INTRODUCTION

Aspects of the present disclosure relate to polymorphic crystalline form of lacosamide, processes for the preparation thereof, and pharmaceutical compositions comprising the polymorphic crystalline form.

The drug compound having the adopted name "lacosamide" can be represented by structural formula (I), and is in a class of functionalized amino acid derivatives that are useful as anticonvulsants.

Lacosamide is a functionalized D-serine derivative the in R-configuration. A chemical name for lacosamide is (R)-2-acetamido-N-benzyl-3-methoxypropionamide, and it is the active ingredient in VIMPAT® (lacosamide) tablets, injection, and oral solution, for the treatment of partial-onset seizures.

U.S. Patent No. 5,654,301 broadly discloses lacosamide and related compounds, pharmaceutical compositions thereof, and their use as potential anticonvulsants.

U.S. Patent No. RE38551 specifically discloses lacosamide and related compounds in the R-configuration, pharmaceutical compositions thereof and a method of treating central nervous system disorders in an animal, comprising administering to said animal in need thereof an anticonvulsant effective amount of the said compounds. It also discloses three routes for preparing lacosamide.

The processes for preparing lacosamide have been described in a number of references, including: D. Choi et al., "Synthesis and Anticonvulsant Activities of N-Benzyl-2-acetamidopropionamide Derivatives, Journal of Medicinal Chemistry, 1996, 39(9), 1907-1916; (II) U.S. Patent No. 6,048,899; (III) S. Andurkaretal., "Synthesis and Anticonvulsant Activities of (R)-(0)-methylserine Derivatives," Tetrahedron Asymmetry, 1998, 9(21), 3841-3854; (IV) U.S. Patent Application Publication No. 2008/0027137 A1; (V) P. Morieux et al., "Synthesis and Anticonvulsant Activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted Propionamide Derivatives," Bioorganic Medicinal Chemistry, 2008, 16(19), 8968-8975; (VI) U.S. Patent Application Publication No. 2009/0143472 A1; (VII) Chinese Patent Application Publication No. 101591300 A; (VIII) Anonymous, "Novel Intermediate Compounds And Their Use In Preparation Of Lacosamide", IP.com Journal 2009, 9(4A), 35; and (IX) International Application Publication No. WO 2010/052011 A1.

The above documents do not contain any information about polymorphic forms of lacosamide.

According to information connected with the approval data by USFDA of the VIMPAT® products, four crystalline polymorphs and one amorphous form of lacosamide have been identified, but only crystalline polymorphs 1 and 2 are routinely formed in the regular synthesis of lacosamide, and only these forms are present in lacosamide production batches. Crystalline polymorphs 3 and 4, and the amorphous state, only form under unique conditions or are not stable, and are not present in lacosamide production batches. Polymorph 3 is a crystalline, metastable modification that appears only by crystallization from methylene chloride at room temperature. Polymorph 4 is stable only up to -120°C and converts to polymorph 1 above that temperature. The amorphous form is highly unstable under normal laboratory conditions and converts rapidly to a crystalline form.
There are no significant effects of polymorphism on dissolution or bioavailability of lacosamide, therefore it is not necessary to control the form. There is no characterization data, like powder X-ray diffraction (PXRD) patterns, differential scanning calorimetry (DSC) curves, thermogravimetric analysis (TGA) curves, or infrared (IR) absorption spectra available of the said polymorphic forms.

U.S. Patent Application Publication No. 2009/0298947 A1 discloses lacosamide crystalline polymorphic forms designated as Form I, Form II, Form III, an amorphous form, and pharmaceutical compositions thereof. It also discloses processes for the preparation of the forms. The forms have been characterized using PXRD patterns, DSC curves, TGA curves, and IR absorption spectra.

Dolberg et al, "Lacosamide (CAS RN = 175481-36-4) Diffraction Pattern", IP.com Journal 2009, 9(9B), 68 discloses a PXRD pattern, DSC curve, and TGA curve of a polymorphic form of lacosamide, crystallised from 2-propanol.

International Application Publication No. WO 2010/060624 A2 discloses lacosamide crystalline polymorphic forms designated as Form R, Form S, and Form T, and pharmaceutical compositions thereof. It also discloses processes for the preparation of the forms. The forms have been characterized by PXRD patterns.

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubility.

Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties.

Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

Therefore, there remains a need for additional polymorphic forms of lacosamide and for processes to prepare polymorphic forms in more environmentally-friendly, cost-effective, and industrially applicable manners.

SUMMARY

In an aspect, the disclosure provides a crystalline polymorphic form of lacosamide designated herein as "Form A." Lacosamide Form A can be characterized by a PXRD pattern having peaks located substantially as depicted in Fig. 1 or Fig. 3.

In an aspect, Form A of lacosamide has a PXRD pattern with peaks located at about 8.4, 9.6, 13.2, 14.3, 16.5, 17.8, 18.6, 19.9, 20.1, 23.2, 24.9 and 25.8 ± 0.2 degrees 2-theta. The PXRD pattern of Form A of lacosamide can also have further peaks located at about 16.8, 20.7 and 33.3 ± 0.2 degrees 2-theta.

In an aspect, the disclosure provides processes for preparing Form A of lacosamide, embodiments comprising:
(1) providing a solution of lacosamide in a solvent;
(2) optionally, filtering the solution remove any particles;
(3) maintaining the solution at low temperatures;
(4) optionally, combining the solution with an anti-solvent; and
(5) isolating the formed solid and drying to obtain Form A of lacosamide.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts a PXRD pattern of lacosamide obtained by the procedure of Example 1.
Fig. 2 depicts a DSC curve of lacosamide obtained by the procedure of Example 1.
Fig. 3 depicts a PXRD pattern of lacosamide obtained by the procedure of Example 2.
Fig. 4 depicts a DSC curve of lacosamide obtained by the procedure of Example 2.

DETAILED DESCRIPTION

In an aspect, this disclosure provides a crystalline polymorphic form of lacosamide designated herein as "Form A." Lacosamide Form A can be characterized by a PXRD pattern having peaks located substantially as depicted in Fig. 1 or Fig. 3.

In an aspect, Form A of lacosamide has a PXRD pattern with peaks located at about 8.4, 9.6, 13.2, 14.3, 16.5, 17.8, 18.6, 19.9, 20.1, 23.2, 24.9 and 25.8 ± 0.2 degrees 2-theta. The PXRD pattern of Form A of lacosamide can also have further peaks located at about 16.8, 20.7 and 33.3 ± 0.2 degrees 2-theta.

In an aspect, the disclosure provides lacosamide crystalline Form A, which is characterized by a DSC curve substantially as depicted in Fig. 2 or Fig. 4.

In an aspect, Form A of lacosamide has a DSC curve having endotherms at about 65-75°C and 125-135°C.

In an aspect, Form A of lacosamide can have a weight loss by TGA up to 4%.

In an aspect, Form A of lacosamide can have moisture content by Karl Fischer analysis up to 4%. Irrespective of the moisture content, the PXRD pattern of Form A of lacosamide remains the same.

In an aspect, Form A of lacosamide is a crystalline polymorphic form which can be anhydrous or it may contain water up to 4%.

In an aspect, the disclosure provides processes for preparing Form A of lacosamide, embodiments comprising:

(1) providing a solution of lacosamide in a solvent;
(2) optionally, filtering the solution to remove any particles;
(3) maintaining the solution at low temperatures;
(4) optionally, combining the solution with an anti-solvent; and
(5) isolating the formed solid and drying to obtain Form A of lacosamide.

In embodiments of step (1), lacosamide which is used as the starting material for the preparation of Form A of lacosamide can be prepared by any method known in the art and optionally, can be purified by any method known in the art to improve its chemical and optical purity.

In embodiments of step (1), lacosamide can be dissolved in any suitable inert solvent. Suitable inert solvents include any solvent that has no adverse effect on the reaction and can dissolve the starting material to a useful extent. Examples of such solvents include: C3 to C6 esters such as ethyl acetate; halogenated hydrocarbons such as dichloromethane; C3 to C7 ketones such as acetone; Cz to C6 nitriles such as acetonitrile; Ci to C6 alcohols such as methanol; aprotic polar solvents such as dimethylformamide; and their combinations in various proportions.

In embodiments of step (1), a solution of lacosamide can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent, or about 10°C to about 50°C, or about 35°C. Stirring may be used to reduce the time required for the dissolution process.

In embodiments of step (2), the solution of lacosamide may be filtered to make it a clear solution, free of any unwanted particles.

In embodiments of step (3), the solution of lacosamide obtained can be maintained at any suitable temperatures, such as about -30°C to about 30°C, or about 0 to about 15°C.

In embodiments of step (3), the solution of lacosamide obtained can be maintained for about 30 minutes to about 10 hours, or longer. In embodiments, the solution of lacosamide is maintained at about 0°C to 15°C for about 30 minutes to 1 hour.

In embodiments of step (4), the solution of lacosamide can be combined with any suitable anti-solvent. In a suitable anti-solvent, lacosamide has less solubility compared to the solubility of lacosamide in a solvent. An anti-solvent generally will have less polarity than the polarity of the solvent. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material to some extent. Examples of such anti-solvents include saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C8 hydrocarbons such as n-heptane, C6 to C12 substituted or non-substituted aromatic hydrocarbons such as xylene, and C2 to C6 ethers such as diethyl ether.

In embodiments of step (4), the mass comprising lacosamide can be maintained at any suitable temperatures, such as about -30°C to about 30°C, or about 0°C to about 15°C.

In embodiments of step (4), the mass comprising lacosamide can be maintained for about 30 minutes to about 10 hours, or longer. In embodiments, the mass comprising lacosamide is maintained at about 0°C to about 15°C for about 30 minutes to 1 hour.

In embodiments of step (5), lacosamide produced in step (3) or optional step (4) can be isolated using any techniques, such as decantation, filtration by gravity or suction, or centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with an anti-solvent to reduce the amount of entrained impurities.

In embodiments of step (5), lacosamide that is isolated can be dried at suitable temperatures, such as about 20-50°C, and suitable pressures for about 1-50 hours, or longer, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve a desired product purity. In specific embodiments, lacosamide is dried in an oven at 30-50°C for 4-15 hours, under vacuum.

In embodiments of step (5), prepared Form A of lacosamide can be chemically and optically pure lacosamide, having chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, and optical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).

Form A of lacosamide produced by a method of the present disclosure can be chirally pure lacosamide having an S-isomer content less than about 1%, or less than about 0.1%, as determined using chiral HPLC.

Form A of lacosamide produced by a method of the present disclosure can be chemically pure lacosamide having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, as determined by HPLC.

Form A of lacosamide produced by a method of present disclosure can be chemically pure lacosamide having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.

The X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (20) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present disclosure includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error no more than about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (26 ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (26) of 7.7° to 8.1°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary somewhat, th&the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the instrument or the settings (for example, whether a Ni filter is used).

Lacosamide is a BCS class I drug and particle sizes of lacosamide have no significant effect on dissolution of the product, as reported in the approval data of lacosamide from the U.S. Food and Drug Administration. Form A of lacosamide obtained according to the process of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling, etc., to produce a desired particle size distribution. Form A of lacosamide obtained according to certain processes of the present application can have a particle size distribution wherein: d(0.5) is less than about 100 urn, or less than about 50 urn, or less than about 20 um; and d(0.9) is less than about 150 urn, or less than about 100 um, or less than about 50 um. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.

An aspect of the present disclosure provides pharmaceutical compositions containing a therapeutically effective amount of Form A of lacosamide, together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions comprising Form A of lacosamide of the disclosure together with one or more pharmaceutically acceptable excipients 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 form 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 may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations 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 or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present disclosure include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, micro-crystalline cellulose, 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 starch, sodium starch glycolate, pregelatinized starches, crospovidones, 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 or 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 pharmaceutical acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colourants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Certain specific aspects and embodiments of the present disclosure 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 disclosure in any manner.

EXAMPLES

EXAMPLE 1: Preparation of lacosamide Form A.

Lacosamide (2.0 g) and dichloromethane (20 mL) are combined at 26°C and stirred at the same temperature to produce a clear solution. The solution is cooled to 10°C over 20 minutes, during which precipitation started. Diethyl ether (40 mL) is added at the same temperature and the mass is maintained at 8°C for 30 minutes. The solid is then filtered under vacuum. The solid is dried in a vacuum tray dryer at 30°C for 3 hours. Yield: 1 g. HPLC purity: 99.92%. TGA weight loss: 2.7%. Residual solvents: dichloromethane not detected; diethyl ether: 37 ppm. PXRD pattern is in accordance with Fig. 1 (peaks at about 8.4, 13.2, 16.5, 17.8, 19.9, 23.2, 24.9, and 25.8 degrees 2-theta). DSC curve is in accordance with Fig. 2 (endothermic peaks at about 69°C and 128°C).

The solid (lacosamide; 0.25 g) is further dried in a vacuum tray dryer at 50°C for 4 hours. TGA weight loss: 0.16%. Residual solvents: dichloromethane not detected; diethyl ether: not detected. PXRD pattern and DSC curve are the same as given above.

EXAMPLE 2: Preparation of lacosamide Form A.

Lacosamide (10.0 g) and dichloromethane (100 mL) are combined at 25°C and stirred at that temperature to produce a clear solution. The solution is filtered. The solution is cooled to 10°C over 20 minutes, during which precipitation started. Diethyl ether (200 mL) is added at the same temperature and the mass is maintained at 5°C for 30 minutes. The formed solid is filtered under vacuum and suction dried at the same temperature for 15 minutes. The solid is dried in a vacuum tray dryer at 26°C for 15 hours. PXRD pattern peaks are in accordance with Fig. 3 (peaks at about 8.4, 13.2, 16.6, 17.8, 19.9, 23.4, 25, and 26 degrees 2-theta). DSC curve is in accordance with Fig. 4 (endothermic peaks at about 72°C and 130°C).

EXAMPLE 3: Preparation of lacosamide Form A.

Lacosamide (5.0 g) and dichloromethane (100 mL) are combined at 26°C and stirred at that temperature to produce a clear solution. The solution is cooled to 5°C over 30 minutes and maintained at that temperature for 30 minutes. The formed solid is filtered under vacuum and suction dried at 26°C for 10 minutes. Yield: 1.42 g. PXRD pattern peaks are observed at about 8.5, 13.3, 16.7, 17.9, 20, 23.5, 25, and 26 degrees 2-theta.

We claim:

1. A process for preparing crystalline Form A of lacosamide, comprising:
(i) providing a solution of lacosamide in an organic solvent; (ii) optionally, filtering the solution remove any particles; (iii) maintaining the solution at low temperatures; (iv) optionally, combining the solution with an anti-solvent; and (v) isolating the crystalline Form A of Lacosamide.

2. The process according to claim 1, wherein an organic solvent is dichloromethane.

3. The process according to claim 1, wherein a solution of lacosamide is maintained at temperatures about 0°C to about 15°C.

4. The process according to claim 1, wherein an anti-solvent is diethyl ether, n-heptane, xylene or any mixtures thereof.

5. The process according to claims 1, wherein an anti-solvent is diethyl ether.

6. A process for preparing crystalline lacosamide Form A of any of claims 1-5, comprising:
(i) providing a solution of lacosamide in dichloromethane; (ii) optionally, filtering the solution remove any particles; (iii) maintaining the solution at low temperatures; (iv) optionally, combining the solution with an anti-solvent; and (v) isolating the crystalline Form A of Lacosamide.

7. The process according to claim 6, wherein an anti-solvent is diethyl ether, n-heptane, xylene or any mixtures thereof.

8. The process according to claim 6, wherein an anti-solvent is diethyl ether.

9. A crystalline lacosamide Form A, which has characteristic PXRD peaks at about 8.4, 9.6, 13.2, 14.3, 16.5, 17.8, 18.6, 19.9, 20.1, 23.2, 24.9 and 25.8 ± 0.2 degrees 2-theta obtained by the process of claim 1.

10. A pharmaceutical composition containing crystalline lacosamide Form A of claim
9 and one or more pharmaceutically acceptable excipients.