DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL POLYMORPH OF DIMETHYL FUMARATE

We, GRANULES INDIA LIMITED,
a company incorporated under the companies act, 1956 having address at
2nd Floor; 3rd Block; My Home Hub; Madhapur; Hyderabad – 500081, India

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

FIELD OF INVENTION

The present invention relates to novel crystalline Form G of Dimethyl Fumarate having the following Formula I

Formula I

BACKGROUND OF THE INVENTION

Dimethyl Fumarate (DMF) is a novel oral immunomodulatory and neuroprotective drug which was approved by FDA in 2013 for relapsing forms of multiple sclerosis (MS) and by EMA for adult patients with relapsing-remitting MS (RRMS). The initial use of Dimethyl Fumarate (DMF) was for the treatment of psoriasis along with other Fumaric acid esters (FAE), where its long-term use was safe and efficacious. It was found that the anti-inflammatory actions of DMF contributed to its efficacy in psoriasis.

DMF is an ester of fumaric acid, which is rapidly hydrolysed to monomethyl fumarate (MMF). The exact mechanism of action of DMF is not fully known.

MS is an inflammatory demyelinating disease of axons in central nervous system. Although the cause of MS is unknown, accumulating evidence suggests that it is an autoimmune disorder mediated by auto reactive myelinspecific CD4+T cells.4 DMF is one of the drugs for MS given by oral route. There are other approved drugs such as teriflunomide and Fingolimod, which can also be given by oral route for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical exacerbations and delay the accumulation of physical disability.

Fumaric acid is an intermediate in the citric acid cycle that is hydrated by the enzyme fumarase to maleic acid. The use of fumaric acid for the treatment of psoriasis was introduced in 1959. Fumaric acid has also been shown to impede the growth of Ehrlich solid tumor cells in mice. Kuroda, K., et al., Cancer Res. 36:1900-1903 (1976).

Previously known salts and derivatives of fumaric acid were not resorbed, or only insufficiently resorbed, due to their relatively strong polar hydrophilic character, during their short residence time on lipophilic organ boundary layers. For this reason, high doses have been used, which resulted in side effects including headaches, eructation, dizziness, nausea, vomiting, abdominal and intestinal cramps, diarrhea, and flushing. High doses of fumaric acid, its salts, and derivatives such as dihydroxy fumaric acid, fumaramide, and fumaronitrile had such an unacceptable rate of side effects and high toxicity that it was necessary to refrain from such therapy. See P. Holland, et al., Brit. J. Dermatol. 85:259-263 (1971).

In the 1980's, more standardized oral preparations of fumaric acid esters were developed, containing Dimethyl Fumarate and monoethyl fumarate as the main components. After oral uptake, Dimethyl Fumarate is rapidly hydrolyzed to methyl hydrogen fumarate. The biological half-life of methyl hydrogen fumarate is 36 hours with 30% being bound by serum proteins. Schilling,S., et al., Clin. Exp. Immunol. 145:101-107 (2006).

US 4,851,439 discloses fumaric acid derivatives in the form of pro-drugs for the treatment of psoriasis.

US 4,959,389 discloses pharmaceutical compositions including at least one salt of fumaric acid monoalkyl ester along with dialkyl fumarate which includes Dimethyl Fumarate for the treatment of psoriasis and psoriatic arthritis.

US 5,451,667 discloses derivatives of fumaric acid of the formula:

wherein R1 is a hydrogen atom, a C1-8 alkyl group, or a metallic cation such as, for example, Na, Ca, or Zn and R2 is a saturated or unsaturated aliphatic C6-24 alkyl group, psoralen-9-yl, retinyl, a-tocopheryl, calciferyl, corticosteroid-21-yl, or monosaccharid-?-yl, for the treatment of cryptogenically-caused diseases.

US 6,277,882 discloses the use of alkyl hydrogen fumarates for preparing compositions for treating psoriasis, psoriatic arthritis, neurodermatitis, and enteritis regionalis Crohn.
US 6,355,676 discloses the use of salts of fumaric acid monoalkyl esters optionally in admixture with a dialkyl fumarate for the treatment of psoriatic arthritis, neurodermatitis, psoriasis, and enteritis regionalis.

US 6,359,003 discloses the use of fumaric acid monoalkyl esters for transplantation medicine.

US 6,858,750 discloses the use of pharmaceutical compositions of fumaric acid derivatives for the treatment of mitochondrial diseases.

US 7,320,999 discloses the use of dialkyl fumarates for the therapy of autoimmune diseases.

The single-crystal structure of dimethyl fumarate is disclosed in Kooijman, H., et al., Acta Crystallographica E60:o917-o918 (2004).

US 2014/0200363 A1 discloses another polymorph namely Form I characterized by peaks in X-ray powder diffraction in degrees 2? at 10.96° and 22.01°. The Form I can be further characterized by peaks in X-ray powder diffraction at 2? of 10.96°, 22.01°, 24.07°, 24.11, 24.17, and 27.39.

WO 2014/203231 claims crystalline Dimethyl-(E)-Butenedioate characterized by X-ray powder diffraction pattern- having at least five peaks selected from the XRPD peak set of 2? 9.82, 10.88, 17.44, 19.81, 23.71 , 23.97, 26.17, 33.26 and 41.26 ± 0.2?.

CN 10409847 also discloses a Dimethyl Fumarate polymorph, a preparation method thereof and a pharmaceutical composition. This patent discloses a stable, high-purity dimethyl fumarate polymorphs, characterized by PXRD values expressed in degrees represented by 2? ± 0.1, and 27.3, 10.9, 22.0, 24.0.

OBJECTIVES OF THE INVENTION

The main object of the present invention is to provide novel crystalline Form G of Dimethyl Fumarate of Formula I.

Another objective of the present invention is to provide a simple and effective process for the preparation of crystalline form of Dimethyl Fumarate of Formula I on a commercial scale.

Yet another objective of the present invention is to provide novel Form G which is devoid of genotoxic impurities such as monomethyl sulfate, dimethyl sulfate, monoethyl sulfate, diethyl sulfate.

Still another objective of the present invention is to provide a process for the preparation of Form I from G using any conventional operations.

SUMMARY OF THE INVENTION

The present invention provides a novel crystalline Form G of Dimethyl Fumarate of Formula I as shown below :

Formula I

The novel crystalline Form G of Dimethyl Fumarate is characterised by a split in the peaks at the diffraction angles 2-theta values at 22.0.

The novel crystalline Form G of Dimethyl Fumarate is further characterised by the peaks at the diffraction angles 2-theta values at 21.94 and 22.17.

The novel crystalline Form G of the present invention shows X-ray diffraction peaks at the diffraction angles 2-theta values of about 11.07 ± 0.2, 11.116 ± 0.2, 16.760 ± 0.2, 17.550 ± 0.2, 17.583 ± 0.2, 20.14 ± 0.2, 21.292 ± 0.2, 21.949 ± 0.2, 22.170 ± 0.2, 24.085 ± 0.2, 25.976 ± 0.2, 26.292 ± 0.2, 26.672 ± 0.2, 27.129 ± 0.2, 27.486 ± 0.2, 28.963 ± 0.2, 33.190 ± 0.2, 33.431 ± 0.2, 33.849 ± 0.2 degrees.

Further, the novel crystalline form of Dimethyl Fumarate can be characterized by a small endotherm at 102.21ºC and a sharp exotherm 103.61ºC ± 2°C in the differential scanning calorimetry (DSC) as shown in Fig 2.

In another embodiment, the present invention also provides novel Form G which is devoid of genotoxic impurities such as monomethyl sulfate, dimethyl sulfate, monoethyl sulfate, diethyl sulfate.

In another embodiment, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the novel crystalline Form G Dimethyl Fumarate and a pharmaceutically acceptable carrier.

In another embodiment the present invention therefore relates to a process for the preparation of the Dimethyl fumarate form G comprising the step of:
i) providing a solution or suspension of Dimethyl fumarate in a ketone solvent or mixtures with other solvents,
ii) heating the above solution to reflux temperature and
iii) isolating the dimethyl fumarate Form G.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of novel Dimethyl Fumarate form G.
Figure 2 is a DSC thermogram of novel Dimethyl Fumarate form G.

DETAILED DESCIPTION OF THE INVENTION

In particular embodiments, the present invention provides a novel crystalline Form G of Dimethyl Fumarate having an X-ray powder diffraction pattern characterized by diffraction peaks as set forth in Table 1 :
Table 1
Index Angle Rel. Intensity 0%
1 11.077 81
2 11.116 88.7
3 16.760 1.2
4 17.550 6.5
5 17.583 6.4
6 20.14 1.0
7 21.292 3.8
8 21.949 100
9 22.170 93.3
10 24.085 59.1
11 25.976 1.4
12 26.292 14.8
13 26.672 2.9
14 27.129 17.6
15 27.486 35.1
16 28.963 1.0
17 33.190 3.6
18 33.431 2.3
19 33.849 5.0

The present invention provides a process for conversion of polymorphic Form G into other known polymorphs like Form I by any known methods like crystallization, micronization, pulverization etc.
Further, the novel crystalline form of dimethyl fumarate can be characterized by a small endotherm at 102.21ºC and a sharp exotherm 103.61ºC ± 2°C in the differential scanning calorimetry (DSC) as shown in Fig 2.

In another embodiment the present invention therefore relates to a process for the preparation of the Dimethyl fumarate form G comprising the step of:
i) providing a solution or suspension of Dimethyl fumarate in a ketone solvent or mixtures with other solvents,
ii) heating the above solution to reflux temperature and
iii) isolating the dimethyl fumarate Form G.

The ketone solvent as used herein refers to acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, cyclobutanone, 2,4-pentadione, 4,4-dimethyl-2-pentanone, 4-penten-2-one, 4-amino-3-isopropyl-2-hexanone, 5-hydroxy-2-cyclohexenone.

The solvent as used herein refers to organic solvent and water. Organic solvent is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, t-butanol; acetates such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate; nitriles such as acetonitrile, hydrocarbon solvents such as toluene, xylene, polar solvents as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methyl pyrrolidine; ethers such as methyl ethyl ether, diethyl ether, di-isopropyl ether, MTBE, pet ether, tetrahydrofuran, methyl tetrahydrofuran, halogenated solvents such as chloroform, dichloromethane, chlorobenzene.

Thus, in one aspect of the invention, there is provided a method for preparing a crystalline polymorph of Dimethyl fumarate of compound of formula herein designated as form G comprising dissolving dimethyl fumarate in acetone and the reaction mass is heated to reflux temperature for about 15 minutes. The reaction mixture is cooled to room temperature and filtered through hyflow. The obtained clear solution is again heated to reflux under acetone and cooled. The crystallized solid is filtered and washed with chilled acetone to produce Dimethyl Form G.

It is noted that the methods set forth herein for the preparation of the novel forms of Dimethyl Fumarate are exemplary in nature, and may be varied as known to a person of skill in the art. Thus, the crystalline form of the present invention can be prepared by a variety of methods, including for example, crystallization/precipitation or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization/precipitation from a supercritical fluid, sonication and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of anti-solvents (counter solvents) to the solvent mixture.

The novel crystalline form of Dimethyl Fumarate (Form G) of the present invention is different from the polymorphic forms reported in the prior art. The Dimethyl Fumarate Form G obtained by the process of the present invention is highly pure, which is greater than 99.9%.

Dimethyl Fumarate is a BCS class I product. Hence, hence the particle size or surface area does not have any impact on the solubility of the product. Form G obtained by the process of the present invention has bigger particle size wherein D0.90 less than 300 ?m.

Further, the novel crystalline Form G of the present invention showed good handling properties and chemical stability that are desirable for formulation.

The expression chemical stability includes, but is not limited to, thermostability and light stability.

In the context of the present invention, a polymorph is a particular crystal form of a chemical compound that can exist in more than one crystal form in the solid state. A crystal form of a compound contains the constituent molecules arranged in orderly repeating patterns extending in all three spatial dimensions (in contrast, an amorphous solid form has no long-range order in the position of molecules). Different polymorphs of a compound have different arrangements of atoms and or molecules in their crystal structure. When the compound is a biologically active compound, such as an insecticide, the difference in crystal structures can lead to different polymorphs having differing chemical, physical and biological properties. Properties which may be affected include crystal shape, density, hardness, colour, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. As such, a specific polymorph may have properties which make it more advantageous in a particular use relative to another polymorph of the same compound: in particular, the physical, chemical and biological properties listed above can have a significant effect on the development of production methods and formulations and the quality and efficacy of plant treatment agents, such as insecticides. It is noted that predicting whether the solid state of a compound may be present as more than one polymorph is not possible and nor is it possible to predict the properties of any of these crystal forms.

Any suitable route of administration may be employed for providing the patient with an effective dosage of the crystalline form of dimethyl fumarate of the present invention. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric-coated capsules and/or tablets, capsules and/or tablets.

Accordingly, there is further provided a pharmaceutical composition comprising novel crystalline Form G of Dimethyl Fumarate, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients.

The compositions of the invention include compositions suitable for peroral or parenteral administration. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.

In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of the crystalline form of Dimethyl Fumarate in any given case will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight, and response of the individual patient.

Transformation of one form to the other when subjected to physical operations and chemical operations is generally observed.

The Polymorph G of the present invention can be used in the preparation of Form I. The process involves reprecipitation of Form G using any crystallization techniques, solvent evaporation technique and /or any of the physical operations which can modify the particle size, such as pulverization, milling, micronization and thereof

The Form G of the present invention is preferably converted to Form I by simple micronization.

The Dimethyl Fumarate Form I obtained by the process of the present invention is highly pure, which is greater than 99.8%.

The Dimethyl Fumarate Form G and Form I obtained by the process of the present invention is devoid of genotoxic impurities such as monomethyl sulfate, dimethyl sulfate, monoethyl sulfate, diethyl sulfate.

Monomethyl fumarate is a conventional impurity in Dimethyl Fumarate. Monomethyl fumarate is less than 0.05 % in the Dimethyl Fumarate Form G and Form I obtained by the process of the present invention.

The following examples to Dimethyl Fumarate illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to limit the scope of the invention.

Example 1 : Preparation of Novel Dimethyl fumarate Form G
50.0 g of Dimethyl fumarate was dissolved in a first lot of 250 ml acetone and refluxed to obtain a clear solution which was filtered through a hyflow. The obtained filtrate was cooled to 35-40°C and followed by maintaining the reaction mass at -2 to 2°C for 1 hour. The solid obtained was filtered, washed with chilled acetone and dried in vacuum to give Dimethyl fumarate Form G.

Example 2 : Preparation of Dimethyl fumarate Form I
25.0 g of Dimethyl fumarate Form G was subjected to micronization. The product obtained was of high purity (greater than 99.9%) and smaller particle size. The XRD pattern of the product obtained matches with XRD pattern given for Form I. ,CLAIMS:We Claims:
1. A novel crystalline Form G of Dimethyl Fumarate characterized by a split in the peaks at
the diffraction angles 2-theta values at 22.0º.

2. Novel crystalline Form G of Dimethyl Fumarate as claimed in claim 1, characterised in
that the PXRD pattern comprises further peaks at 21.94º and 22.17º.

3. Novel crystalline Form G of Dimethyl Fumarate as claimed in claims 1 and 2, characterised in that the PXRD pattern comprises peaks at about 11.07, 11.116, 16.760, 17.550, 17.583, 20.14, 21.292, 21.949, 22.170, 24.085, 25.976, 26.292, 26.672, 27.129, 27.486, 28.963, 33.190, 33.431, 33.849º ± 0.2° 2?.

4. Novel crystalline Form G of Dimethyl Fumarate as claimed in any of the preceding claims is characterised by PXRD pattern as shown in Figure 1 and further characterized by a small endotherm at 102.21ºC and a sharp exotherm at 103.61ºC ± 2 °C in the differential scanning calorimetry (DSC) as shown in Fig 2.

5. Novel crystalline Form G of Dimethyl Fumarate as claimed in any of the preceding claims is devoid of genotoxic impurities such as monomethyl sulfate, dimethyl sulfate, monoethyl sulfate and diethyl sulfate.

6. Novel crystalline Form G of Dimethyl Fumarate as claimed in any of the preceding claims is highly pure, which is greater than 99.8% and it is preferably converted to Form I by simple micronization.

7. A process for the preparation of novel crystalline Form G of Dimethyl Fumarate comprising the step of: providing a solution or suspension of Dimethyl fumarate in a ketone solvent or mixtures with other solvents, heating the above solution to reflux temperature and isolating the Dimethyl Fumarate Form G.

8. The process as claimed in claim 7, wherein the ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, cyclobutanone, 2,4-pentadione, 4,4-dimethyl-2-pentanone, 4-penten-2-one, 4-amino-3-isopropyl-2-hexanone, 5-hydroxy-2-cyclohexenone, preferably acetone.
9. The process as claimed in claim 7, wherein the solvent is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, t-butanol; acetates such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate; nitriles such as acetonitrile, hydrocarbon solvents such as toluene, xylene, polar solvents as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methyl pyrrolidine; ethers such as methyl ethyl ether, diethyl ether, di-isopropyl ether, MTBE, pet ether, tetrahydrofuran, methyl tetrahydrofuran, halogenated solvents such as chloroform, dichloromethane, chlorobenzene and water.

10. A pharmaceutical composition comprising a therapeutically effective amount of the novel crystalline Form G Dimethyl Fumarate and a pharmaceutically acceptable carrier.

Date this Eighteenth (18th) day of May, 2016.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883