mcg/g.
  • TTC toxicological concern
  • Compound X can form under the harsh process conditions in Stage 3b where the solution of migalastat hydrochloride in concentrated hydrochloric acid is aged at elevated temperature in a solution saturated with sodium chloride.
  • Fig. 22 is a half-normal plot generated using data from this study. It illustrates that decreasing the time of the ethanol addition or decreasing the temperature will lead to higher levels of Compound U in the intermediate grade migalastat hydrochloride. This point is further illustrated in the effects plot in Fig. 23, which illustrates that decreasing the temperature will reduce the degree of purging and hence, increase the level of Compound U in the intermediate grade migalastat hydrochloride.
  • CPPs in Stage 3 [0574] Following completion of the evaluating activities for Stage 3, the risk assessment was updated to incorporate data from batches manufactured at commercial scale.
  • the CPPs for control of related impurity CQAs in Stage 3a include temperature, the catalyst quantity, hydrogen pressure, methanol volumes, and time.
  • the CPP for control of residue on ignition in Stage 3b includes filtration temperature.
  • the CPPs for control of the genotoxin Compound X in Stage 3b include the residual weight after the distillation, age time, and age temperature.
  • the CPPs which impact the purging of related impurity CQAs in Stages 3b and 3c include the temperature and time for ethanol addition.
  • Stage 4b following the dissolution in water, the solution was clarified.
  • the solution was adjusted to the crystallization temperature and ethanol (ethanol 1 quantity) was added to induce crystallization.
  • ethanol ethanol 1 quantity
  • the remainder of the ethanol ethanol 2 quantity
  • the migalastat hydrochloride was filtered, washed with ethanol, and dried.
  • the Stage 4a parameter of ethanol quantity was equivalent to the sum of the Stage 4b parameters of ethanol 1 quantity and ethanol 2 quantity.
  • Fig. 25 shows the impact of total quantities of water and ethanol on the relative concentration of sodium chloride solubilized in the crystallization mixture. This shows that a change in the total water quantity between 1.1 and 1.4 weights has a large impact on the concentration of sodium chloride. For this reason, total water quantities in Stage 4a and Stage 4b were assessed to be CPPs for the control of residue on ignition. Fig. 25 also shows that a change in the total ethanol quantity between 8.5 and 10.5 has a smaller impact on the concentration of sodium chloride.
  • Ethanol was the main solvent used in the final stage of manufacture and a CQA of migalastat hydrochloride. Low levels of ethanol are generally observed in batches of migalastat hydrochloride. Parameters in the Stage 4b process were assessed for their potential to influence the ethanol content. Table 40 summarizes those parameters identified as having the potential to impact the ethanol content in Stage 4b. The range studied for each parameter is also given. These were set with reference to solubility and metastable limit data for migalastat hydrochloride.
  • Table 43 shows which of the related impurity CQAs are impacted by Stage 4. Each of these impurities is partially purged in both the Stage 4a and Stage 4b recrystallizations. The genotoxic impurity, Compound X, was demonstrated to be partially purged via the Stage 4 process. Table 43: CQA Impurities Partially Purged in Stage 4
  • NGT Not greater than
  • NLT Not less than
  • Stage 3 The objective of the verification experiments for Stage 3 was to demonstrate that the ranges defined for CPPs in Stage 3 will deliver migalastat hydrochloride which meets specification. This is achieved by selecting settings for the PARs which will increase levels of those CQAs impacted by Stage 3.
  • Stage 3 impacts the drug-related impurity CQAs Compound U, Compound V, Compound W, Compound BB, and Compound Y.
  • Stage 3 also impacts the genotoxin Compound X and the residue on ignition of migalastat hydrochloride.
  • Stage 4 controls the residue on ignition and ethanol content of migalastat hydrochloride, and impacts the drug-related impurity CQAs Compound U, Compound V, Compound Y, and Compound BB.
  • the objective of the verification experiments was to confirm that, at the extremes of the Control Strategy for each CQA impacted by Stage 4, the migalastat hydrochloride produced did not fail the drug substance specification.
  • the experiments were designed to combine CQAs at their specification limit in intermediate grade migalastat hydrochloride with the combination of setpoints for CPPs most likely to cause failure to meet drug substance specification. The following verification experiments were undertaken:
  • Experiment B to confirm that migalastat hydrochloride, produced when incorporating levels of residue on ignition at the specification limit in intermediate grade migalastat hydrochloride, did not fail drug substance specification under conditions designed to maximize levels of residue on ignition and ethanol content.
  • Experiment C to confirm that migalastat hydrochloride produced did not fail drug substance specification under conditions designed to maximize levels of ethanol content.
  • Stage 4a was not carried out on Experiment C.
  • Experiment D to confirm that migalastat hydrochloride, produced when incorporating levels of Compound V, Compound Y, and Compound BB at significantly higher levels than typical in intermediate grade migalastat hydrochloride, did not fail drug substance acceptance criteria.
  • Table 52 shows a summary of the conditions employed in Stage 4 verification experiments.
  • Table 53 shows the analytical data from the migalastat hydrochloride isolated from these experiments.
  • Table 52 Summary of conditions for Stage 4 verification experiments
  • Lucerastat [(2R,3S,4R,5S)-l-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol) is provided or is prepared according to any known method.
  • a suitable method of preparation is reported in International Patent Application Publication No. WO 1994026714A1, which is incorporated by reference herein in its entirety.
  • deoxygalacto nojirimycin (DGJ; Migalastat) is reductively N-alkylated using butyraldehyde in sodium acetate buffer, pH 5.0, in the presence of palladium black under hydrogen.
  • the reaction mixture is stirred at room temperature (ca. 20°C).
  • the reaction mixture is filtered through diatomaceous earth and the solvent removed by evaporation under vacuum.
  • the resulting N-butylated product is purified by ion-exchange chromatography (Dowex® AG50-X12, H + form), eluting in 2M NH3 (aq). The solvent is removed by evaporation.
  • the resulting free base lucerastat is converted to the hydrochloride salt.
  • free base lucerastat is treated with excess concentrated HC1 (37% aqueous) in a lower alcohol, followed by removal of the solvent by evaporation, to provide the hydrochloride salt of lucerastat.
  • Intermediate grade lucerastat hydrochloride prepared as in Example 14, is purified by recrystallization. Generally, a first crystallization is performed in a first mixture comprising water and a Cl to C4 alcohol to give a first crystallized lucerastat hydrochloride slurry or solution. The first crystallized lucerastat hydrochloride is isolated from the slurry or solution e.g., by filtration.
  • a second recrystallization may be subsequently performed, comprising crystallizing the first crystallized lucerastat hydrochloride in a second mixture comprising water and a Cl to C4 alcohol to give a second crystallized lucerastat hydrochloride slurry or solution, followed by isolating the second crystallized lucerastat hydrochloride from the second crystallized lucerastat hydrochloride slurry or solution to give active pharmaceutical ingredient (API) grade lucerastat hydrochloride.
  • API active pharmaceutical ingredient
  • Intermediate grade Migalastat hydrochloride prepared as in Example 7, comprises diasteroisomeric impurities, which are listed in Table 21.
  • the diasteroisomeric impurities may be separated by normal-phase liquid chromatography (NPLC), such as normal-phase flash column chromatography, using a solvent as eluent.
  • NPLC normal-phase liquid chromatography
  • the chromatographic method can be run in either isocratic or gradient elution modes.
  • the eluent may be selected from dichloromethane, ethyl acetate, hexane, acetone or combinations thereof.
  • the diasteroisomeric impurities and migalastat may be converted into a pharmaceutically acceptable salt thereof according to known method before performing NPLC.
  • the diasteroisomeric impurities and migalastat may be treated with alcohol-protecting group, followed by NPLC purification and treatment to remove the alcohol-protecting group.
  • the alcohol-protecting group may be allyl, acetyl, or benzoly, benzyl.
  • the allyl alcohol-protecting group may be removed by hydrolysis or by hydrogenation in the presence of Pd/C.
  • the acetyl or benzoyl alcohol-protecting group may be removed by hydrolysis under acidic conditions or basic conditions.
  • the benzyl alcohol-protecting group may be removed by catalytic hydrogenation. The catalytic hydrogenation may be performed in the presence of homogenous or heterogenous metal catalyst.
  • the metal catalyst may be based on Pd, Pt, Ni, Rh or Ru.
  • the diasteroisomeric impurities and migalastat may be treated with amine-protecting group, followed by NPLC purification and treatment to remove the amine - protecting group.
  • the amino-protecting group may be benzyl, benzhydryl, phenylethyl, benzyloxycarbonyl or tert-butoxycabonyl.
  • the benzyl, benzhydryl, phenylethyl and benzyloxycarbonyl amino-protecting group may be removed by catalytic hydrogenation.
  • the tert- butoxycabonyl amino-protecting group may be removed by treatment with an acid.
  • the acid may include but not limited to trifluoroacetic acid and hydrochloric acid.
  • Example 17 Purification of Intermediate Grade Lucerastat Hydrochloride from Diasteroisomeric Impurities using Chromatography Method
  • Intermediate grade lucerastat hydrochloride prepared as in Example 7, comprises diasteroisomeric impurities, which are listed in Table 21.
  • the diasteroisomeric impurities may be separated by normal-phase liquid chromatography (NPLC), such as normal-phase flash column chromatography, using a solvent as eluent.
  • NPLC normal-phase liquid chromatography
  • the chromatographic method can be run in either isocratic or gradient elution modes.
  • the eluent may be selected from dichloromethane, ethyl acetate, hexane, acetone or combinations thereof.
  • the diasteroisomeric impurities and lucerastat may be converted into a pharmaceutically acceptable salt thereof according to known method before performing NPLC.
  • the diasteroisomeric impurities and lucerastat may be treated with alcohol-protecting group, followed by NPLC purification and treatment to remove the alcohol-protecting group.
  • the alcohol-protecting group may be allyl, acetyl, or benzoly, benzyl.
  • the allyl alcohol-protecting group may be removed by hydrolysis or by hydrogenation in the presence of Pd/C.
  • the acetyl or benzoyl alcohol-protecting group may be removed by hydrolysis under acidic conditions or basic conditions.
  • the benzyl alcohol-protecting group may be removed by catalytic hydrogenation. The catalytic hydrogenation may be performed in the presence of homogenous or heterogenous metal catalyst.
  • the metal catalyst may be based on Pd, Pt, Ni, Rh or Ru.
  • the diasteroisomeric impurities and lucerastat may be treated with amine-protecting group, followed by NPLC purification and treatment to remove the amine - protecting group.
  • the amino-protecting group may be benzyl, benzhydryl, phenylethyl, benzyloxycarbonyl or tert-butoxycabonyl.
  • the benzyl, benzhydryl, phenylethyl and benzyloxycarbonyl amino-protecting group may be removed by catalytic hydrogenation.
  • the tert- butoxycabonyl amino-protecting group may be removed by treatment with an acid.
  • the acid may include but not limited to trifluoroacetic acid and hydrochloric acid.

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  • Crystallography & Structural Chemistry (AREA)
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  • Thermal Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés de production de chlorhydrate de migalastat de qualité ingrédient pharmaceutique actif (API), et de purification de chlorhydrate de migalastat de qualité intermédiaire. L'invention concerne en outre des procédés de production de chlorhydrate de [(2R,3S,4R,5S)-1-butyl-2-(hydroxyméthyl)pipéridine-3,4,5-triol (chlorhydrate de lucérastat) et d'autres composés de 1-désoxygalactonojirimycine, ainsi que des procédés de purification de chlorhydrate de lucérastat de qualité intermédiaire et d'autres composés de 1-désoxygalactonojirimycine.
PCT/US2021/063653 2020-12-16 2021-12-16 Lots hautement purifiés de composés de 1-désoxygalactonojirimycine de qualité pharmaceutique WO2022132992A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN202180085473.4A CN116710185A (zh) 2020-12-16 2021-12-16 高度纯化批次的药品级1-脱氧半乳糖野尻霉素化合物
JP2023536402A JP2023554394A (ja) 2020-12-16 2021-12-16 医薬品グレードの１－デオキシガラクトノジリマイシン化合物の高度精製バッチ
EP21841141.1A EP4263505A1 (fr) 2020-12-16 2021-12-16 Lots hautement purifiés de composés de 1-désoxygalactonojirimycine de qualité pharmaceutique
IL303654A IL303654A (en) 2020-12-16 2021-12-16 Highly purified groups of pharmaceutical compounds in class 1-DEOXYGALACTONOJIRIMYCIN
AU2021401732A AU2021401732A1 (en) 2020-12-16 2021-12-16 Highly purified batches of pharmaceutical grade 1-deoxygalactonojirimycin compounds
KR1020237023996A KR20230121834A (ko) 2020-12-16 2021-12-16 고순도의 원료의약품 등급 1-데옥시갈락토노지리마이신화합물 배치
BR112023011905A BR112023011905A2 (pt) 2020-12-16 2021-12-16 Lotes altamente purificados de compostos de 1-desoxigalactonojirimicina de grau farmacêutico
CA3202291A CA3202291A1 (fr) 2020-12-16 2021-12-16 Lots hautement purifies de composes de 1-desoxygalactonojirimycine de qualite pharmaceutique

Applications Claiming Priority (4)

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US202063126264P 2020-12-16 2020-12-16
US63/126,264 2020-12-16
US17/148,817 US11623916B2 (en) 2020-12-16 2021-01-14 Highly purified batches of pharmaceutical grade migalastat and methods of producing the same
US17/148,817 2021-01-14

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0536402A1 (fr) * 1990-06-29 1993-04-14 Nippon Shinyaku Company, Limited Derive de piperidine
WO1994026714A1 (fr) 1993-05-13 1994-11-24 G.D. Searle & Co. Nouveaux derives de desoxygalactonojirimycine
WO2008045015A1 (fr) * 2005-06-08 2008-04-17 Amicus Therapeutics, Inc. Purification d'imino- et amino-sucre
US20100113517A1 (en) 2007-03-30 2010-05-06 Amicus Therapeutics, Inc. Method for the treatment of fabry disease using pharmacological chaperones
WO2015121488A1 (fr) * 2014-02-17 2015-08-20 Glaxosmithkline Intellectual Property Development Limited Procédé microbiologique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0536402A1 (fr) * 1990-06-29 1993-04-14 Nippon Shinyaku Company, Limited Derive de piperidine
WO1994026714A1 (fr) 1993-05-13 1994-11-24 G.D. Searle & Co. Nouveaux derives de desoxygalactonojirimycine
WO2008045015A1 (fr) * 2005-06-08 2008-04-17 Amicus Therapeutics, Inc. Purification d'imino- et amino-sucre
US20100113517A1 (en) 2007-03-30 2010-05-06 Amicus Therapeutics, Inc. Method for the treatment of fabry disease using pharmacological chaperones
WO2015121488A1 (fr) * 2014-02-17 2015-08-20 Glaxosmithkline Intellectual Property Development Limited Procédé microbiologique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. U78027.1
HARWOOD L M ET AL: "Experimental organic chemistry - Principles and practice", 1 January 1989, EXPERIMENTAL CHEMISTRY - ORGANIC CHEMISTRY AND REACTION,, PAGE(S) 127 - 132, ISBN: 978-0-632-02016-4, XP003025361 *
NORMAN DYSON: "CHROMATOGRAPHIC INTEGRATION METHODS", 1998, THE ROYAL SOCIETY OF CHEMISTRY

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