DESC:Field of invention
This invention provides novel polymorphs of apremilast and processes for preparation thereof.

Background of invention
Tumor necrosis factor alpha (TNFa) is a cytokine produced by monocytes and macrophages. It is found in synovial cells and macrophages in the tissues. It can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.
Apremilast is a new TNFa inhibitor and approved by the FDA under the name as Otezla®. Apremilast is proving useful for treating psoriatic arthritis. It is also used to treat moderate to severe plaque psoriasis in certain patients. The chemical structure of apremilast described in compound 1 as below.

Compound 1
Apremilast is a white to pale yellow powder in appearance. The drug substance is the S- enantiomer of N-[2-[1-(3-ethoxy-4-methoxy-phenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl]acetamide.
The US Patent 7,427,638 describes S - enantiomer of apremilast as a product and process for preparation thereof.
The US Patent 7,893,101 describes a Form B of apremilast and process for preparation thereof.
The US Patent 8,093,283 describes Form A and Form F of apremilast and processes for preparation thereof.
However, there is a need to develop a novel polymorph of apremilast, which will be stable and viable at plant scale. The present invention provides such a polymorph.
Summary of invention
This invention describes novel polymorphs of apremilast and processes for preparation thereof. Particularly, these polymorphs of apremilast are viable and stable at plant scale. Further, present invention provides pharmaceutical compositions of apremilast and one or more pharmaceutically acceptable excipients and a process for preparation thereof.
In one embodiment, the present invention provides a stable crystalline Form M of apremilast, characterized by at least one of the following properties i) a P-X Ray Diffraction pattern substantially in accordance with Figure 4 and or Figure 9; ii) a P-X Ray Diffraction pattern having peaks at 5.3, 8.4, 9.8, 13.98, 14.85, 16.64, 19.59, 21.46, 27.23 + 0.2° 2theta values; ii) a thermogravimetric analysis (TGA) substantially in accordance with Figure 10. (iii) a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 11.
In another embodiment, the present invention provides a process of preparing Form M of apremilast comprising a) contacting apremilast with at least one solvent; b) heating the mixture of step a); c) adding the mixture of step b) to water and cooling the mixture; and e) isolating the Form M of apremilast.
In another embodiment, the present invention provides a crystal of Form M of apremilast and process for preparation thereof.
Brief Description of the drawings
Figure 1 depicts P-X Ray diffraction pattern of Form L of apremilast.
Figure 2 depicts TG thermogram of Form L of apremilast.
Figure 3 depicts DSC thermogram of Form L of apremilast.
Figure 4 depicts P-X Ray diffraction pattern of Form M of apremilast.
Figure 5 depicts TG thermogram of Form M of apremilast.
Figure 6 depicts DSC thermogram of Form M of apremilast.
Figure 7 depicts P-X Ray diffraction pattern of Form N of apremilast.
Figure 8 depicts P-X Ray diffraction pattern of Form O of apremilast.
Figure 9 depicts P-X Ray diffraction pattern of Form M of apremilast prepared by acetone and water.
Figure 10 depicts TG thermogram of Form M of apremilast prepared by acetone and water.
Figure 11 depicts DSC thermogram of Form M of apremilast prepared by acetone and water.

Detailed description
The present invention provides novel polymorphs of apremilast.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Solvent medium and mode of crystallization play very important role in obtaining a new salt or a crystalline form over the other.
The present invention provides a novel polymorphs of Apremilast, which are stable throughout its shelf life and is clinically bioequivalent under FDA standards for this product.
Further, novel polymorphs of apremilast said in this invention are more stable, cost-effective, and viable at plant scale.
The discovery of novel solid forms, including amorphous forms and crystal forms, of pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Novel polymorphs of apremilast have now been discovered by the inventors of the present invention.
The present invention provides processes for preparation of novel polymorphs of apremilast. Wherein, the apremilast can be treated with a water miscible or water immiscible solvents selected from ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents at a particular temperature. The resulting solid is filtered, washed and dried at higher temperature. The solvent/s have treated can be selected from water, acetone, diethylketone, methylisobutylketone, N-methylpyrrolidone, ethyl acetate, n-hexane, n-heptane, toluene, xylene, cyclohexane, N,N’-Dimethylformamide, N,N’-Dimethylacetamide, chloroform, dichloromethane, methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol, diethyl ether, isopropyl ether, dioxane, tetrahydrofuran and acetonitrile in a single solvent or mixture of solvents said herein. The temperature used in the process of present invention may be -5 to 100°C.
The resultant solid analyzed by different techniques such as, thermogravimetric analysis, differential scanning calorimetry, moisture content, powder x-ray diffraction and other available analytical techniques well-known in the literature with the available procedures.
The present invention also provides process/es for preparation of polymorphs of apremilast known in the art. The polymorphs of apremilast include, but not limited to Form A, Form B, Form C, Form D, Form E, Form F, Form G and amorphous form and other polymorphs of apremilast known in the art.
The solvents used for processes for preparation of polymorphs of apremilast known in the art can be water miscible or water immiscible solvents selected from the group consisting of ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents at various temperature and cooled to room temperature/lower temperature. The resulting solid is filtered, washed and dried at higher temperature. The solvent/s have treated can be selected from the group consisting of water, acetone, diethylketone, methylisobutylketone, N-methylpyrrolidone, ethyl acetate, n-hexane, n-heptane, toluene, xylene, cyclohexane, N,N’-Dimethylformamide, N,N’-Dimethylacetamide, chloroform, dichloromethane, methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol, diethyl ether, isopropyl ether, dioxane, tetrahydrofuran and acetonitrile in a single solvent or mixture of solvents said herein.
The present invention provides new and stable polymorphs of apremilast. These polymorphs are stable and viable at any scale. More specifically, a novel polymorph apremilast, designated as Form M, is stable at longer durations as per ICH and USP guidelines.
The Form M of apremilast has good solubility in various medium such as water, hydrochloric acid, acetate Buffer, and phosphate Buffer at different pH.
The term “stability” with respect to a drug dosage form, refers to the chemical and physical integrity of the dosage unit and, when appropriate, the ability of the dosage unit to maintain protection against microbiological contamination. The shelf life of the dosage form is the time lapse from initial preparation to the specified expiration date. The monograph specifications of identity, strength, quality, and purity apply throughout the shelf life of the product.
This process of this novel polymorph of apremilast is feasible at all scale and avoids use of harmful chemicals and solvents. This process for preparation of Form M of apremilast is eco-friendly cost effective, green and industrial applicable one.
Molar equivalents of solvent/s employed for this invention vary with respect to apremilast equivalents.
In the present invention the content of water in apremilast ranges from about 3.0% to about 5.0%. The isolation of this crystalline solid polymorph is carried out by the conventional techniques known in the prior art such as filtration, concentration, and evaporation etc.
In the present invention, apremilast used as a starting material is obtained by the processes known in the art. Thus, apremilast prepared by US Patent 6,962,940 or US Patent 7,427,638 can be used as starting materials for the preparation of the novel polymorph/s of apremilast of the present invention.
According to another aspect of the present invention, a stable crystalline Form M of apremilast characterized by atleast one of the following properties is provided:
i) Powder X-ray diffraction pattern as described in Figure 4 and or Figure 9 having peaks at 5.3, 8.4, 9.8, 13.98, 14.85, 16.64, 19.59, 21.46, 27.23 + 0.2° 2theta values;
ii) Thermogravimetric analysis curve (TGA) shows in Figure 10;
iii) Differential scanning calorimetric (DSC) thermogram as depicted in Figure 11.
Analytical Methods
1) Powder X-ray Diffraction
Using a PANalytical X’Pert powder diffraction meter, the powder x-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV 40 mA) as the x-ray source. Data collection was done in 2theta continuous scan mode in the range of 3.5° to 40°.
2) Thermogravimetric analysis
Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 25 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.
3) Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminum pans and heated from 30 °C to 250 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.
4) Water content
Karl-Fischer auto titrator Metrohm Titrando was used for detection of water content as per methods known in the art.
The described novel polymorphs of apremilast may be used as a pharmaceutical composition with the particular dosage forms for treating the psoriasis or psoriasis related disorders.
Pharmaceutical formulations novel polymorphs of apremilast according to the present invention comprises of one or more pharmaceutically acceptable carriers or excipients such as binders, fillers, disintegrants, surfactants, lubricants or combinations thereof and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
Binders for use in the formulations of the present invention include binders commonly used in the formulation of pharmaceuticals. Examples of binders for use in accordance with the present invention include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and sodium carboxymethyl cellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, targacanth, guar, alginates and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like.
Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals. Examples of fillers or diluents for use in accordance with the present invention include but are not limited to sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cycludextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In certain preferred embodiments the filler or diluent is lactose, microcrystalline cellulose, or combination thereof. Several types of microcrystalline cellulose are suitable for use in the formulations described herein, for example, microcrystalline cellulose selected from the group consisting of AvicelTM types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the formulations described herein, for example, lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flo, directly compressible anhydrous lactose, and modified lactose monohydrate.
Disintegrants for use in the formulations of the present invention include disintegrants commonly used in the formulation of pharmaceuticals. Examples of disintegrants for use in accordance with the present invention include but are not limited to starches, clays, alginates and gums and crosslinked starches, celluloses and polymers, microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crosprovidone, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.
Surfactants for use in the formulations of the present invention include surfactants commonly used in the formulation of pharmaceuticals. Examples of surfactants for use in accordance with the present invention include but are not limited to ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or derivatives thereof, lecithins, phospholipids, combinations thereof, and the like.
Lubricants for use in the formulations of the present invention include lubricants commonly used in the formulation of pharmaceuticals. Examples of lubricants for use in accordance with the present invention include but are not limited to magnesium carbonate, magnesium laurylsulphate, calcium silicate, talc, fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like.
Other polymers commonly used as excipients include but are not limited to methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), methyl hydroxyethylcellulose (MHEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and the like. These polymers, either alone or in various combinations, may serve multiple purposes including but not limited to controlling release of the formulations of the present invention.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.

Example 1-Process for preparation of Form L of apremilast:
In a 2L round bottom flask, 10.3 gm of apremilast was added followed by 14 ml of N,N-dimethylformamide. The reaction temperature was raised to 90 °C and was stirred for 30 minutes. After stirring, the reaction mass was stirred for 30 minutes at 30 to 40 °C. The 500 ml distilled water was slowly added and stirred for 9 to 10 hours at room temperature. After stirring, the resultant solid was filtered and washed with 100 ml water. The solid was dried for 8 hours at 45°C. Yield: 9.6 gm., Moisture content: 0.651%. The P-X Ray diffraction pattern, TG thermogram and DSC thermogram had obtained identical with Fig. 1, 2, and 3 respectively.

Example 2-Process for preparation of Form M of apremilast:
In a 2L round bottom flask, 10 gm of apremilast was added followed by 10 ml of N,N-dimethylformamide. The reaction temperature was raised to 80 °C and was stirred for 10 minutes. After stirring, the reaction mass was cooled down to 25 to 30 °C and 500 ml water was added in dropwise fashion. The slurry was stirred overnight at 25 °C. The solid was filtered under vacuum and was dried under vacuum for 15 to 20 hours at 45 °C. Yield: 8.5 gm. Moisture content: 3 to 3.28%. The P-X Ray diffraction pattern, TG thermogram and DSC thermogram had obtained identical with Fig. 4, 5, and 6 respectively.

Example 3-Process for preparation of Form N of apremilast:
In a 500 ml round bottom flask, 4 gm of apremilast was added followed by 10 ml of chloroform and 155 ml of cyclohexane. The reaction mass stirred for 26 to 27 hours at 25 to 30 °C and solid was generated. The 0.2 gm of apremilast was seeded and solid material was filtered. The solid was dried under vacuum for 10 minutes at room temperature and then in vacuum for 14 to 15 hours at 45 °C. Yield: 3.1 gm. DSC data: 155.98 to 157.72 °C. The P-X Ray diffraction pattern had obtained identical with Fig. 7 respectively.

Example 4-Process for preparation of Form O of apremilast:
In a 100 ml round bottom flask, 3 gm of apremilast was added followed by 5 ml of N-methylpyrrolidone and was heated to 60 °C for 5 minutes. The solid material was filtered at room temperature. The filtrate was left for slow evaporation in a freeze for near about 24 hours at -5 to -10 °C. The precipitate was filtered and dried in a vacuum oven for 4 hours at 45 °C. The dried product was further dried for 7 hours at 45 °C. Yield: 1.49 gm. The P-X Ray diffraction pattern had obtained identical with Fig. 8 respectively.

Example 5-Process for preparation of Form M of apremilast:
In a 500 ml round bottom flask, 100 ml acetone was charged followed by addition of 25 gm of apremilast and was heated at 45 °C to 55 °C to form clear solution. This clear solution was filtered through filter paper and washed with acetone. In another flask, DM water was taken and was chilled to lower temperature. The above acetone solution was added to the chilled water slowly. After addition, reaction mass was maintained for 14 to 21 hours at lower temperature. The solid was precipitated and was filtered, washed with DM water and dried under vacuum at below 45 °C. Yield of the solid was 21.5 gm. The P-X Ray diffraction pattern, TG, and DSC thermogram had obtained identical with Figure 9, 10 and 11 respectively.

Example 6-Process for preparation of Form M of apremilast:
In a 500 ml round bottom flask, 100 ml aqueous acetone solution was charged followed by addition of 25 gm of apremilast and was heated at 45 °C to 55°C to form clear solution. This clear solution was filtered through filter paper and washed with acetone. In another flask, DM water was taken and was chilled to lower temperature. The above acetone solution was added to chilled water slowly. After addition, reaction mass was maintained for 14 to 18 hours at lower temperature. The solid was precipitated and was filtered and washed with 500 ml DM water and dried under vacuum at below 45 °C. Yield: 21 gm.

Example 7-Process for preparation of Form M of apremilast:
In a 500 ml round bottom flask, 100 ml acetone was charged followed by addition of 20 gm of apremilast and was heated at 45 °C to 50 °C to form clear solution. This clear solution was cooled. In another flask, water was cooled and above reaction solution was added. The slurry was formed. The resultant slurry was stirred for 7 to 10 hours at 10 °C to 15 °C. The solid was filetered, washed with water and was dried at 30 °C to 30°C for 10-15 hours. The product was yielded in 15 gm.
,CLAIMS:1. A stable crystalline Form M of apremilast.
2. The stable crystalline Form M of apremilast of claim 1, characterized by atleast one of the following properties i) a P-X Ray Diffraction pattern substantially in accordance with Figure 9; ii) a P-X Ray Diffraction pattern having peaks at 5.3, 8.4, 9.8, 13.98, 14.85, 16.64, 19.59, 21.46, 27.23 + 0.2° 2theta values; ii) a thermogravimetric analysis (TGA) substantially in accordance with Figure 10. (iii) a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 11.
3. A process of preparing Form M of apremilast comprising a) contacting apremilast with at least one solvent; b) heating the mixture of step a); c) adding water to the mixture of step b) ; and thereafter cooling the mixture; and e) isolating the Form M of apremilast.
4. The process of claim 3, wherein in step b), the mixture is heated to a temperature from about 30 °C to about 60 °C.
5. The process of claim 3, wherein in step c), the mixture is cooled to a temperature of about 0 °C to about 20 °C.
6. The process of claim 3, wherein the solvent is selected from the group consisting of acetone, tetrahydrofuran, and N,N-dimethylformamide; or mixture of at least two thereof.
7. A pharmaceutical composition comprising Form M of apremilast and one or more pharmaceutically acceptable excipients.
8. A process for preparing Form M of apremilast as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings and/or examples.