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

AMORPHOUS FORM AND SOLID DISPERSION OF OLAPARIB
INTRODUCTION
Aspects of the present application relate to amorphous form and amorphous solid dispersion form of olaparib and process for preparation thereof.
The drug compound having the adopted name olaparib, has a chemical name 4-[(3-{[4-(cyclopropylcarbonyl) piperazin-1-yl] carbonyl}-4-fluorophenyl) methyl] phthalazin-1(2H) one, and is represented by structure of formula I.

I
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
U.S. Patent No. 7,449,464 discloses process for preparation of olaparib and its isomers, salts, or solvates thereof.
U.S. Patent No. 8,247,416 discloses crystalline Form A of olaparib and process for its preparation.
U.S. Patent No. 8,183,369 discloses crystalline Form L of olaparib and process for its preparation.
U.S. Patent No. 8,475,842 discloses crystalline Form H of olaparib and process for its preparation. Further, it also discloses olaparib pharmaceutical composition in the form of a solid dispersion.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)].
There remains a need to provide stable amorphous form of olaparib and a simple, economic and industrially viable process for preparation of olaparib.

SUMMARY
In the first embodiment, the present application provides stable amorphous form of olaparib.
In the second embodiment, the present application provides stable amorphous form of olaparib characterized by powder X-ray diffraction (PXRD) pattern substantially as illustrated by Figure 1 or Figure 2 or Figure 3 or Figure 4.
In the third embodiment the present application provides a process for preparing stable amorphous form of olaparib, which comprises;
a) providing a solution of olaparib in a solvent;
b) removing solvent from a solution of olaparib obtained in step a); and
c) recovering amorphous form of olaparib.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of olaparib and one or more pharmaceutically acceptable excipients.
In the fifth embodiment, the present application provides a solid dispersion comprising amorphous form of olaparib and one or more pharmaceutically acceptable carriers.
In the sixth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous olaparib and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of olaparib and one or more pharmaceutically
acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous olaparib and one or
more pharmaceutically acceptable carriers.
In the seventh embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous olaparib and one or more pharmaceutically acceptable carriers comprising the steps of:
a) physically blending olaparib and one or more pharmaceutically
acceptable carriers; and
b) isolating solid dispersion comprising amorphous olaparib and one or more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of olaparib prepared according to Example 1.
Figure 2 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of olaparib prepared according to Example 2.
Figure 3 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of olaparib prepared according to Example 3.
Figure 4 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of olaparib prepared according to Example 4.
FIG. 5 is an illustration of powder X-ray diffraction (“PXRD”) pattern of olaparib present in amorphous solid dispersion according to example 16.
FIG. 6 is an illustration of powder X-ray diffraction (“PXRD”) pattern of olaparib present in amorphous solid dispersion according to example 17.
DETAILED DESCRIPTION
In the first embodiment, the present application provides stable amorphous form of olaparib.
In the second embodiment, the present application provides stable amorphous form of olaparib characterized by powder X-ray diffraction (PXRD) pattern substantially as illustrated by Figure 1 or Figure 2 or Figure 3 or Figure 4.
In the third embodiment the present application provides a process for preparing stable amorphous form of olaparib, which comprises;
a) providing a solution of olaparib in a solvent;
b) removing solvent from a solution of olaparib obtained in step a); and
c) recovering amorphous form of olaparib.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing olaparib that is obtained in the
course of its synthesis; or
ii) dissolving olaparib in a solvent.
Any physical form of olaparib may be utilized for providing the solution of olaparib in step a).
Suitable solvents which can be used for dissolving the olaparib include but are not limited to: water, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl 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; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 150°C, less than about 130°C, less than about 100°C, less than about 70°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures, as long as a clear solution of olaparib is obtained without affecting its quality.
After dissolution in step (a), the obtained solution may optionally be 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 removing solvent from a solution of olaparib obtained in step a);
Suitable techniques which can be used for the removal of solvent include but not limited to flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying including agitated thin-film drying, nutsche filter drying including agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Suitable temperatures that may be used in step (b) for removing solvent include less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
Step (c) involves recovering stable amorphous form of olaparib. The said recovery may be carried out using the processes known in the art.
The resulting compound in step (c) may be optionally further dried. 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 60°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 olaparib is not degraded in its quality. The drying may 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 the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of olaparib and one or more pharmaceutically acceptable excipients.
In an aspect, the said amorphous form of olaparib 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 olaparib 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 olaparib of the present invention can be made by any of the numerous methods that result in a solid dispersion comprising amorphous olaparib. 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.
Olaparib 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 olaparib. 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 22° C).
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 olaparib and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of olaparib and one or more pharmaceutically acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous olaparib and one or more pharmaceutically acceptable carriers.
Step (a) involves providing a mixture of olaparib and one or more pharmaceutically acceptable carriers in a solvent;
Any physical form of olaparib may be utilized for providing the mixture of olaparib 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 olaparib 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 olaparib 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 olaparib 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 olaparib and one or more pharmaceutically acceptable polymers or carriers may be carried out by methods as described in step (c) of third embodiment or any other technique known in the art.
The resulting solid dispersion comprising an amorphous form of olaparib 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 olaparib and one or more pharmaceutically acceptable carriers comprising the steps of:
a) physically blending of olaparib and one or more pharmaceutically acceptable carriers; and
b) isolating solid dispersion comprising amorphous olaparib and one or more pharmaceutically acceptable carriers.
Step (a) involves physically blending of olaparib and one or more pharmaceutically acceptable carriers.
Olaparib substantially in amorphous form may be utilized for physical blending of Olaparib 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 olaparib and one or more pharmaceutically acceptable polymers or carriers which can be carried out by any technique known in the art.
The amount of olaparib 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; or about 30% by weight of the solid dispersion. In some aspects, the weight ratio of olaparib to polymer or carrier is about 1:99 to about 99:1. In some aspects, the weight ratio of olaparib 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 olaparib 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 olaparib 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 olaparib 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 olaparib or solid dispersion comprising amorphous form of olaparib 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 olaparib or solid dispersion comprising amorphous form of olaparib, together with one or more pharmaceutically acceptable carriers. olaparib 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.
The resulting amorphous form is stable up on storage. For example, it does not change its description and XRD pattern when stored by packing in a white polyethene bag under ambient conditions for few months.
The resulting amorphous form may have a polymorphic purity by XRD of about 90.0 %, about 95.0 % or about 98.0 % or about 99.0 % or about 99.5 % or about 99.8 % or about 99.9 % or about 100.0 % by weight.
The resulting amorphous form may have a chemical purity by HPLC (High Performance Liquid Chromatography) of about 98.0 % or about 99.0 % or about 99.5 % or about 99.6 % or about 99.7 % or about 99.8 % or about 99.9 % or about 100.0 %.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
The word “Stable” as used herein in the relation to amorphous form refers to the amorphous form that is stable up on storage. For example, it does not change its description and XRD pattern when stored by packing in a white polyethene bag under ambient conditions for about a weeks-time.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.
An “aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has delocalized conjugated p system. Examples of an aromatic hydrocarbon solvent include benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include acetonitrile, propionitrile, butanenitrile and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
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 application. While particular aspects of the present application 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 application.
EXAMPLES
EXAMPLE 1: Preparation of amorphous form of olaparib. Olaparib (1 g) and methanol (60 mL) were charged into a round bottom flask at 25 °C and heated to 60 °C. Solvent was evaporated below 60 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 2: Preparation of amorphous form of olaparib. Olaparib (0.5 g) and dichloromethane (40 mL) were charged into a round bottom flask at 25 °C and heated to 40 °C. Solvent was evaporated below 40 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 3: Preparation of amorphous form of olaparib. Olaparib (0.5 g) and ethanol (60 mL) were charged into a round bottom flask at 25 °C and heated to 70 °C. Solvent was evaporated below 40 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 4: Preparation of amorphous form of olaparib. Olaparib (0.5 g) and acetonitrile (60 mL) were charged into a round bottom flask at 25 °C and heated to 70 °C. Solvent was evaporated below 40 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 5: Preparation of amorphous form of olaparib. Olaparib (1 g) and acetone (120 mL) were charged into a round bottom flask at 25 °C and heated to 57 °C. Solvent was evaporated below 60 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 6: Preparation of amorphous form of olaparib. Olaparib (30 g), methanol (225 mL) and acetonitrile (225 mL) were charged into a round bottom flask at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 70 °C under reduced pressure and the obtained wet compound dried at 50 °C under reduced pressure to afford the title compound.
EXAMPLE 7: Preparation of amorphous form of olaparib. Olaparib (26 g) and methanol (780 mL) were charged into a round bottom flask at 25 °C and heated to 50 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 70 °C under reduced pressure and the obtained wet compound dried at 50 °C under reduced pressure to afford the title compound.
EXAMPLE 8: Preparation of amorphous form of olaparib. Olaparib (25 g), methanol (800 mL) and water (200 mL) were charged into a round bottom flask at 25 °C and heated to 49 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 70 °C under reduced pressure and the obtained wet compound dried at 50 °C under reduced pressure to afford the title compound.
EXAMPLE 9: Preparation of amorphous form of olaparib. Olaparib (1 g) and isopropyl alcohol (100 mL) were charged into a round bottom flask at 25 °C and heated to 80 °C. Solvent was evaporated below 80 °C under reduced pressure in buchi rotavapor to afford the title compound.
EXAMPLE 10: Preparation of amorphous form of olaparib. Olaparib (50 g), methanol (1600 mL) and water (400 mL) were charged into round bottom flask and heated to 60 °C. The reaction mass was filtered to remove undissolved particles. The resultant solution was subjected to spray drying (Temp: 120°C, Aspirator: 70%, Pump: 20% (6mL/min), Out let Temp: 70°C and 5Kg N2 pressure) and the obtained wet compound dried at 50 °C under reduced pressure to afford title compound.
EXAMPLE 11: Preparation of amorphous olaparib solid dispersion with Plasdone. Olaparib (2 g), Plasdone-s-630 (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 12: Preparation of amorphous olaparib solid dispersion with Hypermellose Phthalate. Olaparib (2 g), Hypermellose Phthalate (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 13: Preparation of amorphous olaparib solid dispersion with Eudragit EPO. Olaparib (2 g), Eudragit EPO (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 14: Preparation of amorphous olaparib solid dispersion with Methocel. Olaparib (2 g), Methocel A15 (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 15: Preparation of amorphous olaparib solid dispersion with Syloid. Olaparib (2 g), Syloid (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 16: Preparation of amorphous olaparib solid dispersion with Polyvinylpyrrolidone (PVP). Olaparib (2 g), PVPK-30 (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
EXAMPLE 17: Preparation of amorphous olaparib solid dispersion with HPMC. Olaparib (2 g), HPMC (1 g) and methanol (120 mL) were charged into round bottom flask and stirred for 5 minutes at 25 °C. Acetone (40 mL) was slowly added at 25 °C and heated to 46 °C. The reaction mass was filtered to remove undissolved particles. The resultant filtrate was subjected to solvent evaporation by rotavapor at 60 °C under reduced pressure to afford title compound.
,CLAIMS:We Claim

1. A process for preparing stable amorphous form of olaparib, which comprises;
(a) providing a solution of olaparib in a solvent;
(b) removing solvent from a solution of olaparib obtained in step a); and
(c) recovering amorphous form of olaparib.

2. The process according to claim 1, wherein solvent is selected from water, alcohol, halogenated hydrocarbon, ketone, nitrile or mixtures thereof.

3. The process according to claim 2, wherein the solvent selected from methanol, isopropyl alcohol, dichloromethane, acetone, acetonitrile, water or mixtures thereof.

4. The process according to claim 1, wherein solvent from a solution obtained in step (a) is removed using flash evaporation, rotational drying, spray drying, thin-film drying including agitated thin-film drying or nutsche filter drying.

5. The process according to claim 4, wherein solvent from a solution obtained in step (a) is removed using rotational drying or spray drying.

6. A pharmaceutical composition comprising amorphous form of olaparib and one or more pharmaceutically acceptable excipients.

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