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 CRYSTALLINE FORM OF ARGATROBAN."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar SoJitaire, Plot No.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 CRYSTALLINE FORM OF ARGATROBAN
FIELD OF THE INVENTION:
The present invention relates to a novel crystalline form of argatroban refers herein after as crystalline form III. The present invention further relate to processes of preparing crystalline form III of argatroban and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
The chemical name for argatroban is l-[5-[(aminoiminomethyl) amino]-l-oxo-2-[[(l, 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 1) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of if 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
o
crystalline form I) which is characterized by melting point of 176-182 C; purity at least of 99%; absorption bands in 1. 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.
The prior art polymorphic forms have poor flow property and generate static current during milling. The present applicant of the patent has surprisingly found novel crystalline form of argatroban with good flow property and does not generate static current during milling.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide novel crystalline form III of argatroban.
A second aspect of the present invention is to provide processes of preparing crystalline form HI of argatroban.

A third aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form III of argatroban and pharmaceutically acceptable carrier.
A fourth aspect of the present invention is to provide a process of preparing crystalline form III of argatroban comprising the steps of:
a. providing a solution of argatroban in a mixture of alcohol and water at 50-100°C,
b. gradually cooling the solution of argatroban obtained in step-a up to 20-25°C,
c. isolating crystalline form III of argatroban
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form III of argatroban may be characterized by X-ray diffraction pattern having peaks at 4.5, 7.6, 9.0, 10.6, 10.9, 11.3, 12.2, 13.0,13.6, 14.9, 15.2, 15.8, 16.9 17.4, 18.1, 19.1, 19.9, 20.5, 21.9, 22.7, 23.5, 24.8, 26.2, 27.4, 28.0, ± 0.2 degrees two theta.
A crystalline form III of argatroban may be characterized by differential scanning calorimetry ("DSC") endotherms at 46.28°C and 190.17°C ± 5°C.
A crystalline form III of argatroban may be characterized by X-ray diffraction pattern as depicted in Figure 1.
A crystalline form III of argatroban may be characterized by differential scanning calorimetry ("DSC") spectra as depicted in Figure 2.
The argatroban used 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.
The solution of argatroban in an alcohol solvent may be formed by dissolving argatroban in an alcohol solvent at a temperature in the range of 50°C to 100°C.

The examples of an alcoholic solvent may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof,
The solution of argatroban in a mixture of alcohol and water may be formed by gradually adding water to an alcoholic solution of argatroban and stirred for 15-30 minutes to get clear solution. The resulting clear solution was filter and again heat to get clear solution of argatroban in a mixture of alcohol and water.
The crystalline form III of argatroban may be formed by gradually cooling argatroban solution in a mixture of alcohol solvent and water up to 20-25°C and stirred for 40 minutes to 6 hours.
The crystalline form 111 of argatroban may be isolated by steps of filtration, centrifugation, washing, drying or the combinations thereof.
The crystalline form HI of argatroban may be dried under reduced pressure at a temperature in the range of 40°C to 55°C for a period of 2 hours to 10 hours.
A pharmaceutical composition of argatroban comprising crystalline form III of argatroban and pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts a powder X-ray diffraction pattern for crystalline form III of argatroban.
Figure 2 depicts differential scanning calorimetry ("DSC") spectrum for crystalline form III of
argatroban.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;

Step size [°2-theta]: 0.0170°; Scan step time[s]: 51.04 seconds; Sample spin: 15 rpm; Sample holder: glass; Measurement Temperature [°C]: 25 Anode Material: Cu K-Alpha[A]: 1.54060
Differential scanning calorimetry ("DSC") spectrum was recorded on Waters instrument model no.Q20V23.10Build79.
The Differential scanning calorimetry ("DSC") analysis was carried out using a perforated aluminium crucible at a heating rate of 10°C / minute.
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
The advantages of crystalline form III of argatroban is as follows:
1. Free-flowing nature
2. Low static charge

EXAMPLE:
In the following example, the preferred embodiments of the present invention are 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 III of argatroban
Argatroban (lOgm) was dissolved in ethanol (100ml) at 90-95°C and the resulting solution was
added water (10ml) and stirred for 15-20 minutes. The resulting solution was filtered and filtrate
was again heat to get clear solution. The resulting clear solution was gradually cooled up to 20-
25°C and stirred for 2 hours at same temperature to get solid. The resulting solids were filtered,
washed with ethanol (5ml) and dried at 45-50°C for 8 hours to get title compound.
Yield: 9.8gm
Purity: 99.9% (By HPLC)
XRD: As depicted in Figure 1
DSC: As depicted in Figure 2

WE CLAIM:
1. A compound which is crystalline form 111 of argatroban having substantially the same X-ray diffraction pattern as depicted in Figure 1.
2. The compound of claim no. 1 is further characterized by X-ray diffraction pattern comprising peaks at 4.5, 7.6, 9.0, 10.6, 10.9, 11.3, 12.2, 13.0,13.6, 14.9, 15.2, 15.8, 16.9 17.4, 18.1, 19.1, 19.9, 20.5, 21.9, 22.7, 23.5, 24.8, 26.2, 27.4, 28.0, ± 0.2 degrees two theta.
3. The compound of claim no. 1 is further characterized by differential scanning calorimetry ("DSC") endotherms at 46.28°C and 190.17°C ± 5°C.
4. The compound of claim no. 1 is further characterized differential scanning calorimetry ("DSC") spectra as depicted in Figure 2.
5. A process of preparing crystalline form III of argatroban comprising the steps of:
a. providing a solution of argatroban in a mixture of alcohol and water at 50-100°C,
b. gradually cooling the solution of argatroban obtained in step-a up to 20-25°C,
c. isolating crystalline form III of argatroban
6. The process according to claim no. 5, wherein a solution of argatroban in a mixture of alcohol and water is formed by dissolving argatroban in an alcohol solvent at a temperature in the range of 50°C to 100°C followed by gradually adding water to an alcoholic solution of argatroban and stirred for 15-30 minutes to get clear solution. The resulting clear solution is filter and again heat to get clear solution of argatroban in a mixture of alcohol and water.
7. The process according to claim nos. 5 and 6, wherein examples of an alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof.

8. The process according to claim no. 5, wherein a crystalline form III of argatroban is formed by gradually cooling argatroban solution in a mixture of alcohol solvent and water up to 20-25°C and stirred for 40 minutes to 6 hours.
9. The process according to claim no. 5, wherein a crystalline form III of argatroban is isolated by steps of filtration, centrifugation, washing and drying at a temperature in the range of 40°C to 55°C for a period of 2 hours to 10 hours.
10. A pharmaceutical composition of argatroban comprising crystalline form III of argatroban and pharmaceutical ly acceptable excipients.