DESC:FIELD OF THE INVENTION
The present invention relates to novel processes of blarcamesine, its intermediate compounds,
its pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
The drug compound, having the International Non-Proprietary Name Blarcamesine has a
chemical name Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine, and has the
structure of Formula I:
Blarcamesine hydrochloride (Anavex2-73) is a Sigma-1 receptor agonist developed by Anavex
Life Sciences and is undergoing clinical studies in Rett Syndrome, Alzheimer’s disease and
Parkinson’s disease dementia.
PCT publication WO1997/30983A1 (“the ‘983 publication”) describes Blarcamesine, its
enantiomers and its hydrochloride salt. Preparation of racemic Blarcamesine is exemplified as
compound-7 and its melting point described is 87-90°C. The process exemplified in WO ‘983
is schematically represented below:
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
3
PCT publication WO2017/013498A1 (“the ‘498 publication”) describes crystalline polymorphic forms of Blarcamesine HCl namely Form I, Firm II and Form III, their preparative methods and pharmaceutical compositions thereof.
PCT publication WO2019/200345A1 (“the ‘345 publication”) describes crystalline polymorphic forms of Blarcamesine HCl, process for their preparation and their use in pharmaceutical compositions. WO ‘345 also describes crystalline polymorphic form of Blarcamesine fumarate, Blarcamesine benzoate, Blarcamesine sulfate, Blarcamesine phosphate, Blarcamesine edisylate Blarcamesine mesylate, Blarcamesine oxalate and Blarcamesine base.
PCT publication WO2021/158586A1 (“the ‘586 publication”) describes crystalline polymorphic forms of Blarcamesine HCl, Blarcamesine HBr, Blarcamesine besylate, Blarcamesine tosylate, Blarcamesine maleate, Blarcamesine camphorsulfonate their preparative methods and pharmaceutical compositions.
PCT publication WO2023/208133A1 (“the ‘133 publication”) describes co-crystals of Blarcamesine HCl with tartaric acid, citric acid and malic acid, process for their preparation and their use in pharmaceutical compositions.
PCT publication WO2025/022317A1 (“the ‘317 publication”) describes Blarcamesine HCl co-crystal with ZnCl2 & ZnBr2.
Different solid-state forms of an active pharmaceutical ingredient (API) may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulations, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving chemical and physical stability and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage forms, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient (API) may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid an active pharmaceutical ingredient (API).
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
4
New solid-state forms and solid dispersions of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid dispersions of Blarcamesine HCl.
SUMMARY OF THE INVENTION
The present invention generally relates to solid state forms of Blarcamesine HCl, their preparative methods and pharmaceutical compositions thereof.
In one aspect, the present invention provides a crystalline polymorph of Blarcamesine HCl, designated Form D1. The crystalline form D1 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern having peaks at 9.9, 10.4, 14.9, 19.5 and 21.0 degrees 2-theta ±0.2 degrees 2-theta substantially as depicted in Figure 1 pattern.
In one aspect, the present invention provides a crystalline polymorph of Blarcamesine HCl, designated Form D2. The crystalline form D2 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern having peaks at 5.0, 6.3, 10.0, 15.9 and 18.9 degrees 2-theta ±0.2 degrees 2-theta substantially as depicted in Figure 2 pattern.
In another aspect, the present invention provides amorphous form of Blarcamesine HCl.
In another aspect, the present invention provides amorphous solid dispersion comprising Blarcamesine HCl and one or more pharmaceutically acceptable polymer.
In another aspect, the present invention provides process for preparation of amorphous solid dispersion comprising Blarcamesine HCl and one or more pharmaceutically acceptable polymer, the process comprising:
(a) providing a solution of Blarcamesine HCl in a suitable solvent,
(b) adding a pharmaceutically acceptable polymer to the solution of step (a), and
(c) isolating the amorphous solid dispersion comprising Blarcamesine HCl.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
5
In another aspect the present application provides pharmaceutical compositions comprising crystalline Form D1 of Blarcamesine HCl of the present invention and one or more pharmaceutically acceptable polymer.
In another aspect the present application provides pharmaceutical compositions useful for oral administration comprising amorphous solid dispersion Blarcamesine HCl and one or more pharmaceutically acceptable polymer.
In another aspect the present application provides pharmaceutical compositions comprising amorphous Blarcamesine HCl prepared by the process of the present invention and one or more pharmaceutically acceptable polymer.
In another aspect the present application provides use of pharmaceutical compositions or formulations of any one of Blarcamesine HCl of the present invention for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s disease, Parkinson’s disease dementia and/or Rett syndrome.
BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is powder X-ray diffraction (PXRD) pattern of crystalline Form D1 of Blarcamesine HCl prepared according to example 1.
Figure-2 is powder X-ray diffraction (PXRD) pattern of crystalline Form D2 of Blarcamesine HCl prepared according to example 2.
Figure-3 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with HPC prepared according to example 3.
Figure-4 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with HPMC prepared according to example 4.
Figure-5 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Cellulose Acetate Phthalate prepared according to example 5.
Figure-6 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Alcohol prepared according to example 6.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
6
Figure-7 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Pyrrolidone prepared according to example 7.
Figure-8 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Copovidone prepared according to example 8.
Figure-9 is powder X-ray diffraction (PXRD) pattern of amorphous Blarcamesine HCl prepared according to example 9.
DETAILED DESCRITPION OF THE INVENTION
The present invention provides solid state forms of Blarcamesine HCl, and pharmaceutical compositions thereof.
In one aspect, the present invention provides a crystalline polymorph of Blarcamesine HCl, designated form D1. The crystalline form D1 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern having peaks at 5.6 and 9.9 degrees 2-theta ±0.2 degrees 2-theta. The crystalline form D1 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.
The crystalline form D1 of Blarcamesine HCl is further characterized by an X-ray powder diffraction pattern having peaks at 5.6, 9.9, 10.5 and 11.1 degrees 2-theta ±0.2 degrees 2-theta.
The crystalline form D1 of Blarcamesine HCl may be a solvate form. In one aspect, the present invention provides crystalline form D1 of Blarcamesine HCl is a benzyl alcohol solvate.
Crystalline form D1 of Blarcamesine HCl may be prepared by crystallization from a mixture comprising Blarcamesine HCl and a solvent comprising benzyl alcohol. In one aspect, the process comprises:
(a) providing a mixture comprising Blarcamesine HCl in a solvent comprising benzyl alcohol;
(b) optionally stirring the mixture; and
(c) isolating crystalline form D1 of Blarcamesine HCl from the mixture.
In one aspect of the process, the mixture in step (a) may be prepared by providing a mixture of Blarcamesine free base a solvent comprising benzyl alcohol and combining the mixture with Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
7
hydrochloric acid; or by combining Blarcamesine HCl with a solvent comprising benzyl alcohol. The Blarcamesine HCl may amorphous or in any of crystalline form.
In one aspect of the process, the mixture in step (a) may be prepared by combining Blarcamesine HCl with a solvent comprising benzyl alcohol. The ratio of benzyl alcohol to Blarcamesine HCl may be present in an amount of about 5 to 30 mL per gram of Blarcamesine HCl or about 10 to 20 mL per gram of Blarcamesine HCl.
The step (b) of the process is carried out, preferably by stirring at a temperature of about 25°C to about 100°C, about 40°C to about 80°C. The stirring may be carried out for any suitable time, preferably for about 5 minutes to about 5 hours, about 30 minutes to about 2 hours. The mixture may be stirred at a temperature of about -5°C to about 10°C.
The step (c) of the process comprises isolating crystalline form D1 of Blarcamesine HCl from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifuge, or decantation. Preferably, the isolation is carried out by filtration. The crystals of form D1 of Blarcamesine HCl may be washed with benzyl alcohol, and optionally dried.
In another aspect, the present invention provides a crystalline polymorph of Blarcamesine HCl, designated form D2. The crystalline form D2 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern having peaks at 5.0, 6.3 degrees 2-theta ±0.2 degrees 2-theta. The crystalline form D2 of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2.
The crystalline form D2 of Blarcamesine HCl is further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 6.3, 10.0, 15.9 and 18.9 degrees 2-theta ±0.2 degrees 2-theta.
The crystalline form D2 of Blarcamesine HCl may be a solvate form. In one aspect, the present invention provides crystalline form D2 of Blarcamesine HCl is a hydrate.
Crystalline form D2 of Blarcamesine HCl may be prepared by crystallization from a mixture comprising Blarcamesine HCl and a solvent comprising water. In one aspect, the process comprises:
(a) providing a mixture comprising Blarcamesine HCl in a solvent comprising water;
(b) optionally stirring the mixture; and Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
8
(c) isolating crystalline form D2 of Blarcamesine HCl from the mixture.
In one aspect of the process, the mixture in step (a) may be prepared by providing a mixture of Blarcamesine free base a solvent comprising water and combining the mixture with hydrochloric acid; or by combining Blarcamesine HCl with a solvent comprising water. The Blarcamesine HCl may be amorphous or in any of crystalline form.
In one aspect of the process, the mixture in step (a) may be prepared by combining Blarcamesine HCl with a solvent comprising water. The ratio of water to Blarcamesine HCl may be present in an amount of about 1 to 30 mL per gram of Blarcamesine HCl or about 5 to 20 mL per gram of Blarcamesine HCl.
The step (b) of the process is carried out, preferably by stirring at a temperature of about 25°C to about 100°C, preferably at about 40°C to about 80°C. The stirring may be carried out for any suitable time, preferably for about 5 minutes to about 5 hours, about 30 minutes to about 2 hours. The mixture may be stirred at a temperature of about -5°C to about 10°C.
The step (c) of the process comprises isolating crystalline form D2 of Blarcamesine HCl from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifuge, or decantation. Preferably, the isolation is carried out by filtration. The crystals of form D2 of Blarcamesine HCl may be washed with water, and optionally dried.
In another aspect, the present invention provides amorphous solid dispersion comprising Blarcamesine HCl and one or more pharmaceutically acceptable polymers.
In another aspect, the present invention provides process for preparation of amorphous solid dispersion comprising Blarcamesine HCl and one or more pharmaceutically acceptable polymer, the process comprising:
(a) providing a solution of Blarcamesine HCl in a suitable solvent,
(b) adding a pharmaceutically acceptable polymer to the solution of step (a), and
(c) isolating the amorphous solid dispersion comprising Blarcamesine HCl.
Providing a solution in step (a) includes direct use of a reaction mixture containing Blarcamesine HCl that is obtained in the course of its synthesis or dissolving Blarcamesine HCl in a suitable solvent. Any physical form of Blarcamesine HCl may be utilized for providing the solution of Blarcamesine HCl in step (a). Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
9
The solvent may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitriles, such as acetonitrile; hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, acetic acid and the like; water; or mixtures thereof. Preferably the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, dichloromethane and THF and mixture thereof.
The step (b) involves addition of a pharmaceutically acceptable polymer to the solution obtained in step (a).
Suitable polymers for use in the subject solid dispersions include, but are not limited to cellulose esters; cellulose ethers; polyalkylene oxides; polyacrylates; polymethacrylates; homopolymers and copolymers of N-vinyl lactams, polyacrylamides, vinyl acetate polymers; graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate; oligosaccharides; polysaccharides; and mixtures thereof.
In some embodiments, the polymer is a cellulose ether polymer. For example, the polymer may be selected from methyl cellulose, ethyl cellulose, (hydroxyalkyl) cellulose (e.g., hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC)), or (hydroxyalkyl)alkyl-cellulose (e.g., hydroxypropyl methyl cellulose (HPMC or hypromellose)). In some embodiments, the polymer is methyl cellulose. In some embodiments, the polymer is ethyl cellulose. In some embodiments, the polymer is HEC. In some embodiments, the polymer is HPC. In some embodiments, the polymer is HPMC.
In some embodiments, the polymer is a cellulose ester polymer. In some embodiments, the polymer is cellulose phthalate (e.g., cellulose acetate phthalate or hypromellose phthalate (HPMCP)) or cellulose succinate (e.g., hypromellose succinate (HPMCS) or hypromellose Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
10
acetate succinate (HPMCAS)). In some embodiments, the polymer is HPMCP. In some embodiments, the polymer is HPMCAS.
Cellulose polymers described herein may be further defined by a particular grade. For example, an HPMC polymer may be selected from HPMC E3, HPMC E5, HPMC E6, HPMC El 5, HPMC K3, HPMC A4, or HPMC A 15. In some embodiments, the HPMCAS is HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, or HPMCAS-HG. In some embodiments, the HPMCP is HPMCP 50 or HPMCP 55.
In some embodiments, the polymer is HPMCP. In some embodiments, the polymer is HPMCP 50. In some embodiments, the polymer is HPMCAS-L, HPMCAS-M, or HPMCAS-H. In some embodiments, the polymer is HPMCAS- H. In some embodiments, the polymer is HPMCAS-HG.
In some embodiments, the polymer is a polyalkylene oxide. In some embodiments, the polymer is a high molecular weight polyalkylene oxide. In some embodiments, the polymer is polyethylene oxide (PEG or PEO) or copolymers of ethylene oxide and propylene oxide (poloxamers). Suitable PEGs include, without limitation, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and mixtures thereof. Suitable poloxamers include, without limitation, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof. In one embodiment, the polymer is poly(ethylene glycol) methyl. In some embodiments, the polymer is polyethylene glycol 6000 (PEG 6000).
In some embodiments, the polymer is a polyacrylate or polymethacrylate. In some embodiments, the polymer is methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2 -dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), or poly(hydroxyalkyl methacrylates). Suitable polyacrylate or polymethacrylate include, without limitation, those sold under the Eudragit™ trademark of Rohm GmbH as Eudragit RS 100, Eudragit L 100, Eudragit L 100-55, and Eudragit S 100, products of other manufacturer’s equivalent thereto, and mixtures thereof. In one embodiment, the polymer is Eudragit RS 100. In some embodiments, the polymer is Eudragit S 100.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
11
In some embodiments, the polymer is a homopolymer or copolymer of N-vinyl lactams. In some embodiments, the polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. In some embodiments, the polymer is a homopolymer of polyvinylpyrrolidone (PVP or povidone) or a copolymer (e.g., those comprising monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl propionate). Suitable povidones include, without limitation, those having a K-value (a measure of viscosity of an aqueous solution of the povidone) of about 12, about 15, about 17, about 25, about 30 or about 90, and mixtures thereof. In some embodiments, the polymer is polyvinylpyrrolidone K30. In some embodiments, the polymer is poly(l-vinylpyrrolidone-co-vinyl acetate).
In some embodiments, the polymer is a polyacrylamide. In some embodiments, the polymer is a vinyl acetate polymer (e.g., copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, or partially hydrolyzed polyvinyl acetate). In some embodiments, the polymer is a graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., SOLUPLUS™ of BASF or equivalent product). In some embodiments, the polymer is an oligo- or polysaccharide (e.g., carrageenans, galactomannans, or xanthan gum).
Preferably, the pharmaceutically acceptable polymer is selected from the group consisting of Hydroxy propyl cellulose (HPC), Polyvinyl acetate Phthalate (PVAP), Cellulose acetate Phthalate (CAP), Soluplus, Polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC), Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), copovidone and Eudragit.
Blarcamesine HCl and the polymer are mixed in a ratio of 1 to 0.5 up to 1 to 10. Preferably in a ratio of Blarcamesine HCl to polymer of 1:0.5 to 1:4.
The polymer may be mixed with a suitable solvent and the mixture is added to the Blarcamesine HCl solution and is stirred for about 10 minutes to about 10 hours at a suitable temperature to get a clear solution.
Step (c) involves isolating the amorphous solid dispersion. The amorphous solid dispersion is isolated by removing the solvent.
The removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
12
pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The resulting Blarcamesine HCl solid dispersion may optionally be further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In another aspect, the amorphous solid dispersion of Blarcamesine HCl of the present invention are stable under thermal, humid and stress conditions.
The amorphous solid dispersion of Blarcamesine HCl disclosed herein may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), modulated differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), Karl Fischer water titration (KF), residual solvent, particle size, bulk density, tapped density, high pressure liquid chromatography (HPLC).
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and hydroxy propyl cellulose. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and hydroxy propyl cellulose is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3.
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and hydroxy propyl methylcellulose. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and hydroxy propyl methylcellulose is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4.
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and cellulose acetate phthalate. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and cellulose acetate phthalate is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 5. Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
13
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and polyvinyl alcohol. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and polyvinyl alcohol is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 6.
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and polyvinyl pyrrolidone. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and polyvinyl pyrrolidone is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 7.
In another aspect, the present invention provides amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and copovidone. The amorphous solid dispersion of Blarcamesine HCl comprising Blarcamesine HCl and copovidone is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 8.
In another aspect, the amorphous solid dispersion of Blarcamesine HCl of the present invention or the pharmaceutical compositions thereof comprises Blarcamesine HCl with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In another aspect, the present invention provides amorphous form of Blarcamesine HCl. The amorphous form of Blarcamesine HCl is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 9.
In another aspect, the present invention provides process for preparation of amorphous form of Blarcamesine HCl, comprising:
(a) providing a solution of Blarcamesine HCl in a suitable solvent,
(b) optionally stirring the solution of step (a), and
(c) isolating amorphous form of Blarcamesine HCl.
Providing a solution in step (a) includes direct use of a reaction mixture containing Blarcamesine HCl that is obtained in the course of its synthesis or dissolving Blarcamesine HCl in a suitable solvent. Any physical form of Blarcamesine HCl may be utilized for providing the solution of Blarcamesine HCl in step (a).
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
14
The solvent may be selected from the group comprising of methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, THF, dichloromethane, ethyl acetate and mixture thereof. Preferably, the solvent is methanol.
In one aspect of the process, the solution in step (a) may be prepared by combining Blarcamesine HCl with the solvent. The ratio of solvent to Blarcamesine HCl may be present in an amount of about 5 to 50 mL per gram of Blarcamesine HCl or about 10 to 40 mL per gram of Blarcamesine HCl.
The step (b) of the process is carried out, preferably by stirring at a temperature of about 5°C to about 50°C, about 20°C to about 40°C. The stirring may be carried out for any suitable time, preferably for about 5 minutes to about 5 hours, about 30 minutes to about 2 hours.
The step (c) of the process comprises isolating amorphous form of Blarcamesine HCl from the solution. The isolation is carried out by spray drying method.
In another aspect, the present application provides pharmaceutical compositions comprising crystalline form D1 or crystalline form D2 of Blarcamesine HCl and one or more pharmaceutically acceptable polymer.
In another aspect, the present application provides pharmaceutical compositions comprising amorphous solid dispersion of Blarcamesine HCl and one or more pharmaceutically acceptable polymer.
In another aspect, the present application provides pharmaceutical compositions comprising amorphous form of Blarcamesine HCl and one or more pharmaceutically acceptable polymer.
The solid-state forms of Blarcamesine HCl prepared by the process of the present invention and their pharmaceutical compositions or formulations may be used as medicaments, particularly for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s diseases, Parkinson’s disease dementia and/or Rett syndrome.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
15
The terms “amorphous” and “amorphous form” are used herein to describe a substance, component, or product that is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more crystal forms on a weight basis. In other embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form).
Unless otherwise specified, the term “solid dispersion” refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature.
The term “polymer” refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end- capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term “copolymer” refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).
The term “pharmaceutically acceptable excipient” includes, without limitation, any adjuvant, carrier, excipient, binder, filler, disintegrant, lubricant, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
16
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example-1: Preparation of crystalline Form D1 of Blarcamesine HCl
Blarcamesine HCl (500 mg) and benzyl alcohol (0.5 mL) were charged into a conical flask and stirred the mixture at 80 °C for 30 minutes. The mixture was cooled using an ice bath for 30 minutes. The precipitation formed was filtered through a Buchner funnel to get 450 mg of solid. PXRD is shown in Figure 1.
Example-2: Preparation of crystalline Form D2 of Blarcamesine HCl
Blarcamesine HCl (500 mg) and water (0.2 mL) were charged into a conical flask and stirred the mixture at 80 °C for 30 minutes. The mixture was cooled using an ice bath for 30 minutes. The precipitation formed was filtered through a Buchner funnel to get 400 mg of solid. PXRD is shown in Figure 2.
Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
17
Example-3: Preparation of amorphous solid dispersion comprising Blarcamesine HCl and hydroxy propyl cellulose
Blarcamesine HCl (100 mg) and methanol (2 mL) were charged into a conical flask and stirred the mixture at 30°C for 5 minutes. Hydroxy propyl cellulose (HPC) polymer (200 mg) and methanol (20 mL) were charged into another conical flask and stirred the mixture at 30°C until clear solution is obtained. Both the solutions were mixed and stirred at 30°C for 10 minutes. The mixture was concentrated using a rotavapor under vacuum at 70°C until solid obtained. Yield: 250 mg. PXRD is shown in Figure 3.
Example-4: Preparation of amorphous solid dispersion comprising Blarcamesine HCl and hydroxy propyl methylcellulose
Blarcamesine HCl (100 mg) and methanol (2 mL) were charged into a conical flask and stirred the mixture at 30°C for 5 minutes. Hydroxy propyl methylcellulose (HPMC) polymer (200 mg) and methanol (20 mL) were charged into another conical flask and stirred the mixture at 30°C until clear solution is obtained. Both the solutions were mixed and stirred at 30°C for 10 minutes. The mixture was concentrated using a rotavapor under vacuum at 70°C until solid obtained. Yield: 260 mg. PXRD is shown in Figure 4.
Example-5: Preparation of amorphous solid dispersion comprising Blarcamesine HCl and cellulose acetate phthalate
Blarcamesine HCl (100 mg) and methanol (2 mL) were charged into a conical flask and stirred the mixture at 30°C for 5 minutes. cellulose acetate phthalate (CAP) polymer (200 mg) and methanol (20 mL) were charged into another conical flask and stirred the mixture at 30°C until clear solution is obtained. Both the solutions were mixed and stirred at 30°C for 10 minutes. The mixture was concentrated using a rotavapor under vacuum at 70°C until solid obtained. Yield: 250 mg. PXRD is shown in Figure 5.
Example-6: Preparation of amorphous solid dispersion comprising Blarcamesine HCl and polyvinyl alcohol
Blarcamesine HCl (100 mg) and methanol (2 mL) were charged into a conical flask and stirred the mixture at 30°C for 5 minutes. polyvinyl alcohol (PVA) polymer (200 mg) and methanol (20 mL) were charged into another conical flask and stirred the mixture at 30°C until clear Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
18
solution is obtained. Both the solutions were mixed and stirred at 30°C for 10 minutes. The mixture was concentrated using a rotavapor under vacuum at 70°C until solid obtained. Yield: 250 mg. PXRD is shown in Figure 6.
Example-7: Preparation of amorphous solid dispersion comprising Blarcamesine HCl and polyvinyl pyrrolidone
Blarcamesine HCl (100 mg) and methanol (2 mL) were charged into a conical flask and stirred the mixture at 30°C for 5 minutes. polyvinyl pyrrolidone (PVP K15 & PVP K90) polymer (200 mg) and methanol (20 mL) were charged into another conical flask and stirred the mixture at 30°C until clear solution is obtained. Both the solutions were mixed and stirred at 30°C for 10 minutes. The mixture was concentrated using a rotavapor under vacuum at 70°C until solid obtained. Yield: 265 mg. PXRD is shown in Figure 7.
Example-8: ,CLAIMS:1. Solid-state forms of Blarcamesine HCl, selected from the group comprising:
a) crystalline Blarcamesine HCl Form D1,
b) crystalline Blarcamesine HCl Form D2,
c) amorphous Blarcamesine HCl,
d) amorphous solid dispersion of Blarcamesine HCl with HPC,
e) amorphous solid dispersion of Blarcamesine HCl with HPMC,
f) amorphous solid dispersion of Blarcamesine HCl with Cellulose Acetate Phthalate,
g) amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Alcohol,
h) amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Pyrrolidone, and
i) amorphous solid dispersion of Blarcamesine HCl with Copovidone,
2. The Solid-state forms of Blarcamesine HCl according to claim 1, which are characterized by:
a) powder X-ray diffraction (PXRD) pattern of crystalline Form D1 of Blarcamesine HCl as depicted in Figure 1,
b) powder X-ray diffraction (PXRD) pattern of crystalline Form D2 of Blarcamesine HCl as depicted in Figure 2,
c) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with HPC as depicted in Figure 3,
d) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with HPMC as depicted in Figure 4,
e) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Cellulose Acetate Phthalate as depicted in Figure 5,
f) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Alcohol as depicted in Figure 6,
g) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Polyvinyl Pyrrolidone as depicted in Figure 7,
h) powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Blarcamesine HCl with Copovidone as depicted in Figure 8, and
i) powder X-ray diffraction (PXRD) pattern of amorphous Blarcamesine HCl as depicted in Figure 9.
3. A process for preparation of crystalline Form D1 of Blarcamesine HCl, comprises: Docusign Envelope ID: E32F244E-8CFF-4B7B-819F-DFC88AF6CE4E
20
(a) providing a mixture comprising Blarcamesine HCl in a solvent comprising benzyl alcohol;
(b) optionally stirring the mixture; and
(c) isolating crystalline form D1 of Blarcamesine HCl from the mixture.
4. A process for preparation of crystalline Form D2 of Blarcamesine HCl, comprises:
(a) providing a mixture comprising Blarcamesine HCl in a solvent comprising water;
(a) optionally stirring the mixture; and
(b) isolating crystalline form D2 of Blarcamesine HCl from the mixture.
5. A process for preparation of amorphous solid dispersion of Blarcamesine HCl, comprises:
(a) providing a solution of Blarcamesine HCl in a suitable solvent,
(b) adding a pharmaceutically acceptable polymer to the solution of step (a), and
(c) isolating the amorphous solid dispersion comprising Blarcamesine HCl.
6. The process of claim 5, wherein the pharmaceutically acceptable polymer is selected from the group consisting of HPC, HPMC, Cellulose Acetate Phthalate, Polyvinyl Alcohol, Polyvinyl Pyrrolidone and Copovidone.
7. A process for preparation of amorphous form of Blarcamesine HCl, comprising:
(a) providing a solution of Blarcamesine HCl in a suitable solvent,
(b) optionally stirring the solution of step (a), and
(c) isolating amorphous form of Blarcamesine HCl.
8. The process of claim 7, wherein the suitable solvent is selected from the group consisting of methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, THF, dichloromethane and ethyl acetate.
9. Use of a slod-state forms of Blarcamesine HCl as defined in any of Claims 1 to 8, for the preparation of other solid-state forms of Blarcamesine, Blarcamesine co-crystals, Blarcamesine salts and their solid-state forms.
10. A pharmaceutical composition comprising solid-state forms of Blarcamesine HCl as defined in any of Claims 1 to 9 and at least one pharmaceutically acceptable excipient, preferably wherein the pharmaceutical composition is for oral administration.