WO2013155595A1 - Procédé pour la préparation d'un sel monosodique de h-d-glu-(l-trp-oh)-oh et une forme cristalline de celui-ci - Google Patents

Procédé pour la préparation d'un sel monosodique de h-d-glu-(l-trp-oh)-oh et une forme cristalline de celui-ci Download PDF

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WO2013155595A1
WO2013155595A1 PCT/CA2013/000338 CA2013000338W WO2013155595A1 WO 2013155595 A1 WO2013155595 A1 WO 2013155595A1 CA 2013000338 W CA2013000338 W CA 2013000338W WO 2013155595 A1 WO2013155595 A1 WO 2013155595A1
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glu
trp
hci
bzl
isopropanol
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PCT/CA2013/000338
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English (en)
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Tim Fat Tam
Regis Leung-Toung
Yanqing Zhao
Yingsheng Wang
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Apotex Technologies Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides

Definitions

  • This invention relates to a monosodium salt of H-D-Glu(L-Trp-OH)-OH, its crystalline form and the process for its manufacturing.
  • Golotimod refers to a dipeptide H-D-Glu(L-Trp-OH)-OH with the lUPAC name (R)-2-amino-5-(((S)-1-carboxy-2-(1 H-indol-3-yl)ethyl)amino)-5- oxopentanoic acid. It is also known as SCV-07 or gamma-D-glutamyl-L-tryptophan or bestim. It is disclosed in US5.916,878:
  • lung cancer WO 2009/025830A1
  • tuberculosis WO 2003/013572 A1
  • genital viral infections WO 2006/076169
  • melanoma WO 2007/123847
  • hemorrhagic viral infections WO 2006/047702
  • respiratory viral infections WO 2005/1 12639
  • hepatitis C WO 2010/017178
  • injury or damage due to disease of mucosa WO 2008/100458.
  • SCV-07 is also reported as a vaccine enhancer (WO 2006/116053).
  • the Pd/C is not used in a catalytic amount;
  • preparative HPLC is used to purify the crude gamma-D-glutamyl-L-tryptophan (260 mg) to pure gamma-D- glutamyl-L-tryptophan (190 mg), the eluant is a mixture of 0.1 % trifluoroacetic acid and acetoniti'ile;
  • the material is obtained by lyophilization. The yield is not reported, and the calculated yield of the transformation is about 61.5%.
  • H-D- Glu(L-Trp- OH)-OH is synthesized from D-glutamine and L-tryptophan through the
  • the present invention is based, at least in part, on a crystal form of a monosodium salt of H-D-Glu(L- » r rp-OH)-OH.
  • the present invention is based, at least in part, on processes for manufacturing large quantities of a momosodium salt of H-D-Glu(L-Trp-OH)-OH, which processes do not require chromatographic purification and/or hydrogenation conditions.
  • the processes of the present invention are illustrated in Table 1. Table 1
  • crystalline material crystalline material. crystalline material. crystalline material.
  • the starting material for processes described herein is H-D-Glu(L-Trp-0-T)-0-G wherein T is methyl, ethyl, propyl, isopropyl, or benzyl and G is methyl, ethyl, propyl, or isopropyl.
  • a preferred starting material is the compound H-D-Glu(L-Trp-0-T)-0-G wherein T is methyl and G is benzyl, namely H-D-Glu(L-Trp-0-CH 3 )-0-Bzl, which can be synthesized in two simple steps from Boc-D-Glu-OBzl and L-H-Trp-OCH 3 .
  • process A a solution of H-D-Glu(L-Trp-0-T)-0-G hydrochloride salt wherein G and T are as defined above in isopropanol and water, is reacted with sodium hydroxide. Upon reaction completion, an insoluble particulate is filtered off. The filtrate is acidified to pH 6 with acetic acid and the suspension is stirred with additional isopropanol. The precipitated solid is collected by filtration and then dried to give the monosodium salt of H-D-Glu(L-Trp-OH)-OH.
  • H-D-Glu(L-Trp-0-T)-0-G hydrochloride salt wherein G and T are as defined above in ethanol is first reacted with 1 equivalent of ammonium hydroxide to give H-D-Glu(L-Trp-0-T)-0-G which is then reacted with sodium hydroxide.
  • the filtrate is acidified to pH 6 with acetic acid and the suspension is stirred with additional ethanol.
  • the precipitated solid is filtered and then dried to give the monosodium salt of H-D-Glu(L-Trp-OH)-OH.
  • Process C is similar to process B except methanol is used instead of ethanol. Since the monosodium salt of H-D-Glu(L-Trp-OH)-OH is more soluble in methanol, the overall yield of the isolated product in process C is slightly lower than in process B.
  • Process of the present invention may afford the monosodium salt of golotimod in pharmaceutical grade. Further, processes of the present invention are suitable for industrial scale production. This is due, at least in part, to a step in which the monosodium salt of golotimod can be made and isolated from the base hydrolysis of the diester of golotimod, thereby reducing the need to isolate golotimod followed by conversion to the monosodium salt with sodium hydroxide in a separate process step.
  • processes of the present invention reduce and/or eliminate the use of hydrogenation and the use of palladium on charcoal, avoid the use of acetonitrile in the last step of isolation, and avoid the use of the more expensive intermediate CBz-D-Glu(L-Trp-OBzl)-OBzl and CBz-D-Glu-OBzl as a starting material to produce CBz-D-Glu(L-Trp-OBzl)-OBzl.
  • a pure crystalline form of the mono-sodium salt of golotimod is the product of processes of the present invention.
  • the compound H-D-Glu(L-Trp-0- T)-0-G.HCI wherein G is benzyl and T is methyl is used as an illustrative example of the starting material for the process.
  • Other starting materials may be substituted in place of this specific compound in processes described herein.
  • an X-ray powder diffraction pattern comprising at least three peak positions (degrees 2-theta + 0.2) selected from the group consisting of: 12.24, 15.45, 20.61 , 25.78, and 31.03.
  • a crystal form described herein characterized by an X-ray powder diffraction pattern comprising at least one peak position (degrees 2-theta + 0.2) selected from the group consisting of 12.24, 15.45, and
  • a crystal form described herein characterized by an IR absorption spectrum comprising peaks, in cm “1 , at 745, 810, 940, 1008, 1103, 1234, 1341 , 1402, 1457, and 3423.
  • a crystal form described herein characterized by a differential scanning calorimetry thermogram having an endotherm in the range of from about 175°C to about 225°C with a peak onset at about 209.0 ⁇ 2.5 °C and a peak apex at about 218.9 ⁇ 2.5 °C.
  • a crystal form described herein characterized by a differential scanning calorimetry thermogram having an endotherm in the range of from about 175°C to about 225°C with a peak onset at about 209.0 ⁇ 2.5 °C and a peak apex at about 218.9 ⁇ 2.5 °C.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a crystal form as described herein.
  • the process comprising: (a) forming an aqueous layer by reacting sodium hydroxide with either (i) a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in isopropanol and water, or (ii) a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in ethanol and one equivalent of ammonium hydroxide per equivalent of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI, or (iii) a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in methanol and one equivalent of ammonium hydroxide per equivalent of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI; (b) filtering the aqueous layer and collecting a filtrate; (c) acidifying the filtrate to pH 6 with ace
  • the forming the aqueous layer comprises reacting sodium hydroxide with a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in isopropanol and water; the adding comprises adding isopropanol; and the washing comprises washing with isopropanol.
  • the forming the aqueous layer comprises reacting sodium hydroxide with a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in ethanol and one equivalent of ammonium hydroxide per equivalent of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI; the adding comprises adding ethanol; and the washing comprises washing with ethanol.
  • the forming the aqueous layer comprises reacting sodium hydroxide with a solution of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI in methanol and one equivalent of ammonium hydroxide per equivalent of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI; the adding comprises adding methanol; and the washing comprises washing with methanol.
  • a process for the preparation of the mono sodium salt of H-D-Glu(L-Trp-OH)-OH comprising: (a) milling H-D-Glu(L-Trp-OH)-OH, thereby forming a fine powder; (b) adding, in an ice bath, 1 equivalent of sodium hydroxide solution to a suspension of 1 equivalent of the fine powder in isopropanol, thereby forming a reaction mixture; (c) adding isopropanol slowly to the reaction mixture and stirring thereby forming a thick suspension; (d) filtering off the mono sodium salt of H-D-Glu(L-Trp-OH)-OH from the think suspension and washing the mono sodium salt of H-D-Glu(L-Trp-OH)-OH with isopropanol; (e) drying the mono sodium salt of H-D-Glu(L-Trp-OH)-OH at 40°C-45°C under vacuum.
  • the monosodium salt of H-D-Glu(L-Trp-OH)-OH is characterized by an X-ray powder diffraction pattern comprising at least three peak positions (degrees 2-theta + 0.2) selected from the group consisting of: 12.24, 15.45, 20.61 , 25.78, and 31.03.
  • FIG. 1 shows the powder X-ray diffraction pattern of Apo8 6Na Form A
  • FIG. 2 shows the solid state 3 C NMR spectrum for Apo8 6Na Form A, the monosodium salt of H-D-Glu(L-Trp-OH)-OH.
  • FIG. 3 shows the FTIR (KBr) of Apo816Na Form A, the monosodium salt of H-D-Glu(L- Trp-OH)-OH in KBr disk.
  • FIG. 4 shows the differential scanning calorimetry thermogram of the monosodium salt of H-D-Glu(L-Trp-OH)-OH (Apo816Na From A).
  • FIG. 5 shows the Thermogravimetric Analysis thermogram of the monosodium salt of H- D-Glu(L-Trp-OH)-OH (Apo816Na From A).
  • FIG. 6 shows the speciation plot of H-D-Glu(L-Trp-OH)-OH.
  • L is H-D-Glu(L-Trp-0 0 ⁇
  • the counter ion in this case is Na + .
  • FIG. 7 shows the overlays of the powder X-ray diffraction patterns of the materials from Examples 2A, 2B and 3.
  • Apo816 refers to the dipeptide H-D-Glu(L-Trp-OH)-OH with the chemical structure
  • Apo816Na refers to the monosodium salt of H-D-Glu(L-Trp-OH)-OH with the chemical structure
  • H-D-Glu(L-Trp-OMe)-OBzl or H-D-Glu(L-Trp-OCH 3 )-OCH 2 Ph refers to the chemical structure:
  • a method for the preparation of pharmaceutical grade monosodium salt of H-D-Glu(L-Trp-OH)-OH from a diester H-D-Glu(L-Trp-0-G)-0-T or its hydrochloride salt and sodium hydroxide is provided.
  • the product monosodium salt of H-D-Glu(L-Trp-OH)- OH is isolated in a crystalline form.
  • the crystalline form may be characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern set out in Figure 1. This crystalline form of the sodium salt may be termed Apo816Na Form A.
  • Apo816Na Form A may be characterized by at least one of the following characteristics:
  • solid state C NMR spectrum may be substantially similar to that spectrum set out in Figure 2.
  • an IR spectrum comprising absorption maxima at approximately 745, 810, 940, 1008, 1103, 1234, 1341 , 1402, 1457, 3423 cm “1 .
  • the IR spectrum may be substantially similar to that spectrum set out in Figure 3.
  • thermogram (d) a differential scanning calorimetry thermogram having an endotherm in a range of from about 175°C to about 225°C with a peak onset at about 209.0 ⁇ 2.5 °C and peak apex at about 218.9 ⁇ 2.5 °C.
  • the thermogram may be substantially similar to that thermogram set out in Figure 4.
  • a method, process A, for the manufacturing of Apo816Na Form A, monosodium salt of H-D-Glu(L-Trp-OH)-OH without chromatographic purification which comprises:
  • a method, process B, for the manufacturing of Apo816Na Form A, monosodium salt of H-D-Glu(L-Trp-OH)-OH without chromatographic purification which comprises:
  • step (6) Drying the material from step (6) under vacuum at 40 to 45°C to give the monosodium salt of H-D-Glu(L-Trp-OH)-OH;
  • a method, process C, for the manufacturing of Apo816Na Form A, monosodium salt of H-D-Glu(L-Trp-OH)-OH without chromatographic purification which comprises:
  • step (7) Drying the material from step (6) under vacuum at 40 to 45°C to give the monosodium salt of H-D-Glu(L-Trp-OH)-OH.
  • H-D-Glu(L-Trp-OH)-OH is available from Chem-lmpex International as well as Bachem
  • a method, process D for the preparation of the monosodium salt of H-D-Glu(L-Trp-OH)-OH from H-D-Glu(L-Trp-OH)-OH without chromatography which comprises:
  • process D a large volume of isopropanol (5 to 20 volume of isopropanol to the volume of water in the aqueous solution is required.
  • the Apo816Na Form A can be obtained in pharmaceutical grade without chromatographic purifications.
  • a method, process E, for the preparation of the monosodium salt of H-D-Glu(L-Trp-OH)-OH from H-D-Glu(L-Trp-OH)-OH without chromatography which comprises:
  • step (b) Adding 1 equivalent of sodium hydroxide solution to a suspension of 1 equivalent of the fine powder of H-D-Glu(L-Trp-OH)-OH from step (a) in isopropanol an ice-bath;
  • step (c) Adding isopropanol slowly to the reaction mixture in step (b) with stirring to maintain a thick suspension;
  • Process E avoids the use of large amount of isopropanol and water to prepare the Apo816Na Form A.
  • the Apo816Na Form A can be obtained in pharmaceutical grade without chromatographic purifications.
  • Process E is a convenient process for the preparation of Apo816Na Form A from H-D-Glu(L-Trp-OH)-OH (Apo816).
  • H-D-Glu(L-Trp-OH)-OH can exist in different protonated forms, namely H 3 L, H 2 L, HL, L.
  • the definition of these species is shown in Scheme 1 below:
  • the speciation distribution of H 3 L, H 2 L, HL, L depends on the pH of the solution and can be computed using the experimental pKas of the compound with the HySS 2009 software (Protonic Software, UK).
  • the compound H-D-Glu(L-Trp-OH)-OH has three pKas (2.1, 3.45, & 9.33).
  • the speciation plot analysis is shown in Figure 6.
  • the monosodium salt HL (monosodium salt of H-D-Glu(L-Trp-OH)-OH) is the predominant species when the pH is between 5.0 and 8.5, preferably between 5.5 and 7.2, most preferably between 5.9 and 6.7.
  • Table 2 Speciation composition of H-D-Glu(L-Trp-OH)-OH and its sodium salt.
  • solvent media are devised to allow the formation of the desired crystalline form as a solid in the reaction mixture, at the optimal pH for the formation of the monosodium salt of H-D-Glu(L-Trp-OH)-OH, as per computed data shown in Table 2.
  • H-D-Glu(L-Trp-OH)-OH The total concentration of H-D-Glu(L-Trp-OH)-OH of 2 x 10 "3 M, regardless of its protonated or unprotonated species: H-D-Glu(L-Trp-OH)-OH.HCI (H 3 L), H-D-Glu(L-Trp-OH)-OH (H 2 L), monosodium salt (HL), disodium salt (L), and the log beta values of 9.33, 12.78, 4.88 are used for the HL, H 2 L and H 3 L respectively in this computation with the software HySS 2009.
  • the pure monosodium salt of H-D-Glu(L-Trp-OH)-OH is formed as a solid between pH 5.0 and 8.5, preferably between 5.5 and 7.2 and most preferably between 5.9 and 6.7, and slowly precipitated out of the reaction media.
  • the solvent media for such precipitation is a mixture of alcohol and water. Examples of those alcohols are methanol, isopropanol and ethanol.
  • the speciation data as shown in Table 2 supports that the monosodium salt of H-D-Glu(L-Trp-OH)-OH is the main species formed in over 99% in the mixture at pH 5.5 and 7.2, and most preferably between 5.9 and 6.7.
  • An original selection of the solvent media such as a mixture of alcohol and water allows the pure monosodium salt of H-D- Glu(L-Trp-OH)-OH to be precipitated as a crystalline material, as characterized by the powder X-ray diffraction pattern substantially in accordance with FIG. 1.
  • conditions are designed to optimize the isolated yield and purity of the monosodium salt of H-D-Glu(L-Trp-OH)-OH by precipitation and the salts such as sodium chloride or sodium acetate are removed by further washing with alcohols.
  • the starting material for the production of the monosodium salt of H-D-Glu(L-Trp-OH)- OH is Boc-D-Glu(L-Trp-0-T)-0-G.
  • Boc-D-Glu(L-Trp-0-T)-0-G wherein G is benzyl and T is methyl is chosen as a starting material (Scheme 2).
  • Both reagents Boc-D-Glu-OBzl and H-L-Trp-OMe. HCI are available in kg amounts.
  • Boc-D-Glu-OBzl and H-L-Trp-OMe can be coupled with EDCI or DCC or EDCI/HOBt to give the dipeptide Boc-D- Glu(L-Trp-0-CH 3 )-OBzl which can be isolated in more than 97% purity (HPLC, area under curve) without chromatographic purification.
  • Treatment of Boc-D-Glu(L-Trp-OCH 3 )-OBzl with HCI in ethyl acetate affords H-D-Glu(L-Trp-0-CH 3 )-OBzl.HCI, which is isolated by filtration of the reaction mixture.
  • H-D-Glu(L-Trp-0-CH 3 )-OBzl.HCI can be produced in >0.5 kg amounts in two simple steps from commercially available materials.
  • Any of process A or B or C may be used to convert H-D-Glu(L-Trp-0-CH 3 )-OBzl.HCI to the monosodium salt of H-D-Glu(L-Trp-OH)-OH.
  • Hydrochloric acid is often used to adjust the pH of a basic solution to 6 or 7 after the sodium hydroxide hydrolysis of H-D-Glu(L-Trp-0-CH 3 )-0-Bzl.HCI. This results in the formation of sodium chloride as an inorganic by-product which co-precipitates with the Apo816Na from the alcohol and water based reaction mixture. Since both sodium chloride and Apo816Na are very soluble in water, the sodium chloride cannot be removed from the solid product mixture by pulping in water without significant loss of Apo816Na in the aqueous washings. Acetic acid may be used to neutralize the sodium hydroxide reaction mixture in any of processes A or B or C.
  • Sodium acetate is formed as a by-product of this neutralization using acetic acid. Since sodium acetate is very soluble in alcohol (5.3 g of NaOAc.3H 2 0 dissolves in 100 mL ethanol), the co-precipitated sodium acetate can be easily removed by washing the crude Apo816Na with ethanol or methanol.
  • procedures may be designed to improve the product yield and to facilitate the removal of sodium chloride and/or sodium acetate by-products in the reaction mixture.
  • H-D-Glu(L-Trp-OCH 3 )-OBzl.HCI is mixed with alcohol solvent such as isopropanol or ethanol or methanol and sodium hydroxide solution to hydrolyze the diester H-D- Glu(L-Trp-OCH 3 )-OBzl.HCI.
  • Conditions in all three processes A, B and C may be designed in such a manner to wash out the sodium chloride or sodium acetate with alcohol solvents.
  • the effluents from each washing are collected separately and are tested with silver nitrate solution to ensure that inorganic sodium chloride is no longer present in the final Apo816Na product.
  • Process B provides the highest recovery of the Apo816Na (-60% yield).
  • Apo816Na is a distinct crystalline material (Apo816Na Form A) characterized by the PXRD pattern, solid state 3 C NMR, FTIR and DSC as shown in the Examples and as set out in the Figures.
  • H-D-Glu(L-Trp-OH)-OH may also react with one equivalent of sodium hydroxide in water to give Apo816Na, the monosodium salt of H-D-Glu(L-Trp-OH)-OH. Since the sodium salt is soluble in water, solvent evaporation of water is required to give crude Apo816Na. The purity of the crystalline form Apo816 Form A cannot be assured by using this method. Processes D and E may be adapted for the production of Apo816 Form A from H-D-Glu(L-Trp-OH)-OH without chromatographic purifications.
  • process D a solution of H-D-Glu(L-Trp-OH)-OH in one equivalent of sodium hydroxide is reacted to give Apo816Na in solution.
  • the monosodium salt of H-D-Glu(L-Trp- OH)-OH may be isolated by using large amount of isopropanol as an antisolvent (1 mL of aqueous solution of Apo816Na to 20 mL of isopropanol) to precipitate the Apo816Na.
  • This material has similar FTIR and PRXD pattern to the material Apo816 (Apo816Na Form A).
  • Apo816Na may be prepared from a suspension of milled fine particle of H-D-Glu(L-Trp- OH)-OH in isopropanol and sodium hydroxide solution to give pharmaceutical grade Apo816Na (Apo816Na Form A). This avoids the use of large amount of isopropanol and water, as required in process D.
  • Processes of the present invention may afford a simple method for the production of Apo816Na and eliminate the use of chromatographic purification and hydrogenation conditions. Furthermore, the use of pure H-D-Glu(L-Trp-OH)-OH as a starting material is not required. Processes of the present invention may also eliminate concerns regarding removing inorganic chloride by-products. Apo816Na Form A is water soluble and can be manufactured in large amounts with a short production cycle time using processes of the present invention.
  • compositions of the present invention contain Apo816Na Form A or mixtures of Apo816Na Form A and/or other crystalline or amorphous forms thereof, optionally in mixtures with one or more other active ingredient(s).
  • compositions of the present invention may include, for example, excipients such as diluent, binder, disintegrant, glidant, and lubricant may be added to produce a solid dose formulation such as a tablet.
  • excipients such as diluent, binder, disintegrant, glidant, and lubricant
  • a solid dose formulation such as a tablet.
  • Apo816 Form A and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • emulsifying agents, viscosity enhancing agent, sweetening agents may be added to prepare the liquid formulation.
  • the selection of excipients and the amounts to use may be readily determined by the experience of the formulation scientist.
  • Typical finished dosage forms include, but are not limited to, solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs.
  • a pharmaceutical composition of Apo816Na Form A contains Apo816Na Form A and at least one pharmaceutical excipient.
  • Example 4 Preparation of the monosodium salt of D-Glu(L-Trp-OH)-OH (Apo816Na) from D-Glu(L-Trp-OH)-OH (Apo816DL).
  • Procedure A To a finely ground suspension of Apo816DL (8.0g) in isopropanol (16ml_) was added dropwise a solution of 6N NaOH (4ml_) with cooling at ice water bath temperature. A further 56ml_ of isopropanol was added, and the resulting suspension was stirred for 1.5h. The solid was collected via filtration, washed with isopropanol, and then air-dried for overnight. The solid was further dried under vacuum at 40°C for 4.5h to afford 8.69g of Apo816Na. The solution 1 H NMR pattern (D 2 0, 400MHz) and MS spectra of this material were similar to those as described in Example 2, Procedure A above. Anal. Calcd.
  • Procedure B Apo816DL (2.0 g, 6.0 mmol) was added portionwise to a solution of 1 N NaOH (6 ml_, 6 mmol) cooled in an ice-water bath. After clarification filtration, the filtrate was added dropwise to 50mL of isopropanoi, and the mixture was then stirred for overnight. The solid was collected via suction filtration, and washed with isopropanoi (15 mt_x2). The solid was air dried for overnight and then under vacuum at 40°C for 4 h to give Apo816Na (1.9 g). A small sample of the product was dissolved in water and it was shown to be chloride free by the silver nitrate test.
  • the PXRD analysis of Apo816Na was performed on a PANalytical X'Pert Pro Multipurpose X-ray Diffraction (MPD) system with X'Pert Data Collector Ver. 2.2d using CuK alpha irradiation.
  • the X-ray tube was operated at a Voltage of 45 kV and a current of 40 mA. Each sample was scanned between 4° and 40° in two-theta (2 ⁇ ) angles with step size of 0.017° and a counting time of 10.3 s per step. The sample was loaded into Zero-background sample holder after grinding.
  • the PXRD pattern of the material from Example 2, Procedure A is shown in FIG. 1.
  • the respective peak information such as two-theta (2 ⁇ ) angles, d-values and relative intensities are reported in Table 3.
  • Procedure B, and Example 3 are shown in FIG. 7.
  • the three batches of material displayed similar PXRD patterns.
  • the solid-state 13 C cross-polarization magic-angle spinning (CP MAS) NMR experiments were performed on a Varian Infinity Plus 400 NMR spectrometer utilizing a Varian triple- resonance 4.0 mm HXY magic-angle spinning NMR probe.
  • 1100 scans were acquired using a spinning rate of 13.0 kHz, a 9 s recycle delay, a 3 ms contact time, a 50 kHz sweep width, and a 40.96 ms acquisition time.
  • 1H decoupling was achieved using TPPM decoupling with a 15-degree tip angle and 76.9 kHz decoupling field was applied during acquisition and the amplitude of the 13C channel pulse was increased during the contact time (variable-amplitude CP).
  • the FT-IR spectra were obtained using a Perkin Elmer Paragon 1000PC Fourier Transform-IR spectrophotometer at a resolution of 4 cm-1 over a range of 4400 cm-1 to 600 cm- 1.
  • the sample was mixed with KBr by gently grinding with an agate pestle and mortar, and then the mixture was pressed into a disc.
  • the FT-IR spectrum in KBr disc for Apo816Na from Example 2, Procedure A is presented in FIG.3.
  • TGA analysis was performed on a TA Instruments Q500 Q Series TGA unit. The sample was heated from ambient temperature to 300°C at a rate of 10°C/min using a dynamic high-resolution mode. All activities were carried out under a nitrogen purge (balance purge at 10 mlJmin, sample purge at 60 mL/min).
  • the TGA thermogram for Apo816Na from Example 2, Procedure A displaying the thermal events and percent weight losses is shown in FIG. 5.
  • the monosodium salt of H-D-Glu(L-Trp-OH)-OH, prepared in accordance with an aspect of the present invention, was evaluated by PXRD Analysis at the time of preparation.
  • the material was then stored in an amber bottle at ambient temperature. After 20 months of storage, the crystalline form was again evaluated by PXRD Analysis.
  • the PXRD pattern after 20 months of storage remained unchanged from that at time of preparation (Table 4).
  • the crystalline form of the monosodium salt of H-D-Glu(L-Trp-OH)-OH, prepared in accordance with an aspect of the present invention is stable to storage.

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Abstract

L'invention porte sur une forme cristalline du sel monosodique de H-D-Glu-(L-Trp-OH)-OH de formule : (formule (I)) et sur des procédés pour la fabrication du sel monosodique de H-D-Glu-(L-Trp-OH)-OH.
PCT/CA2013/000338 2012-04-18 2013-04-08 Procédé pour la préparation d'un sel monosodique de h-d-glu-(l-trp-oh)-oh et une forme cristalline de celui-ci WO2013155595A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2316310A1 (fr) * 1997-12-25 1999-07-08 Edward T. Wei Composes immunomodulateurs contenant une fraction gamma-glutamyle ou beta-aspartyle, et procedes afferents
CA2569204A1 (fr) * 2006-11-28 2008-05-28 Apotex Technologies Inc. D-isoglutamyl-d-tryptophane cristallin et sel de monoammonium de d-isoglutamyl-d-tryptophane
CA2579119C (fr) * 2007-02-16 2013-03-05 Apotex Technologies Inc. Formes cristallines du sel monosodique de d-isoglutamyl-d-tryptophane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2316310A1 (fr) * 1997-12-25 1999-07-08 Edward T. Wei Composes immunomodulateurs contenant une fraction gamma-glutamyle ou beta-aspartyle, et procedes afferents
CA2569204A1 (fr) * 2006-11-28 2008-05-28 Apotex Technologies Inc. D-isoglutamyl-d-tryptophane cristallin et sel de monoammonium de d-isoglutamyl-d-tryptophane
CA2579119C (fr) * 2007-02-16 2013-03-05 Apotex Technologies Inc. Formes cristallines du sel monosodique de d-isoglutamyl-d-tryptophane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA, M. R.: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208 *

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