DESC:The following specification particularly describes the invention and the manner in
which it is to be performed:

FIELD OF THE INVENTION
The present application relates to amorphous form and amorphous solid dispersion form of Verubecestat and processes for preparation thereof.
The drug compound having the adopted name “Verubecestat”, is an inhibitor of beta-secretase (BACE-1 and BACE-2), chemically designated as N-[3-[(5R)-3-amino-5,6- dihydro-2,5-dimethyl- 1, 1 -dioxido-2H- 1 ,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoro-2- pyridinecarboxamide by structure of Formula I.

Formula I
U.S. Patent No. 8,729,071 discloses Verubecestat and process for its preparation. Also disclosed is the use of Verubecestat in treating, preventing, ameliorating, and/or delaying the onset of an ?ß pathology and/or a symptom or symptoms thereof, including Alzheimer's disease.
PCT application No. WO 2016/025364A1 and WO 2016/053767A1 discloses different crystalline forms of Verubecestat and its tosylate salt.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to prepare a stable amorphous form of Verubecestat.
Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, such dispersions are generally unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however provides stable amorphous solid dispersions of Verubecestat. Moreover, the present invention provides solid dispersions of Verubecestat which may be reproduced easily and is amenable for processing into a dosage form.
SUMMARY OF THE INVENTION
In the first embodiment, the present application provides Verubecestat in amorphous form.
In the second embodiment, the present application provides amorphous Verubecestat that can be characterized by its PXRD pattern as illustrated by Figure 1.
In the third embodiment, the present application provides a process for preparing an amorphous form of Verubecestat, comprising the steps of:
a) providing a solution of Verubecestat in a solvent; and
b) isolating amorphous Verubecestat.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of Verubecestat and one or more pharmaceutically acceptable excipients.
In the fifth embodiment, the present application provides a solid dispersion comprising amorphous form of Verubecestat and one or more pharmaceutically acceptable carriers.
In the sixth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of Verubecestat and one or more pharmaceutically acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.
In the seventh embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers comprising the steps of:
a) physically blending Verubecestat and one or more pharmaceutically acceptable carriers; and
b) isolating solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat prepared according to example 1.
FIG. 2 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat prepared according to example 2.
FIG. 3 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat prepared according to example 3.
FIG. 4 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 4
FIG. 5 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 5.
FIG. 6 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat prepared according to example 6.
FIG. 7 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat prepared according to example 7.
FIG. 8 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 8.
FIG. 9 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 9.
FIG. 10 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 10.
FIG. 11 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Verubecestat according to example 11.
FIG. 12 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Verubecestat present in amorphous solid dispersion according to example 12.
DESCRIPTION OF THE INVENTION
In the first embodiment, the present application provides Verubecestat in amorphous form.
In the second embodiment, the present application provides amorphous Verubecestat that can be characterized by its PXRD pattern as illustrated by Figure 1.
In an aspect, the present application provides amorphous Verubecestat that can be characterized by its PXRD pattern as illustrated by Figure 2.
In the third embodiment, the present application provides a process for preparing an amorphous form of Verubecestat, comprising the steps of:
a) providing a solution of Verubecestat in a solvent; and
b) isolating amorphous Verubecestat.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Verubecestat that is obtained in the course of its synthesis; or
ii) dissolving Verubecestat salt in a solvent.
Any physical form of Verubecestat may be utilized for providing the solution of Verubecestat in step (a).
Suitable solvents which can be used in step (a) include but are not limited to: water, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and the like; Nitrile solvents such as acetonitrile, propionitrile and the like; and any mixtures thereof.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 80°C, less than about 70°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 0°C, or any other suitable temperatures, as long as a clear solution of Verubecestat is obtained without affecting its quality.
The solution obtained in step (a) may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves isolating the amorphous Verubecestat.
In one aspect present application involves isolation of amorphous Verubecestat by removing solvent from a solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art.
The solvent can be removed, optionally under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C or any other suitable temperatures.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The isolated solid may be optionally further dried to afford an amorphous form of Verubecestat. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 80°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Verubecestat is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In an aspect, thee present application provides amorphous form of Verubecestat by ball milling the any physical form or mixture of one or more physical form of Verubecestat.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of Verubecestat and one or more pharmaceutically acceptable excipients.
In an aspect, the said amorphous form of Verubecestat may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
In the fifth embodiment, the present application provides a solid dispersion comprising amorphous form of Verubecestat and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer or carrier or excipient in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a polymer or carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
The solid dispersion of Verubecestat of the present invention can be made by any of the numerous methods that result in a solid dispersion comprising amorphous Verubecestat. Several approaches can be used for the preparation of solid dispersion which includes spray drying, fusion method, solvent evaporation, hot-melt extrusion, ball milling, particle size reduction, supercritical fluid (SCF) processes, kneading, inclusion complexes, electrostatic spinning method, melt crystallization and surface-active carriers.
Verubecestat can be incorporated in the dispersion in amorphous state.
The dispersing agent is typically composed of a pharmaceutically acceptable substance that does not substantially interfere with the pharmaceutical action of Verubecestat. The phrase "pharmaceutically acceptable" is employed herein to refer to those substances which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the carrier is a solid at room temperature (e.g., about 22oC).
Non-limiting examples of suitable polymers or carriers are celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses); polysaccharides, heteropolysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the like. Further examples of carriers include copolymer systems such as polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatized copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and N-vinylpyrrolidone.
An enteric coating polymer can also be used according to the present invention. Specific examples of the enteric coating polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.
In an aspect of the invention, the polymer or carrier is polyvinylpyrrolidone (PVP) or a derivative thereof. PVP is a polyamide that forms complexes with a wide variety of substances and is considered to be chemically and physiologically inert. Examples of suitable PVPs include polyvinylpyrrolidones having an average molecular weight from about 10,000 to about 50,000. In some embodiments, the polyvinylpyrrolidone has an average molecular weight of about 10,000 to about 20,000. In further embodiments, the polyvinylpyrrolidone has a molecular weight of about 15,000 to about 20,000.
In the sixth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of Verubecestat and one or more pharmaceutically acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.
Step (a) involves providing a mixture of Verubecestat and one or more pharmaceutically acceptable carriers in a solvent;
Any physical form of Verubecestat may be utilized for providing the mixture of Verubecestat in step (a).
Suitable pharmaceutically acceptable polymers or carriers that are dispersing agents which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, copovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide (Syloid, Aerosil, Cab-o-sil etc.) and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Suitable solvent which can be used for preparing the solid dispersion of Verubecestat are the same as described in step (a) of third embodiment.
Any undissolved particles in the solution obtained in step (a) may be removed by suitable method as described herein above or any other technique known in the art.
Step (b) involves isolation of solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.
Isolation of solid dispersion in step (b) may be carried out by removing solvent from a solution or suspension or mixture obtained in step (a). Suitable techniques which can be used for the removal of solvent are the same as described in step (b) of third embodiment or any other technique known in the art.
Although the solid dispersions of the present invention are preferably prepared using conventional spray drying techniques, it will be understood that suitable solid dispersions may be formed utilizing other conventional techniques known to those skilled in the art, such as vacuum drying, fluid-bed drying, freeze-drying, rotary evaporation, rotary vacuum paddle dryer, drum drying, or other solvent removal process.
Another aspect of the invention involves preparation of solid dispersions of Verubecestat by melt processing, wherein the compound and a carrier are heated to a temperature above the melting point of both the carrier and compound, which results in the formation of a fine colloidal (as opposed to molecular) dispersion of compound particles, with some solubilization of the compound in the carrier matrix. Processing of such a molten mixture often includes rapid cooling, which results in the formation of a congealed mass which must be subsequently milled to produce a powder which can be filled into capsules or made into tablets.
Recovery of solid dispersion comprising an amorphous form of Verubecestat and one or more pharmaceutically acceptable polymers or carriers may be carried out by methods as described in step (b) of third embodiment or any other technique known in the art.
The resulting solid dispersion comprising an amorphous form of Verubecestat and one or more pharmaceutically acceptable polymers or carriers may be optionally further dried. Drying can be can be carried out by methods as described in step (b) of third embodiment herein above or any other technique known in the art.
In the seventh embodiment, present application provides a method for preparing a solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers comprising the steps of:
a) physically blending of Verubecestat and one or more pharmaceutically acceptable carriers; and
b) isolating solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.
Step (a) involves physically blending of Verubecestat and one or more pharmaceutically acceptable carriers.
Verubecestat substantially in amorphous form may be utilized for physical blending of Verubecestat in step (a).
Suitable pharmaceutically acceptable polymers or carriers that are dispersing agents which can be used in step (a) are the same as dispersing agents defined in step (a) of sixth embodiment.
Physical blending as used in step a) involves dry blending in motor pistol, flask or any other suitable container or any other technique known in the art.
Step (b) involves isolation of solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable polymers or carriers which can be carried out by any technique known in the art.
The amount of Verubecestat in the solid dispersions of the present invention ranges from about 0.1% to about 90% by weight of the solid dispersion; or from about 10% to about 70% by weight of the solid dispersion; or from about 20% to about 60% by weight of the solid dispersion; or from about 20% to about 40% by weight of the solid dispersion. In some aspects, the weight ratio of Verubecestat to polymer or carrier is about 1:99 to about 99:1. In some aspects, the weight ratio of Verubecestat to polymer or carrier is about 1:99 to about 75:25 or about 1:99 to about 60: 40. In further aspects, the weight ratio of Verubecestat to polymer or carrier is about 1:99 to about 15:85; about 1:99 to about 10:90; or about 1:99 to about 5:95. In further aspects, the weight ratio of Verubecestat to polymer or carrier is about 25:75 to about 75:25, about 40:60 to about 60:40 or about 1:1 or about 2:1.
Amorphous form or the solid dispersions of Verubecestat of the present application can be optionally subjected to a particle size reduction procedures before or after the completion of drying of the product to produce desired particle sizes and distributions. Milling or micronization can be performed to achieve the desired particle sizes or distributions. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
In another general aspect, there is provided amorphous form of Verubecestat or solid dispersion comprising amorphous form of Verubecestat having particle size distributions wherein D90 is less than about 500 microns or less than about 200 microns or less than about 100 microns or less than about 50 microns or less than about 40 microns or less than about 30 microns or less than about 20 microns or less than about 10 microns or any other suitable particle sizes.
In an aspect, the present application provides pharmaceutical formulations comprising an amorphous form of Verubecestat or solid dispersion comprising amorphous form of Verubecestat, together with one or more pharmaceutically acceptable carriers. Verubecestat together with one or more pharmaceutically acceptable carriers of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, copovidone, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
The pharmaceutical dosage form according to the present invention may be coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
The pharmaceutical dosage form according to the present invention can further comprise additional excipients and adjuvants, which are pharmaceutically acceptable and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention. Such further excipients and adjuvants are known to the person skilled in the art.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tableting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
Verubecestat which may be used as the input in the process for preparation of the solid states of the present application can be prepared by any process known in the art.
The solid form of Verubecestat of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 Å and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer and PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
The D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Methods for determining D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.
DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula.
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
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 unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Where this document refers to a material, such as in this instance, Verubecestat and its solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
As used herein, the term "room temperature" refers to a temperature of from about 20oC to about 35oC, from about 25oC to about 35oC, from about 25oC to about 30oC, or for example, about 25oC.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "polymer" or “carrier” or “excipient” as used herein interchangeably refer to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
The term “dispersed” means random distribution of a therapeutically active substance throughout the carrier.
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 amorphous Verubecestat: Verubecestat (500 mg) and methanol (25 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 1.
Example 2: Preparation of amorphous Verubecestat: Verubecestat (500 mg) and acetone (25 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 2.
Example 3: Preparation of amorphous Verubecestat: Verubecestat (1.5 g) and methanol (75 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant solution was subjected to spray drying using ProCept spray dryer
(Inlet gas temperature of 120 °C, Feed pump speed 60 rpm, Nozzle diameter 0.8 mm, Inlet gas flow rate 0.25 m3/min and Nozzle gas pressure of 2 bar) to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 3.
Example 4: Preparation of Verubecestat solid dispersion with Hydroxypropylcellulose (1:1 W/W): Verubecestat (500 mg), HPC (500 mg) and methanol (25 mL) were charged into round bottom flask and stirred for 10 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 4.
Example 5: Preparation of Verubecestat solid dispersion with Pvpk-25 (1:1 w/w):
Verubecestat (500 mg) and PVPK-25 (500 mg) and methanol (25 mL) were charged into round bottom flask and stirred for 10 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 5.
Example 6: Preparation of Verubecestat solid dispersion with Syliod: Amorphous Verubecestat (100 mg) obtained in example-2 and Syloid (100 mg) were ground into mortar-pestle for about 5 minutes to afford the title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat solid dispersion obtained in above example is in accordance with Figure 6.
Example 7: Preparation of Verubecestat solid dispersion with copovidone va 64 (1:1 w/w): Verubecestat (500 mg) and Copovidone VA 64 (500 mg) were charged into round bottom flask and stirred for 10 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure. A thin transparent film was obtained in the flask. The resultant compound was dissolved in methanol (20 mL) and the obtained solution was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat solid dispersion obtained in above example is in accordance with Figure 7.
Example 8: Preparation of Verubecestat solid dispersion with Syloid: Verubecestat amorphous solid dispersion (150 mg) obtained in example-5 and Syloid (75 mg) were ground into mortar-pestle for about 5 minutes to afford the title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat solid dispersion obtained in above example is in accordance with Figure 8.
Example 9: Preparation of Verubecestat solid dispersion with HPMC-AS (1:1 w/w)
Verubecestat (500 mg), HPMC-AS (500 mg) and methanol (25 mL) were charged into round bottom flask and stirred for 30 minutes at 25 °C. The resultant turbid solution was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure. Solid powder with thin transparent film was obtained in the flask. The resultant compound was dissolved in acetone (20 mL) and the obtained solution was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure. The obtained solid product was scrapped, collected and grinded in a mortar-pestle to fine powder to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 9.
Example 10: Preparation of Verubecestat solid dispersion with HPMC (1:1 w/w): Verubecestat (500 mg), HPMC (500 mg) and methanol (25 mL) were charged into round bottom flask and stirred for 30 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 10.
Example 11: Stability of Amorphous Form of Verubecestat
In a petty dish, Verubecestat amorphous form covered with aluminum foil with holes was kept in a chamber set at 30°C and 60% RH for 24 hours.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat obtained in above example is in accordance with Figure 11.
Example 12: Preparation of Verubecestat solid dispersion with Eudragit (1:1 w/w).
Verubecestat (500 mg), Eudragit-S 100 (500 mg), acetone (100 mL) and water (3 mL) charged in a round bottom flask and stirred for 10 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure. The obtained solid product was scrapped, collected and grinded in a mortar-pestle to fine powder to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Verubecestat solid dispersion obtained in above example is in accordance with Figure 12.
Example 13: Preparation of amorphous Verubecestat solid dispersion with hydroxypropylcellulose (HPC) and Syloid
Verubecestat (500 mg), HPC (500 mg), acetone (25 mL) and water (2.5 mL) were charged into round bottom flask and stirred for 10 minutes at 25 °C. The reaction mass was filtered to remove undissolved particles. Syloid (500 mg) was added to the filtrate and the resultant turbid solution was subjected to solvent evaporation by rotavapor at 50 °C under reduced pressure to afford title compound.
,CLAIMS:WE CLAIM:

1. A process for preparing an amorphous form of Verubecestat, comprising the steps of:
a) providing a solution of Verubecestat in a solvent; and
b) isolating amorphous Verubecestat.

2. The process according to claim 1, where in the solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, acetonitrile and propionitrile.

3. The process according to claim 1, wherein amorphous Verubecestat isolated using techniques selected from evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying and rotary vacuum paddle dryer.

4. A pharmaceutical composition comprising amorphous form of Verubecestat and one or more pharmaceutically acceptable excipients.

5. A method for preparing a solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of Verubecestat and one or more pharmaceutically acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous Verubecestat and one or more pharmaceutically acceptable carriers.