FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
“NOVEL CRYSTALLINE FORM OF APREPITANT AND PROCESS FOR THE
PREPARATION THEREOF"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to novel polymorphic Form III of 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methylmorpholine, which is also known as aprepitant and a process for its preparation, pharmaceutical compositions containing same and a method of treatment of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin for comprising administration of the novel polymorphic forms are provided.
The present invention also relates to a process for the preparation of aprepitant in amorphous form.
The polymorphic form of the present invention has advantages over the other known forms of aprepitant in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.
2. Description of the Related Art
Aprepitant (also known as 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methylmorpholine) is of the general Formula I:

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NKi) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine and corticosteroid receptors, which are the targets of some therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy,
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including high-dose cisplatin and is commercially sold under the trade name Emend®
See, e.g., Physician's Desk Reference, "Emend," 60th Edition, pp. 1944-1949 (2005).
Morphological forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the morphological form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next. Once a pharmaceutical compound is produces for use, it is important to recognize the morphological form delivered in each dosage form to assure that the production processes use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single morphological form or some known combination of morphological forms is present. In addition, certain morphological forms may exhibit enhanced thermodynamic stability and may be more suitable than other morphological forms for inclusion in pharmaceutical formulations. As used herein, a polymorphic form of a chemical compound is the same chemical entity, but in a different crystalline arrangement.
The difference in the physical properties of different morphological forms results from the orientation and intermolecular interactions of adjacent molecules are complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantages physical properties compared to other crystalline forms of the same compound or complex.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance of characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
US patent No. 6,096,742 discloses a polymorphic form of Aprepitant characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8 degrees. (2 theta) which is substantially free of a polymorphic form of the compound Aprepitant characterized by an X-ray powder diffraction pattern with key reflections at
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approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8.degrees. (2 theta)
US patent No. 6,583,142 discloses polymorphic form of Aprepitant characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8.degrees (2 theta) which is substantially free of a polymorphic form of the compound Aprepitant characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8.degree (2 theta).
There is a need of novel crystalline form of aprepitant and process for the preparation thereof.
BREIF DESCRIPTION OF THE DRAWING
FIG. 1 is an X-ray powder diffraction pattern of Form III of Aprepitant
FIG. 2 is Raman Spectra of Form III of Aprepitant
FIG. 3 is the DSC of Form III of Aprepitant
FIG. 4 is an X-ray powder diffraction pattern of the amorphous form of Aprepitant
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses novel polymorphic Form III of Aprepitant and process for the preparation thereof.
The polymorphic form of present invention herein designated as Form III have superior properties over other crystalline forms of the compound in that it is thermodynamically more stable suitable for inclusion in pharmaceutical formulations. The present invention further encompasses crystalline Form III of Aprepitant characterized by an X-ray powder diffraction pattern with key reflections at approximately: 6.9, 7.5, 9.6, 10.5, 13.5, 14.8, 17.4, 20.1, and 23.1 (2 theta).
The present invention provides process for the preparation of polymorphic Form III of Aprepitant which comprises:
a) providing a solution of Aprepitant in one or more solvents capable of dissolving
Aprepitant;
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b) substantially removing the solvent from the solution to provide the novel polymorphic Form III of Aprepitant.
The step of providing a solution of aprepitant may include dissolving any form of aprepitant in a suitable solvent or obtaining an existing solution from a previous processing step. Suitable solvents include, but not limited to, alcoholic solvents having from 1 to 12 carbon atoms, halogenated solvents, aromatic solvents and non-aromatic solvents and mixtures thereof. Preferably, mixture of halogenated solvents and alcohol. The dissolution can be carried out at a temperature ranging from about 20°C to about 65°C and preferably at 47°C . The clear solution optionally filtered to remove any extraneous matter present in the solution using any standard filtration techniques known in the art.
The starting material used in present invention may be any crystalline or other form of aprepitant, including various solvates and hydrates. With crystallization processes, the crystalline form of the starting material does not usually affect the final result since the original crystalline form is lost once a material goes into solution.
The present invention further provides the amorphous form of aprepitant.
The present invention further provides process for the preparation of amorphous form of aprepitant which comprises:
a) providing a solution of aprepitant in one or more solvents capable of dissolving aprepitant;
b) recovering aprepitant in the amorphous form from the solution thereof by the removal of solvent.
The step of providing a solution of aprepitant may include dissolving any form of aprepitant in a suitable solvent or obtaining an existing solution from a previous processing step. Suitable solvents include, but not limited to, one or more of lower alkanols, ethers, esters, ketones, polar aprotic solvents, water, or mixtures thereof. The lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms. The lower alkanol may include one or more of methanol, ethanol, n-propanol, and isopropanol.
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Removal of solvent can be achieved by one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, Recantation and centrifugation. Preferably Aprepitant in an amorphous form recovered from the solution by freeze-drying.
The amorphous form of novel polymorphic forms of aprepitant was stored under various solvent atmospheres and at different RH conditions.

Solvent Vapours Humidity Conditions (%)
MeOH 11 (LiCl.H20)
EtOH 33 (MgCl2.6H20)
IPA 62 (NH4NO3)
MEK 92 (KNO3)
Acetone
MeCN
All amorphous samples stored under an organic solvent environment were found to crystalline rapidly.
In another aspect of the present invention provides novel polymorphic Form III of Aprepitant, having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more.
In one embodiment, the novel polymorphic Form III of aprepitant disclosed herein for use in the preparation of pharmaceutically acceptable salts or pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 100 microns, still more preferably less than about 10 microns and most preferably less than about 5 microns. The particle sizes can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state novel polymorphic forms of aprepitant disclosed herein into any of the foregoing desired particle size range.
Yet another aspect of the present invention is directed to the pharmaceutical compositions containing novel polymorphic Form III of Aprepitant in as disclosed herein.
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Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, and rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The dosage forms may contain the novel polymorphic Form III of aprepitant disclosed herein as is or, alternatively, may contain the novel polymorphic Form III of aprepitant disclosed herein as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.
Capsule dosages will contain novel polymorphic Form III of Aprepitant and inactive ingredients such as sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide.
A composition for tableting or capsule filing can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
A tabletting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can be compressed subsequently into a tablet. As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules.
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Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
Actual dosage levels of novel polymorphic Form III of aprepitant disclosed herein may be varied to obtain an amount that is effective to obtain a desired therapeutic response for a particular composition and method of administration for treatment of a mammal. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the novel polymorph administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the
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invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
CHARACTERIZATION
1. Polarized Optical Microscopy
The crystal habit of the material was determined using an Olympus RX50 polarized optical microscope equipped with a high resolution JVC camera and image capture software. All images were recorded at 100X magnifications.
2. Raman Spectroscopy
All analyses were performed on a Nicolet Almega Dispersive Raman using a 780nm diode laser operating at 100% power. The Raman spectra were recorded from 98-3917 cm"1 with a typical resolution of 10-19 cm"1. All analyses were performed in duplicate.
3. Differential Scanning Calorimetry
Approximately 1-5 mg of sample was accurately weighed into an aluminum DSC pan with lid. The sample was then placed into a Pyris Diamond DSC (Perkin-Elmer) equipped with a liquid nitrogen cooling unit and allowed to equilibrate at 25°C until a stable heat flow response was seen. A dry helium purge gas at a flow rate of 20 ml/min was used to produce an inert atmosphere and prevent oxidation of the sample during heating. The sample was then scanned from -10°C - 300°C at a scan rate of 200°C/min and the resulting heat flow response (mW) measured against temperature. Prior to experimental analysis the instrument was temperature and heat-flow calibrated using indium as reference standard.
4. X-Ray Powder Diffraction (XRPD)
Approximately 30 mg of sample was gently compressed on the XRPD zero back ground single obliquely cut silica sample holder. The sample was then loaded into a Philips X-Pert MPD diffractometer and analysed using the following experimental conditions.
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Tube anode: Cu
Generator tension: 40 kV Tube current: 40 mA Wavelength alpha 1: 1.5406 A Wavelength alpha2: 1.5444 A Start angle [2 0]: 5
End angle [2 0]: 50
Time per step: 2.5 seconds Scan step size: 0.02
Example 1: Preparation of Form III of Aprepitant
50mg of Aprepitant was suspended in a mixture of 2ml of chloroform: ethanol (40:60) and the suspension stored at 47°C for 30 minutes with agitation. The suspension was filtered through a 0.45 um syringe filter and the resultant solution stored at -20°C for 14 days. After such time, the crystalline material was separated from the solvent and the sample dried under vacuum for 24 hours.
Example 2: Preparation of amorphous form of Aprepitant
250 mg of Aprepitant was dissolved in 50ml of t-butanol and the sample filtered through a 0.45 um PTFE syringe filter. The solution was added dropwise to liquid nitrogen and the sample freeze dried.
Dated this Tweleveth (12th) day of October, 2006

(Signed)
VISHAL AMRUTLAL SODHA
SENIOR MANAGER
GLENMARK PHARMACEUTICALS LIMITED
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