WO2022249200A1 - Novel crystalline forms of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridine-3-yl) methoxy)benzaldehyde - Google Patents
Novel crystalline forms of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridine-3-yl) methoxy)benzaldehyde Download PDFInfo
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- WO2022249200A1 WO2022249200A1 PCT/IN2022/050489 IN2022050489W WO2022249200A1 WO 2022249200 A1 WO2022249200 A1 WO 2022249200A1 IN 2022050489 W IN2022050489 W IN 2022050489W WO 2022249200 A1 WO2022249200 A1 WO 2022249200A1
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- methyl
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- FWCVZAQENIZVMY-UHFFFAOYSA-N 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O FWCVZAQENIZVMY-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 52
- 229940070141 voxelotor Drugs 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 39
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 36
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 26
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 26
- 229960002216 methylparaben Drugs 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 15
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
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- 239000007935 oral tablet Substances 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
Definitions
- the present invention relates to novel crystalline forms of 2-hydroxy-6-((2-(l- isopropyl-lH-pyrazol-5-yl) pyridine-3-yl)methoxy)benzaldehyde (I) and process for its preparation thereof.
- the compound of formula (I) is represented by the following structural formula.
- Voxelotor 2-Hydroxy-6-((2-( 1 -isopropyl- lif-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I) is commonly known as “Voxelotor” and it is a hemoglobin S polymerization inhibitor, indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older. Voxelotor is approved by United States Federal Drug Administration (USFDA) on Nov 28, 2018 to Global Blood Therapeutics Inc under the brand name OXBRYTATM. It is available in 500mg oral tablet.
- USFDA United States Federal Drug Administration
- US patent 9447071 B2 describes Form-I, Form-II and Form-N of Voxelotor and process for its preparation thereof.
- Voxelotor belongs to BCS class-II drug which means low solubility drug.
- Crystalline solid forms of a drug is a necessary stage for many orally available drugs. Suitable solid forms possess the desired properties of a particular drug. Such suitable forms often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself or may be used as a drug product intermediate during the preparation of the drug. For example, new drug formulations comprising crystalline forms of a given drug may have superior properties, such as solubility, dissolution and storage stability over existing formulations of the drug.
- Inventors of the present invention surprisingly found two novel crystalline forms of Voxelotor and also process for their preparation thereof.
- the present invention provides crystalline Form-M of Voxelotor: methyl paraben and process for its preparation thereof.
- the present invention provides crystalline Form-S of Voxelotor: hydroquinone and process for its preparation thereof.
- Figure 1 Illustrates powdered X-Ray diffraction (PXRD) pattern of crystalline Form-M of Voxelotor: methyl paraben.
- FIG. 2 Illustrates PXRD pattern of crystalline Form-S of Voxelotor: hydroquinone. Detailed description of the invention:
- solvent used in the present invention refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents” such as dichloro solvents
- the present invention provides crystalline Form-M of Voxelotor: methyl paraben.
- Voxelotor Methylparaben is obtained as a co-crystal which is represented by the following structural formula:
- crystalline Form-M of Voxelotor methyl paraben is characterized by one or more of the following characteristics:
- the present invention provides a process for the preparation of crystalline Form-M of Voxelotor: methyl paraben, comprising: a) providing a solution of Voxelotor and methyl paraben in a solvent, b) isolating crystalline Form-M of Voxelotor: methyl paraben.
- the solvent is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert -butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrol
- the amount of Methylparaben is about 0.25 mole equivalent to about 5 mole equivalents with respect to Voxelotor.
- the amount of Methylparaben is about 0.8 mole equivalent to about 2.5 mole equivalents with respect to Voxelotor.
- Crystallie form-M of Voxelotor Methylparaben is stable under various stability conditions.
- the present invention provides crystalline Form-S of Voxelotor: hydroquinone.
- crystalline Form-S of Voxelotor hydroquinone is characterized by PXRD pattern as illustrated in figure-2.
- the present invention provides a process for the preparation of crystalline Form-S of Voxelotor: hydroquinone, comprising: a) providing a solution of Voxelotor and hydroquinone in a solvent, b) isolating crystalline Form-S of Voxelotor: hydroquinone.
- the solvent is selected from alcohol solvents such as methanol, ethanol, n- propanol, isopropanol, n-butanol, 2-methylpropan-ol, 2-butanol, t-butanol and the like; chloro solvents such as dichlorome thane, dichloroethane and the like; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert -butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester solvents such as
- Voxelotor used in the preparation of polymorphic forms of the present invention is prepared by any of the processes disclosed in literature such as US 9018210 B2, US 9447071 B2 or any other relevant references.
- Crystalline Form-M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone produced by the processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
- Techniques that may be used for particle size reduction include but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
- Co-crystal of Voxelotor Methyl paraben i.e., Crystalline form-M; crystalline Form-S of Voxelotor: hydroquinone of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
- the third embodiment of the present invention provides the use of Crystalline form- M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone for the preparation of various pharmaceutical formulations.
- the fourth embodiment of the present invention provides a pharmaceutical composition comprising any one of Crystalline form-M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone and one or more pharmaceutically acceptable excipient.
- compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- suitable pharmaceutically acceptable excipients selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants.
- Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatin, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glyceryl dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic
- Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta- cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.
- Example 1 Preparation of crystalline Form-M of Voxelotor: methyl paraben.
- Voxelotor 500 mg
- methyl paraben 225 mg
- methyl paraben 225 mg
- the obtained mixture was cooled to 25-30°C and stirred for about 30 min filtered the precipitated solid and then dried to afford the title compound.
- Example 2 Preparation of crystalline Form-S of Voxelotor: hydroquinone.
- Voxelotor 100 mg
- hydroquinone 32.6 mg
- methanol and dichloromethane 2 ml, 1:1
- the obtained compound was characterized by PXRD pattern as illustrated in figure-2.
- Example 3 Preparation of crystalline Form-M of Voxelotor: methyl paraben.
- the obtained compound was characterized by the PXRD pattern similar to the figure- 1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides novel crystalline forms of 2- hydroxy -6- ( (2- (1-isopropyl- 1H- pyrazol- 5 - yl ) pyridine- 3- yl ) methoxy ) benzaldehyde (I) of formula (I) and its process for its preparation thereof. The compound of formula (I) is represented by the following structural formula.
Description
Novel crystalline forms of 2-hvdroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridine-3-yl) methoxylbenzaldehyde
Related Application:
This application claims the benefit of priority to our Indian patent application number 202141023311 filed on May 25, 2021, the disclosures of all that are incorporated by reference in their entirety.
Field of the invention:
The present invention relates to novel crystalline forms of 2-hydroxy-6-((2-(l- isopropyl-lH-pyrazol-5-yl) pyridine-3-yl)methoxy)benzaldehyde (I) and process for its preparation thereof. The compound of formula (I) is represented by the following structural formula.
Formula (I)
Background of the invention:
2-Hydroxy-6-((2-( 1 -isopropyl- lif-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I) is commonly known as “Voxelotor” and it is a hemoglobin S polymerization inhibitor, indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older. Voxelotor is approved by United States Federal Drug Administration (USFDA) on Nov 28, 2018 to Global Blood Therapeutics Inc under the brand name OXBRYTA™. It is available in 500mg oral tablet. Recommended dosage for sickle cell disease is 1500 mg and for hepatic impairment patients with severe hepatic impairment (Child Pugh C) is 1000 mg taken orally once daily with or without food.
US patent 9018210 B2 describes purification of Voxelotor by silicagel using ethyl acetate and hexane. But this patent publication silent about crystalline forms of Voxelotor.
US patent 9447071 B2 describes Form-I, Form-II and Form-N of Voxelotor and process for its preparation thereof.
It is described in USFDA chemical reviews that Voxelotor belongs to BCS class-II drug which means low solubility drug.
Crystalline solid forms of a drug is a necessary stage for many orally available drugs. Suitable solid forms possess the desired properties of a particular drug. Such suitable forms often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself or may be used as a drug product intermediate during the preparation of the drug. For example, new drug formulations comprising crystalline forms of a given drug may have superior properties, such as solubility, dissolution and storage stability over existing formulations of the drug.
Inventors of the present invention surprisingly found two novel crystalline forms of Voxelotor and also process for their preparation thereof.
Brief description of the invention:
In first embodiment, the present invention provides crystalline Form-M of Voxelotor: methyl paraben and process for its preparation thereof.
In second embodiment, the present invention provides crystalline Form-S of Voxelotor: hydroquinone and process for its preparation thereof.
Brief description of the drawings:
Figure 1: Illustrates powdered X-Ray diffraction (PXRD) pattern of crystalline Form-M of Voxelotor: methyl paraben.
Figure 2: Illustrates PXRD pattern of crystalline Form-S of Voxelotor: hydroquinone.
Detailed description of the invention:
The term "solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichlorome thane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
In first embodiment, the present invention provides crystalline Form-M of Voxelotor: methyl paraben.
In the first aspect of the first embodiment, Voxelotor : Methylparaben is obtained as a co-crystal which is represented by the following structural formula:
In second aspect of the first embodiment crystalline Form-M of Voxelotor: methyl paraben is characterized by one or more of the following characteristics:
(i) PXRD (Powder X-Ray diffraction) pattern having peaks at about 8.7°, 13.9° and 22.4° 2Q± 0.2° 2Q, or
(ii) PXRD (Powder X-Ray diffraction) pattern having peaks at about 7.1°, 8.7°, 13.9°, 16.5°, 17.5°, 22.4° and 27.3° 2Q± 0.2° 2Q, or
(iii) PXRD pattern as illustrated in figure- 1.
In third aspect of first embodiment, the present invention provides a process for the preparation of crystalline Form-M of Voxelotor: methyl paraben, comprising: a) providing a solution of Voxelotor and methyl paraben in a solvent, b) isolating crystalline Form-M of Voxelotor: methyl paraben.
Wherein in step-a) the solvent is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert -butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2- methylpropan-ol, 2-butanol, t-butanol and the like; or mixture of the solvents thereof; the suitable temperature for providing solution is ranging between 25°C to reflux temperature of the solvent used; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture or cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture.
In the fourth aspect of first embodiment, the amount of Methylparaben is about 0.25 mole equivalent to about 5 mole equivalents with respect to Voxelotor. Preferably, the amount of Methylparaben is about 0.8 mole equivalent to about 2.5 mole equivalents with respect to Voxelotor.
In the fifth aspect of first embodiment of the first embodiment, Crystallie form-M of Voxelotor: Methylparaben is stable under various stability conditions.
In second embodiment, the present invention provides crystalline Form-S of Voxelotor: hydroquinone.
In first aspect of second embodiment, crystalline Form-S of Voxelotor: hydroquinone is characterized by PXRD pattern as illustrated in figure-2.
In second aspect of first embodiment, the present invention provides a process for the preparation of crystalline Form-S of Voxelotor: hydroquinone, comprising: a) providing a solution of Voxelotor and hydroquinone in a solvent, b) isolating crystalline Form-S of Voxelotor: hydroquinone.
Wherein in step-a) the solvent is selected from alcohol solvents such as methanol, ethanol, n- propanol, isopropanol, n-butanol, 2-methylpropan-ol, 2-butanol, t-butanol and the like; chloro solvents such as dichlorome thane, dichloroethane and the like; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert -butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; or mixture of the solvents thereof; the suitable temperature for providing solution is ranging between 30°C to reflux temperature of the solvent used; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.
Voxelotor used in the preparation of polymorphic forms of the present invention is prepared by any of the processes disclosed in literature such as US 9018210 B2, US 9447071 B2 or any other relevant references.
Crystalline Form-M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone produced according to the present invention is having purity of greater than about 99%, preferably greater than about 99.5%, more preferably greater than about 99.7%, most preferably greater than about 99.8% by HPLC {High Performance Liquid Chromatography } .
Crystalline Form-M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone produced by the processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
Co-crystal of Voxelotor: Methyl paraben i.e., Crystalline form-M; crystalline Form-S of Voxelotor: hydroquinone of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
The third embodiment of the present invention provides the use of Crystalline form- M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone for the preparation of various pharmaceutical formulations.
The fourth embodiment of the present invention provides a pharmaceutical composition comprising any one of Crystalline form-M of Voxelotor: methyl paraben; crystalline Form-S of Voxelotor: hydroquinone and one or more pharmaceutically acceptable excipient.
As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Wherein, suitable pharmaceutically acceptable excipients selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatin, acacia, agar, alginic acid, carbomer, chitosan, dextrates,
cyclodextrin, dextrin, glyceryl dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fmctose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta- cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.
PXRD analysis of the crystalline forms and crystalline of the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu-Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example 1: Preparation of crystalline Form-M of Voxelotor: methyl paraben.
Voxelotor (500 mg) and methyl paraben (225 mg) were dissolved in methyl tert-butyl ether (5 ml) at 45-50°C. The obtained mixture was cooled to 25-30°C and stirred for about 30 min filtered the precipitated solid and then dried to afford the title compound.
(Yield: 600 mg).
The obtained compound was characterized by the PXRD pattern as illustrated in figure- 1.
Example 2: Preparation of crystalline Form-S of Voxelotor: hydroquinone.
Voxelotor (100 mg) and hydroquinone (32.6 mg) were dissolved in a mixture of methanol and dichloromethane (2 ml, 1:1) at 25-30°C and stirred the obtained mixture followed by evoperated the solvent to afford the title compound.
The obtained compound was characterized by PXRD pattern as illustrated in figure-2.
Example 3: Preparation of crystalline Form-M of Voxelotor: methyl paraben.
Dissolved Voxelotor (60 g) in ethyl acetate at 28°C. Water was charged into the obtained solution. Separated the organic layer from the mixture and carbon treatment given to the obtained organic layer. Distilled off the solvent form the solution and co-distilled with methyl tert-butyl ether. Methyl paraben (27 g) and methyl tert-butyl ether (600 ml) were added to the obtained compound at 28°C. Heated the mixture to 50°C and stirred. Cooled the obtained solution to 28°C and stirred. Seeded the solution with the crystalline Form-M and further stirred the mixture. The mixture was further cooled to 10°C and stirred. Filtered the solid and then dried to afford the title compound.
(Yield: 60.6 g).
The obtained compound was characterized by the PXRD pattern similar to the figure- 1.
Claims
1. Co-crystal of Voxelotor: methyl paraben
2. The co-crystal of Voxelotor: methyl paraben as claimed in claim 1 , which is in crystalline form-M.
3. The crystalline form-M of claim 2, is further characterized by one or more of the following characteristics:
(i) PXRD (Powder X-Ray diffraction) pattern having peaks at about 8.7°, 13.9° and 22.4° 2Q± 0.2° 2Q, or
(ii) PXRD (Powder X-Ray diffraction) pattern having peaks at about 7.1°, 8.7°, 13.9°, 16.5°, 17.5°, 22.4° and 27.3° 2Q± 0.2° 2Q, or
(iii) PXRD pattern as illustrated in figure- 1.
4. A process for the preparation of Crystalline Form-M of claim 2, comprising: a) providing a solution of Voxelotor and methyl paraben in a solvent, b) isolating crystalline Form-M of Voxelotor: methyl paraben.
5. The process as claimed in claim 4, wherein the solvent in step-a) is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n- heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester
solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvents such as dichlorome thane, dichloroe thane and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-ol, 2-butanol, t- butanol and the like; or mixture of the solvents thereof; the suitable temperature for providing solution is ranging between 30°C to reflux temperature of the solvent used; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture or cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture.
6. Crystalline Form-S of Voxelotor: hydroquinone, which is characterized by PXRD pattern as illustrated in figure-2.
7. A process for the preparation of crystalline Form-S of Voxelotor: hydroquinone of claim 6, comprising: a) providing a solution of Voxelotor and hydroquinone in a solvent, b) isolating crystalline Form-S of Voxelotor: hydroquinone.
8. The process as claimed in claim 7, wherein the solvent in step-a) is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan- ol, 2-butanol, t-butanol and the like; chloro solvents such as dichlorome thane, dichloroethane and the like; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone
(NMP) and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; or mixture of the solvents thereof; the suitable temperature for providing solution is ranging between 30°C to reflux temperature of the solvent used; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.
9. A pharmaceutical composition comprising the Co-crystal of Voxelotor: methyl paraben of claim 1 and one or more pharmaceutically acceptable excipients.
10. A method of treating a mammal by administering a therapeutically effective amount of Co-crystal of Voxelotor: methyl paraben of claim 1 for the treating sickle cell disease in adults and pediatric patients 12 years of age and older.
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| WO2015120133A1 (en) * | 2014-02-07 | 2015-08-13 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
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| WO2015120133A1 (en) * | 2014-02-07 | 2015-08-13 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
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