.
FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL POLYMORPH OF ARGATROBAN."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 1 17thFloor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705

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

NOVEL POLYMORPH OF ARGATROBAN

FIELD OF THE INVENTION:

The present invention relates to a novel polymorph of argatroban refer herein after as crystalline form II. The present invention further relate to processes of preparing crystalline form II of argatroban and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION:

The chemical name for argatroban is 1-[5-[(aminoiminomethyl) amino]-1-oxo-2-[[(1, 2, 3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl] amino] pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate and is known from U.S. Patent No. 4,258,192 and is represented by compound of structural formula I.

Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.

Argatroban has been approved in USA and is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia.

U.S. Patent No. 4,201,863 discloses amorphous form of argatroban.

PCT Publication no. 2009/124906 discloses argatroban monohydrate (refer herein after as crystalline form I) which is characterized by melting point of 176-182C; purity at least of 99%; absorption bands in I. R. spectrum (KBr) at 3416, 1272 and 1157 cm-1; differential scanning calorimetry (DSC) with an endothermic event at about 150C; thermogravimetric analysis (TGA) with a water loss of 3.68% in a temperature range from 85°C to 177°C; XRD pattern having peaks at 4.680, 9.230, 13.850, 15.980, 17.120, 18.040, 18.430, 18.950, 20.080, 20.560, 21.260, 21.590, 22.820, 23.740, 24.480, 26.140, 27.620, 28.980, 31.320, 33.440 and 37.210 degree two-theta. The crystalline form I of argatroban monohydrate is being prepared by separating argatroban monohydrate from concentrated reaction mass containing crude argatroban or from a purified argatroban by crystallization from a medium solvent consisting of methanol and water, heating the mass at the reflux temperature and gradual cooling from the reflux temperature to a temperature between 15-25C in a time comprised between 11-17 hours.

Chinese patent publication no. 101362746 discloses polymorph A and polymorph B of argatroban.

Chinese patent publication no. 101235031 discloses 21(S) argatroban hydrate I and 21(S) argatroban hydrate II.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance 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.

Accordingly there is provided a novel polymorph of Argatroban.

SUMMARY OF THE INVENTION:

A first aspect of the present invention is to provide novel crystalline form II of argatroban.

A second aspect of the present invention is to provide processes of preparing crystalline form II of argatroban.

A third aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form II of argatroban and pharmaceutically acceptable carrier.

A fourth aspect of the present invention is to provide a process of preparing crystalline form II of argatroban comprising the steps of:
a. providing a suspension of purified argatroban in water,
b. dissolving suspension of purified argatroban in a mixture of alcohol and halogenated aliphatic hydrocarbon solvent and
c. isolating crystalline form II of argatroban.

DETAIL DESCRIPTION OF THE INVENTION:

The purified argatroban may be formed by crystallizing crude argatroban in an alcoholic solvent.

The crystallization of crude argatroban in an alcoholic solvent may be carried out at a temperature in the range of 30C to 85C.

The crystallization of crude argatroban in an alcoholic solvent may be carried out more than one time.

The crude argatroban may be obtained by following the prior-art methods such as those described in U.S. Patent No. 4,258,192 and U.S. Patent No. 5,925,760 which are incorporated herein by reference only.

A suspension of argatroban in water may be formed by treating purified argatroban with 5 volumes / weight to 30 volumes / weight of water for a period of 15 minutes to 60 minutes at a temperature in the range of 0°C to 100C followed by decanting aqueous layer.

The suspension of argatroban may be dissolved in a mixture of alcohol and halogenated aliphatic hydrocarbon solvent at a temperature in the range of 0C to 80C to get a solution of argatroban.

The examples of alcoholic solvent may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof.

The examples of halogenated aliphatic hydrocarbon solvents may include dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

The crystalline form II of argatroban may be isolated by concentrating the solution of argatroban at a temperature in the range of 40 to 50C under reduced pressure.

A crystalline form II of argatroban may be dried at a temperature in the range of 40°C to 60°C for a period of 6 hours to 14 hours under reduced pressure.

A crystalline form II of argatroban may be characterized by differential scanning calorimetry ("DSC") spectra as depicted in Figure 1.

A crystalline form II of argatroban may be characterized by endotherms at 163.2C, 198.5C and 278.9C ± 5C.

The details of DSC endotherms are described below in table no. 1.

Peak Integration Start Onset
(C) Onset Temp
(C) Maximum
(C) Stop
(C) Area
(J/g)
138.27 153.69 153.69 163.22 172.54 72.21
194.28 196.18 196.18 198.54 209.33 17.37
248.36 263.96 263.96 278.99 311.29 191.9

Table No. 1

A pharmaceutical composition of argatroban comprising crystalline form II of argatroban and pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 depicts differential scanning calorimetry ("DSC") spectrum for crystalline form II of argatroban.
Differential scanning calorimetry ("DSC") spectrum was recorded on Waters instrument model no. Q20 V23.10 Build 79.

The Differential scanning calorimetry ("DSC") analysis was carried out using a perforated aluminium crucible at a heating rate of 10C / minute.

EXAMPLE:
In the following example, the preferred embodiment of the present invention is described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of crystalline form II of argatroban

Crude argatroban (10gm) was dissolved in ethanol (100ml) at 80-85C and then resulting solution was cooled to 25C and agitated for 1 hour at the same temperature. The resulting solids were filtered, washed with ethanol (10ml) and dried at 40C to get purified argatroban. The purified argatroban was added water (150ml) and resulting suspension was agitated for 15 minutes and then decanting an aqueous layer to get suspension of purified argatroban. The suspension of purified argatroban was dissolved in a mixture of methanol (10ml) and dichloromethane (60ml) followed by concentrating resulting solution at 45C under reduced pressure to get a solid residue, which was dried at 45C for 12 hours to get title compound.
Yield: 10.3gm
DSC: As depicted in Figure 1
Purity: 99.6% (By HPLC)

WE CLAIM:

1. A compound which is crystalline form II of argatroban having substantially the same differential scanning calorimetry ("DSC") spectra as depicted in Figure 1.

2. The compound of claim no. 1 having DSC endotherms at 163.2C, 198.5C and 278.9C ± 5C.

3. A process of preparing crystalline form II of argatroban comprising the steps of:
a. providing a suspension of purified argatroban in water,
b. dissolving suspension of purified argatroban in a mixture of alcohol and halogenated aliphatic hydrocarbon solvent and
c. isolating crystalline form II of argatroban.

4. The process according to claim no. 3, wherein purified argatroban is formed by crystallizing crude argatroban in an alcoholic solvent.

5. The process according to claim no. 4, wherein crystallization of crude argatroban in an alcoholic solvent is carried out at a temperature in the range of 30C to 85C.

6. The process according to claim no. 3, wherein suspension of argatroban in water is formed by treating purified argatroban with 5 volumes / weight to 30 volumes / weight of water for a period of 15 minutes to 60 minutes at a temperature in the range of 0°C to 100C followed by decanting aqueous layer.

7. The process according to claim no. 3, wherein suspension of argatroban is dissolved in a mixture of alcohol and halogenated aliphatic hydrocarbon solvent at a temperature in the range of 0C to 80C to get a solution of argatroban.

8. The process according to claim nos. 3, 4, 5 and 7, wherein examples of alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof and examples of halogenated aliphatic hydrocarbon solvents is selected from the group comprising of dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

9. The process according to claim no. 3, wherein crystalline form II of argatroban is isolated by concentrating the solution of argatroban at a temperature in the range of 40 to 50C under reduced pressure and dried at a temperature in the range of 40°C to 60°C for a period of 6 hours to 14 hours under reduced pressure.

10. A pharmaceutical composition of argatroban comprising crystalline form II of argatroban and pharmaceutically acceptable excipients.