Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4192—1,2,3-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/056—Triazole or tetrazole radicals

Definitions

• the present invention relates to a polymorph of 3,3'-Dideoxy-3,3 '-bis-[4-(3- fluorophenyl)-l H-l ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside.
• Idiopathic pulmonary fibrosis represents a massive worldwide health burden. It is a chronic condition of unknown etiology in which repeated acute lung injury causes progressive fibrosis resulting in destruction of lung architecture, deteriorating lung function with consequent respiratory failure and death.
• idiopathic pulmonary fibrosis IPF
• numerous respiratory diseases can progress to pulmonary fibrosis, and this usually signifies a worse prognosis.
• the median time to death from diagnosis is 2.5 years and the incidence and prevalence of IPF continues to rise. It remains one of the few respiratory conditions for which there are no effective therapies, and there are no reliable biomarkers to predict disease progression.
• IPF transforming growth factor-Bl
• 3 ,3 '-Dideoxy-3 ,3 ' -bis-[4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '-sulfanediyl-di- ⁇ - D-galactopyranoside is a white to off white crystalline solid where 6 polymorphs as well as an amorphous form have been identified.
• the present invention relates to a polymorph of a compound of formula (I)
• the compound of formula (I) is 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH-l ,2,3-triazol-l- yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside and has the polymorphic Form 1 as identified in the XRPD diffractogram peak list
• polymorphic form 1 of 3,3'-Dideoxy-3,3 '-bis-[4-(3-fiuorophenyl)-lH-l,2,3- triazol-1 -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside can be identified in the XRPD diffractogram in Figure 1 or Figure 2.
• a polymorph of 3,3'-Dideoxy-3,3 '-bis-[4-(3- fluorophenyl)-! H-1 ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside is designated Form 1 and is a hydrated crystalline form.
• the hydrate is not stoichiometric but rather a channel hydrate.
• Form 1 is dried upon synthesis, however it will pickup moisture and equilibrate at around 3-5% water content.
• Form 1 is stable and does not convert to the other forms over time.
• form 1 can be further processed by micronization, which is particularly useful when preparing a composition for use in dry powder delivery to the lungs, in particular the narrowest parts of the lung tissue that is the bronchioles and the alveoli.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a polymorph of the present invention, and optionally a pharmaceutically acceptable additive.
• the present invention relates to a process of making a polymorph of the present invention comprising the steps of suspending or dissolving 3,3'-Dideoxy-3,3'- bis-[4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '-sulfanediyl-di- -D-galactopyranoside in an organic solvent and then making form 1 by temperature cycling, crash cooling or evaporation, or a combination thereof.
• the present invention relates to a process for preparing an amorphous form of a compound of formula (I)
• the present invention relates to a method for treatment of pulmonary fibrosis in a human comprising administering to the narrowest parts of the lung tissue of the human an amount of a polymorph of the present invention effective to treat said pulmonary fibrosis.
• Figure 1 XRPD Diffractogram for Form 1.
• Figure 2 XRPD Diffractogram for Form 1.
• Figure 3 XRPD Diffractogram for Form 2.
• Figure 6 XRPD Diffractogram for Form 5.
• Figure 7 XRPD Diffractogram for Form 6.
• Figure 8 XRPD Diffractogram for micro nized form 1.
• Figure 9 XRPD Diffractogram for micro nized form 1.
• Figure 10 XRPD Diffractogram for micronized form 1.
• the compound of formula (I) has the chemical name (IUPAC) 3,3'-Dideoxy-3,3'-bis- [4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '-sulfanediyl-di- -D-galactopyranoside .
• the compound of formula (I) may be prepared as described in US2014/0121 179 or WO2014/067986, wherein an amorphous solid is produced.
• the present invention concerns a polymorph of a compound of formula (I)
• the compound of formula (I) is 3,3'-Dideoxy-3,3'-bis-[4-(3- fluorophenyl)-l H-1 ,2 ,3 -triazol- 1 -yl] - 1 ,1 '-sulfanediyl-di- -D-galactopyranoside and has the polymorphic form 1 as identified in the XRPD diffractogram peak list Pos. [°2Th.] Rel. Int. [%]
• the compound of formula (I) is 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH-l ,2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside and has the polymorphic form 1 as identified in the XRPD diffractogram in Figure 1.
• the compound of formula (I) is 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH-l ,2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside and has the polymorphic form 1 as identified in the XRPD diffractogram in Figure 2.
• the compound of formula (I) is 3,3'-Dideoxy-3,3 '-bis-[4-(3- fluorophenyl)-l H-1 ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside as a hydrate.
• the 3,3'-Dideoxy-3,3 '-bis-[4-(3-fiuorophenyl)-lH-l,2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside hydrate contains 3-5 % water (weight%).
• the compound of formula (I) is 3,3'-Dideoxy-3,3 '-bis-[4-(3- fluorophenyl)-l H-1 ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside selected from Form 2, 3, 4, 5 or 6 as identified in the XRPD diffractogram in Figures 3-7, respectively.
• Form 5 (figure 6) is particularly interesting as it is stable and suitable for use in a nebulizer for pulmonary administration.
• the polymorph is a dry powder, such as micronized polymorph.
• micronized polymorph Such as, micronized Form 1.
• the polymorph such as Form 1
• the polymorph is micronized to a size that can reach the narrowest parts of the lung tissue of the human, such as the bronchioles and the alveoli.
• the present invention relates to a polymorph of the present invention for use in a method for treatment of pulmonary fibrosis in a human.
• the polymorph for use in treatment of pulmonary fibrosis is selected from Form 1 and 5 , typically Form 1.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising the polymorph of the present invention, and optionally a pharmaceutically acceptable additive.
• the polymorph used in the composition is Form 1 as a dry powder, such as micronized dry powder neat or mixed with an additive, such as lactose.
• the present invention relates to a DPI comprising a polymorph of the present invention, such as form 1.
• the polymorph, such as Form 1 is micronized to a size that can reach the narrowest parts of the lung tissue of the human, such as the bronchioles and the alveoli.
• the DPI comprising the polymorph of form 1 for use in a method for treatment of pulmonary fibrosis in a human.
• the DPI is a single or multiple dose DPI inhaler.
• the dry powder inhaler is RS01 Monodose Dry Powder Inhaler (Plastiape).
• Another aspect concerns a process of making a polymorph Form 1 of the present invention comprising the steps of suspending or dissolving 3,3'-Dideoxy-3,3'-bis-[4-(3- fluorophenyl)-lH-l ,2,3-triazol-l -yl]-l , -sulfanediyl-di- -D-galactopyranoside in an organic solvent and then making Form 1 by temperature cycling, crash cooling or evaporation, or a combination thereof.
• the compound 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH-l , 2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside used as starting material may be amorphous or any crystalline form since the above process will generate Form 1.
• the organic solvent is selected from methanol, ethanol, acetone, acetonitrile, toluene, tert-butylmethylether, hexane and diisopropylether as well as mixtures thereof.
• a further aspect concerns a process for preparing an amorphous form of a compound of formula (I)
• the compound 3,3'-Dideoxy-3,3 '-bis-[4-(3- fluorophenyl)-l H-l ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside used as starting material may be any crystalline form since the above process will generate the amorphous form from the dissolved compound.
• the organic solvent is selected from a mixture of acetone and water, such as acetone:water 50:50 to 80:20.
• the dissolved compound is introduced in a drying chamber at a feed concentration of from 0.5% to 20% by weigth, such as from 1-10 % weight, such as from 2-7% weight, e.g. about 3.5 % weight.
• the drying chamber has a drying gas temperature at the inlet of from 120-160 °C, such as from 140-150 °C, e.g. about 144 °C.
• the drying chamber has a drying gas temperature at the outlet of from 60-90 °C, such as from 70-80 °C, e.g. about 75 °C.
• drying time in the drying chamber is from 30-120 minutes, such as from 45-75 minutes, e.g. about 50 minutes.
• the present invention relates to a method for treatment of pulmonary fibrosis in a human comprising administering to the narrowest parts of the lung tissue of the human an amount of a polymorph of the present invention, such as Form 1 or 5, effective to treat said pulmonary fibrosis.
• the pulmonary fibrosis is Idiopathic pulmonary fibrosis (IPF).
• the administration is carried out by a dry powder inhaler. Typically, a single or multiple dose DPI inhaler is used. In one particular embodiment, the dry powder inhaler is RS01 Monodose Dry Powder Inhaler (Plastiape).
• a polymorph of the compound of formula (I), typically Form 1 is formulated as a dry powder it may be present in a suitable particle size selected from a mean mass aerodynamic diameter (MMAD) between 0.1 and 20 ⁇ , such as a MMAD between 0.5 and 10 ⁇ , such as between 1 and 5 ⁇ , typically between 2 and 3 ⁇ .
• MMAD mean mass aerodynamic diameter
• the selected ranges do not exclude the presence of particles sizes outside these ranges, but the selected ranges are those that provide the desired effect as described herein.
• the narrowest parts of the lung tissue are the bronchioles and the alveoli.
• the once daily amount is from 0.15 mg to 50 mg, such as 0.15 mg to 0.50 mg, 0.50 mg to 0.75 mg, 0.75 mg to 1.25 mg, 1.25 mg to 1.5 mg, 1 ,5 mg to 1.75 mg, 1.75 mg to 2 mg, 2 mg to 2.25 mg, 2.25 mg to 2.5 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3 mg, 3 mg to 5 mg, 5 mg to 7 mg, 7 mg to 8 mg, 8 mg to 10 mg, 10 mg to 20 mg and 20 mg to 50 mg.
• the once daily amount form 1.5 mg to 20 mg result in a concentration of the active compound of formula (I) in BAL fluids or macrophages or both of from 1 nM to 500 ⁇ .
• the once daily amount form 1.5 mg to 20 mg result in a concentration of the active compound of formula (I) in BAL fluids or macrophages or both of from 1 nM to 100 ⁇ . More preferred concentrations of from 10 nM to 10 ⁇ or more preferred 100 nM to 1 ⁇ can be provided with once daily amount from 1 mg to 10 mg, such as from 1 mg to 3 mg or 3 mg to 10 mg, e.g. 1 mg to 3 mg.
• Other preferred concentrations of the active compound of formula (I) in BAL fluids is from 10 nM to 10 ⁇ , such as from 100 nM to 10 ⁇ , typically from 500 nM to 10 ⁇ , such as up to 4 ⁇ .
• Other preferred concentrations of the active compound of formula (I) in macrophages is from 1 ⁇ to 500 ⁇ , such as from 10 ⁇ to 250 ⁇ , typically from 50 ⁇ to 200 ⁇ , such as up to 100 ⁇ .
• the treatment is chronic treatment.
• treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
• the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
• the treatment is performed in a chronic way.
• the patient to be treated is a human subject diagnosed with pulmonary fibrosis or other types of lung fibrosis.
• (I) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of pulmonary fibrosis and its complications. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
• pharmaceutically acceptable additive is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.
• the adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (I) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction.
• the adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person within the art.
• compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier.
• the pharmaceutical composition contains neat compound of formula I.
• the pharmaceutical compositions comprise from 1 to 99 weight % of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 weight % of a compound of formula I as herein disclosed.
• the combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight (100 %w/w) of the composition, particularly the pharmaceutical composition.
• the pharmaceutical composition may consist of neat compound of formula I (that is 100 %w/w compound of formula I) or contain a 1 -90 %w/w, such as 2-20 %w/w, for instance a 3 %w/w blend of the compound of formula I or a 10 %w/w blend of the compound of formula I.
• the 3 %w/w blend is a pharmaceutical composition containing 3 %w/w compound of formula I and 97 %w/w lactose carrier.
• the 10 %w/w blend is a pharmaceutical composition containing 10 %w/w compound of formula I and 90 %w/w lactose carrier.
• MMAD mean mass aerodynamic diameter
• DPI Dry powder inhalers
• Pre-metered DPIs contain previously measured doses or dose fractions in some type of units (e.g., single or multiple presentations in blisters, capsules, or other cavities) that are subsequently inserted into the device during manufacture or by the patient before use. Thereafter, the dose may be inhaled directly from the pre-metered unit or it may be transferred to a chamber before being inhaled by the patient.
• Device-metered DPIs have an internal reservoir containing sufficient formulation for multiple doses that are metered by the device itself during actuation by the patient.
• Pressurized Metered-Dose Inhalers may also be suitable delivery devices for the present compound of formula (I) and are described in Controlled Pulmonary Drug Delivery, Smith and Hickey, Editors, Springer 2011 , chapter 8.
• U.S. Patent No. 5,503,144 to Bacon shows a breath-actuated dry- powder inhaler.
• the device includes a dry powder reservoir for containing a dry powdered medicament, a metering chamber for removal of the powdered medicament from the reservoir in discrete amounts, and an air inlet for entraining the removed powdered medicament through a mouthpiece upon patient inhalation.
• U.S. Patent No. 5,458,135 discloses a method and apparatus for producing an aerosolized dose of a medicament for subsequent inhalation by a patient.
• the method comprises first dispersing a preselected amount of the medicament in a predetermined volume of gas, usually air.
• the dispersion may be formed from a liquid or a dry powder.
• the method relies on flowing substantially the entire aerosolized dose into a chamber that is initially filled with air and open through a mouthpiece to the ambient. After the aerosolized medicament, has been transferred to the chamber, the patient will inhale the entire dose in a single breath.
• US 6,065,472 discloses a powder inhalation device comprising a housing containing a pharmacologically active compound, a conduit with an outlet extending into the housing through which a user can inhale to create an airflow through the conduit, a dosing unit for de- livering a dose of the compound to the conduit and baffles arranged within the said conduit to aid disintegration of powder agglomerates entrained in said airflow.
• the dry powder medicament is composed of very small particles, and often provided in a composition including a carrier such as lactose, non-defined agglomerates or aggregates of the medicament form at random prior to being dispensed. It has therefore been found preferably to provide breath-actuated dry powder inhalers with means for breaking down the agglomerates of medicament or medicament and carrier before inhalation of the medicament.
• Raspimat is a mechanical nebulizer of the soft mist inhaler type.
• This mechanical nebulizer is operated by hand without any need for a gas propellant and no need for electrical power.
• Another mechani- cal nebulizer is a human powered nebulizer developed by a team from Marquette University. This nebulizer can by operated by an electrical compressor, but it is also suitable for simple mechanical pumps in order to provide a mist into the lungs of patients.
• nebulizers of the electrical type are ultrasonic nebulizers based on the vibrating mesh technology developed by inter alia PARI, Respironics, Omron, Beurer, Aerogen, or ultrasonic nebulizers based on an electronic oscillator that generate a high frequency ultrasonic wave developed by inter alia Omron and Beurer.
• a further electrical nebulizer is a jet nebulizer also known as atomizers.
• the nebulizer is selected from a mechanical nebulizer, such as a soft mist inhaler or a human powered nebulizer.
• the nebulizer is selected from an electrical nebulizer, such as a nebulizer based on ultrasonic vibrating mesh tech- nology, a jet nebulizer, or an ultrasonic wave nebulizer.
• Particular suitable nebulizers are based on vibrating mesh technology such as eFlow from PARI.
• nebulizer such as an electronic nebulizer
• nebulizers are Tyvaso inhalation system from United Therapeutics, Allera nebulizer system from Gilead, Bronchitol inhaler from Pharmaxis, Diskhaler from GSK, jet and ultrasonic nebulizers from Actelion and Profile Pharma.
• polymorphic Form 1 of 3,3'-Dideoxy-3,3'-bis-[4-(3- fluorophenyl)-lH-l ,2,3-triazol-l -yl]-l, -sulfanediyl-di- -D-galactopyranoside involves a final purification step with either trituration or crystallization from ethanol to produce Form 1.
• Form 1 of 3 ,3 '-Dideoxy-3 ,3 ' -bis-[4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '- sulfanediyl-di- -D-galactopyranoside can be prepared via trituration following the steps below:
• Form 1 of 3 ,3 '-Dideoxy-3 ,3 '-bis- [4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '-sulfanediyl-di- ⁇ -D-galactopyranoside can be prepared via crystallization following the steps below: ⁇ Combine crystalline or amorphous 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH-l ,2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside with ethanol (3.5 vol) and water (1.5vol).
• a polymorph screen was conducted using Form 1 material generated via trituration as the final purification step.
• the polymorph screen results indicated that there are 6 potential polymorphs for 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl) H ,2,3-triazol-l -yl]-l ,l '-sulfanediyl-di- -D- galactopyranoside.
• Table 2 indicates conditions that generated each polymorph (Form 1-6).
• Form 1 is a hydrated form and can be produced from temperature cycling, crash cooling and evaporation experiments in 8 different solvents including methanol, ethanol, acetone, acetonitrile, toluene, tert-butylmethylether, hexane and diisopropylether.
• Form 2 is a channel hydrate or hygroscopic form and can be produced from temperature cycling, crash cooling, anti- solvent addition and evaporation experiments in 7 different solvents including acetone, acetone:water (20%), methylethyl ketone, tetrahydrofuran, di- chloromethane, dimethylformamide and dimethylacetamide.
• Form 3 is a solvate and can be produced from temperature cycling, anti-solvent addition and evaporation in 9 different solvents including dichloromethane, dimethylacetamide, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, tertahydrofuran, acetone, acetone :water (20%) and dimethylacetamide.
• Form 4 is a solvate and can be produced from temperature cycling in 2-propanol.
• Form 5 is a hydrate and can be produced from temperature cycling in dimethylsulfoxide, water, water: propylene glycol (75:25) and water: PEG400: ethanol (65:25:10).
• Form 6 is a hydrate/solvate and can be produced from temperature cycling and evaporation experiments in dimethylformamide and -methyl-2-pyrrolidone.
• 3 ,3 '-Dideoxy-3 ,3 ' -bis-[4-(3 -fluorophenyl)- 1 H- 1 ,2 ,3 -triazol- 1 -yl] -1 ,1 '-sulfanediyl-di- ⁇ - ⁇ - galactopyranoside Form 5 has also been prepared via micro fluidization (wet polishing) using water as an anti-solvent.
• an aerodynamic particle size determination was performed via New Generation Impactor (NGI) for Form 5 material produced via micro fluidization and the amorphous form produced via spray drying. These were compared with the APSD obtained from micronized Form 1 material.
• NTI New Generation Impactor
• Figure 8 shows XRPD scan at Initial time point.
• Figure 9 shows XRPD scan at 6 Months at 40°C/75RH.
• Figure 10 shows XRPD scan at 12 Months at 25°C/60RH. Examples:
• amorphous form or alternately 900 ul methanol was added to lOOmg 3,3'-Dideoxy-3,3'-bis-[4-(3-fiuorophenyl)-lH-l,2,3- triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside (e.g. amorphous form) to form a slurry.
• the slurry was temperature cycled between room temperature (RT) and 40°C (4 hour cycles) for about 6 or 7 days.
• the sample was filtered and allowed to dry at ambient followed by about 2 hours drying under vacuum.
• Form 1 has been shown to have suitable characteristics that justifies its use in a dry powder inhaler (DPI).
• DPI dry powder inhaler
• amorphous form or alternately 300 ul acetone:water (20%) was added to lOOmg 3,3'-Dideoxy-3,3'- bis-[4-(3 -fluorophenyl)- 1H- 1 ,2, 3 -triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside (e.g. amorphous form) to form a slurry.
• the slurry was temperature cycled between RT and 40°C (4 hour cycles) for about 6-7 days.
• the sample was filtered and allowed to dry at ambient followed by about 2 hours drying under vacuum.
• MIBK methyl isobutyl ketone
• H-l ,2,3-triazol-l -yl]-l ,1 '-sulfanediyl-di- -D-galactopyranoside e.g. amor- phous form
• the slurry was temperature cycled between RT and 40°C (4 hour cycles) for about 6-7 days.
• the sample was filtered and allowed to dry at ambient followed by about 2-3 hours drying under vacuum.
• amorphous form or alternately 500ul of 2-propanol was added to lOOmg 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-lH- l ,2,3-triazol-l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside (e.g. amorphous form) to form a slurry.
• the slurry was temperature cycled between RT and 40°C (4 hour cycles) for about 6-7 days.
• the sample was filtered and allowed to dry at ambient followed by about 2-3 hours drying under vacuum.
• amorphous form or alternately 800 ul water was added to lOOmg 3,3'-Dideoxy-3,3'-bis-[4-(3-fiuorophenyl)-lH-l ,2,3-triazol- l -yl]-l ,l '-sulfanediyl-di- -D-galactopyranoside (e.g. amorphous form) to form a slurry.
• the slurry was temperature cycled between RT and 40°C (4 hour cycles) for about 6-7 days.
• the sample was filtered and allowed to dry at ambient followed by about 2-3 hours drying under vacuum.
• Form 5 can also be prepared by microfluidization to produce material with a particle size in the respirable range.
• DMF dimethylformamide
• Preparation of Amorphous Table 4 provides an example of spray-drying conditions used to prepare amorphous 3,3'- Dideoxy-3 ,3 '-bis-[4-(3-fiuorophenyl)- 1 H- 1 ,2,3-triazol- 1 -yl]-l , 1 '-sulfanediyl-di- -D- galactopyranoside.
• the spray-drying solvent can have other proportions of ace- tone:water from 50:50 to 80:20.

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• 2016
  • 2016-12-16 EP EP21175042.7A patent/EP3896075A1/en not_active Withdrawn
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  • 2016-12-16 CN CN201680071057.8A patent/CN108602847A/zh active Pending
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  • 2016-12-16 JP JP2018528313A patent/JP6863984B2/ja not_active Expired - Fee Related
• 2018
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