FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
PROCESS FOR THE PREPARATION OF CRYSTALLINE FORMS OF
LORNOXICAM
UNICHEM LABORATORIES TIMITED
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI -
400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR THE PREPARATION OF CRYSTALLINE FORMS OF
LORNOXICAM
TECHNICAL FIELD
The present invention describes the processes for preparation of crystalline forms of Lornoxicam.
BACKGROUND OF THE INVENTION
Lornoxicam is a non steroidal drug, chemically known as 6-chloro-4-hydroxy-2-methyl-3-
(2-pyridylcarbamoyl)2H-thieno[2,3-e]-l,2-thiazine-1,1-dioxide of formula (I), is a
thienothiazine derivative, useful as antf-inflammatory, analgesic and anti-rheumatic agent.

Formula (I)
U.S. patent, 4,180,662, (Pfister et al, 1979), discloses Lornoxicam and its process for preparation. According to '662 patent, Lornoxicam is synthesized in seven chemical steps by using 2, 5-dichlorothiophene as starting raw material. The process involves chlorosulphonation using chlorosulphonic acid, carboxylation using butylithium and carbondioxide in cryogenic conditions. The process for preparation of Lornoxicam in the last step, involves the condensation of 2-aminopyridine and 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2-H-thieno [2, 3-e]-l,

2-thiazine-l, 1-dioxide by using xylene. Lomoxicam is obtained in '662 patent by precipitation in xylene.
Indian patent application no., 221/MUM/2006 (Joshi, Narendra et al) covers solvates of Lomoxicam and describes the process for the preparation of Lornoxicam solvates.
In literature, there is not mentioned anything about different crystal forms of Lornoxicam. Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of drug substance to exist in two or more crystalline phases that have different arrangement and/ or conformations of the molecule in the crystal lattice. Polymorphism refers to occurrence of different crystalline form of the same drug substance. The different crystalline forms have different physical properties like melting point, x ray diffraction pattern, infra red spectra and solid state NMR spectrum.
The difference in physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, the polymorphs are distinct solids sharing the same molecular formulae, yet having different physical properties compared to other crystalline forms of the same compound. The different polymorphs, pseudopolymorphs or the amorphous form differ in their physical properties such as melting point, solubility etc and hence may affect pharmaceutical properties such as dissolution rate and bioavailability of the drug substance. Hence, the discovery of new or different polymorphs is essential. Since a new polymorph may aide in the manufacture of the drug product formulation which may prove to be more effective absorption in gastrointestinal tract.

Therefore, there is continued need for new polymorphic forms for commercial interest since formulation scientists may design a dosage form for a new target release profile.
OBJECT OF THE INVENTION
One object of the present invention is to provide the process for the preparation of crystalline form I of Lornoxicam which exhibits a characteristic peaks as given in Table 1.
Another object of the present invention is to provide the process for the preparation of crystalline form II of Lornoxicam which exhibits a characteristic peaks as given in Table 2.
SUMMARY OF THE INVENTION
The present invention relates to the process for the preparation of novel crystalline forms of Lornoxicam referred to as Form-I and Form-II, characterized by the infrared spectra (IR Spectra) and X-ray powder diffraction patterns (XRPD).
In one aspect of the present invention, the crystalline Form-I of Lornoxicam is prepared comprising, the dissolution of Lornoxicam in a solvent to get a clear solution, cooling of the resultant mass to get the precipitated mass and heating in an organic solvent, cooling followed by filtration of the cooled mass to obtain Form-I after drying.
In another aspect of the present invention, the crystalline Form-II of Lornoxicam is obtained by dissolution of Lornoxicam in a solvent to get a clear solution, cooling of the resulting mass to get the precipitated mass, filtration of the precipitated mass and with or without washing with an organic solvent to obtain Form-II after drying.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1 is a powder X-Ray diffraction pattern diagram (XRPD) of the crystalline Form-I of
Lornoxicam
Figure-2 is an infrared absorption spectrum (IR Spectrum) of Lornoxicam Form-I
Figure-3 is a powder X-Ray diffraction pattern diagram (XRPD) of the crystalline Form-II of
Lornoxicam
Figure-4 is an infrared absorption spectrum (IR Spectrum) of Lornoxicam Form-II
DETAILED DESCRIPTION OF INVENTION:
The present invention relates to the process for the preparation of crystalline Form-I and Form-II of Lornoxicam. Lornoxicam used for the synthesis of polymorph can be made by the process described in the US Patent No 4,180,662 or by other processes described in literature. The polymorphic forms of Lornoxicam are characterized by the X-Ray powder diffraction pattern (XRPD Pattern) and the Infra red spectra (IR Spectra) of the crystal form of the molecule.
X-Ray powder diffraction Diagram
The X-Ray powder diffraction profile of Form-I and Form-II were measured on PAnalytical XPERT PRO X powder diffractometer equipped with XCelerator Detector. The Cu Kdl X-Ray tube was operated at 45 KV and 40 Ma. The experiments were conducted over 29 range of 3°29 to 50°29 with step size of 0.017. The XRPD patterns of the figures have a vertical axis that is intensity unit, and a horizontal axis that is 29 angle in degrees.

The IR spectra of form-I and Form-II were recorded on Perkin Elmer spectrum one. The samples were prepared by mixing the sample in KBr and pressed into a disc and scanned from 450 to 4000 cm'1.
Crystalline Form-I of Lornoxicam is characterized by powder X-ray diffraction pattern diagram as represented in Figure-1 having following 20 peaks

20 peak Intensity %
8.8 4.40
13.08 15.67
13.50 12.26
13.93 27.85
14.35 7.28
15.14 15.63
17.08 3.95
17.65 7.40
18.29 10.72
18.93 21.87
20.55 4.28
21.56 34.31
22.62 5.28
22.99 28.42
24.71 100.0
25.43 25.54
25.59 17.87
26.30 12.59
26.98 13.04
27.18 4.15
27.47 6.02
27.62 8.26
28.05 28.18
30.52 24.35
31.00 11.43
32.34 10.63
34.32 6.22
37.43 9.42
39.66 9.71

' Crystalline Form-I of Lornoxicam can be further characterized by significant characteristic peaks
having 26 peaks at 13.08, 13.50, 14.35, 18.93, 21.56, 24.71, 25.43, 25.99, 28.05, 32.34, 39.66 ± 02° 28 values.
The crystalline Form-I of Lornoxicam is characterized by the characteristic peaks of stretching and bending as represented in Figure-2.
The crystalline Form-I of Lornoxicam is further characterized by having IR peaks at 3468, 3134, 3101, 3067, 2926, 2876, 1732, 1647, 1621, 1594, 1536, 1501,1452, 1424, 1381, 1326, 1236, 1186, 1173, 1145, 1122, 1083, 1035,982,950,905,886,869,828,791,764,736,716,688, 639, 628, 612, 576, 543, 521, 499, 488 cm"1 in FT-IR Spectra.
The crystalline Form-I of Lornoxicam can be further characterized by an IR spectrum having absorption bands at 3067, 1732, 1621, 1452, 1326, 1186, 1173, 791cm"1
Crystalline Form-I I of Lornoxicam is characterized by X-ray powder diffraction pattern diagram as represented in Figure-3 having following 28 values

20 peak Intensity %
9.4 6.43
12.17 38.21
14.03 48.22
15.08 100.0
15.42 5.51
15.97 9.23
16.95 4.48
18.45 22.73
19.36 21.62
20.18 5.44
20.89 23.16


Crystalline Form-Il of Lornoxicam can be further characterized by significant characteristic peaks
having 20 peaks at 9.4, 12.17, 19.36, 20.89, 21.12, 22.51, 23.13, 28.31 ± 0.2° 20
The crystalline Form-U of Lornoxicam is further characterized by an IR spectrum having
absorption bands of stretching and bending as represented in Figure-4.
The crystalline Form-H of Lornoxicam is characterized by having IR peaks at
3451,3090,2978,2931,2357,2065, 1846, 1643, 1597, 1557, 1538, 1500, 1427, 1387, 1354, 1336,
1317, 1294, 1240, 1202, 1157, 1145, 1125, 1098, 1080, 1040,999,933,868,847,827,
779, 766, 736, 725, 719, 689, 640, 626, 614, 583, 549, 523, 505, 490, 459, 429, 417, 404 cm"1.
The crystalline Form-I of Lornoxicam can be further characterized by an IR spectrum having absorption bands at 3090, 2065, 1846, 1557, 1354, 1336, 1294, 1157, 1098, 999, 933, 847, 779, 725 cm-1
In an aspect of the present invention, a process for the preparation of crystalline Form-I of the Lornoxicam comprises the dissolution of the Lornoxicam in suitable organic solvent and obtaining

the Lornoxicam by cooling and filtration of the precipitated product. Lornoxicam, thus obtained is taken in another solvent and heated, refluxed, cooled and filtered. After drying at 30 - 100°C preferably at 100°C of the solid, Form-I is obtained. The suitable organic which can be used for dissolution are xylene, monochlorobenzene and N, N- dimethyl formamide preferably N, N-dimethyl formamide. The solvents which can be used for heating the precipitated product are methanol, acetone, ethyl acetate and acetonitrile preferably methanol.
In another aspect of the present invention, a process for the preparation of crystalline Form-II of Lornoxicam comprises the dissolution of Lornoxicam in suitable organic solvent to get a clear solution and Lornoxicam is obtained by cooling and filtration of the precipitated product. The filtered product is washed with solvent and dried at 30 - 120°C preferably 60-120°C to obtain Lornoxicam Form-II. The suitable solvent which can be used for dissolution are xylene, monochlorobenzene and N, N- dimethyl formamide preferably N, N-dimethyl formamide. The solvents which can be used for washing the precipitated product are methanol or tetrahydrofuran, preferably methanol.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below,

EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Example-I: Preparation of Polymorph Form-I of Lornoxicam
In a clean and dry 4 neck RBF having overhead stirrer 150 gm of Lornoxicam and 6000 ml of N, N-Dimethylformamide was charged. The reaction mass was heated to 70-75 °C to obtain a clear solution. 2% activated charcoal was added and stirring was continued for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C and the filtrate was cooled gradually to 10-15 °C and stirred for 1 hour. It was filtered and washed with 300 ml of methanol immediately before the reaction cake dried. It was sucked dry and transferred to another R.B.F. having 750 ml of methanol and stirred at 55-60 °C for lhour. It was cooled to 15-20 °C, stirred for 1 hour, filtered and washed with 150 ml chilled methanol. It was unloaded and dried in vacuum oven at 100 °C to get Lornoxicam Form-I; 117.0 gm.
Example-II: Preparation of Polymorph Form-I of Lornoxicam
5.0 gm of Lornoxicam and 200 ml of N, N-Dimethylformamide was charged in R.B.F. The reaction mass was heated to 70-75 °C till a clear reaction mass was obtained. Charged 0.1 gm activated charcoal to it and continued stirring for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C. The filtrate was cooled gradually up to 10-15 °C, stirred for 1 hour, filtered and washed with 10 ml of ethyl acetate immediately before the cake dried. It was sucked dry and transferred to another R.B.F. Charged 25ml ethyl acetate into it and stirred at 70-75 °C for lhour. The solid obtained was cooled to 15-20 °C, stirred for 1 hour, then filtered and

washed with 5ml chilled ethyl acetate. It was unloaded and dried in vacuum oven at 100 °C to get Lornoxicam Form-I; 4.1 gm.
Example-Ill: Preparation of Polymorph Form-I of Lornoxicam
10 gm of Lornoxicam and 400 ml of N.N-Dimethylformamide was charged in RBF. The reaction mass was heated to 70-75 °C and a clear reaction mass was obtained. Charged 2% activated charcoal to it and continued stirring for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C. The filtrate was cooled gradually up to 10-15 °C and stirred for 1 hour. The solid was then filtered and washed with 20 ml chilled acetonitrile immediately before the reaction cake dried. It was sucked dry; 50ml acetonitrile was charged and stirred at 75-80 °C for lhour. The solid was cooled to 15-20 °C, stirred for 1 hour, then filtered and washed with 10 ml chilled acetonitrile. It was unloaded and dried in vacuum oven at 100 °C to get Lornoxicam Form-I; 8.3 gm.
Example-IV: Preparation of Polymorph Form-I of Lornoxicam
5.0 gm of Lornoxicam in R.B.F. and 200 ml of N, N-Dimethylformamide was charged in RBF. The reaction mass was heated to 70-75 °C and a clear reaction mass was obtained. Charged 2% activated charcoal to it and continued stirring for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C. The filtrate was cooled gradually up to 10-15 °C and stirred for 1 hour. The solid was then filtered and washed with 20 ml chilled acetone immediately before the reaction cake dried. It was sucked dry and transferred to another R.B.F. 25ml acetone was charged and stirred at 50-55 °C for lhour. The solid was cooled to 15-20 °C. stirred for 1 hour, then filtered and washed with 10 ml chilled acetone. It was unloaded and dried in vacuum oven at 100 °C to get Lornoxicam Form-I; 4.2 gm.

Example-V: Preparation of Polymorph Form-II of Lornoxicam
In a clean and dry 4 neck RBF having overhead stirrer, charged 20 gm of Lornoxicam and 800 ml of N3 N-Dimethylfbrmamide. The reaction mass was heared up to 70-75 °C and a clear reaction mass was obtained. Charged 2% activated charcoal to it and continued stirring for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C. The filtrate was cooled gradually to 10-15 °C and stirred for 1 hour. The solid was theP filtered and washed with 40ml chilled methanol. It was unloaded and dried in vacuum oven at i 20 °C to get Lornoxicam Form-II; 4.2 gm.
Example VI: Preparation of Polymorph-II of Lornoxicam
43 gm of kornoxicam and 40 volume of N,NDimethy formamide was, charged in. RBE. The. reaction mass was heated to 70-75 °C and a clear reaction mass was obtained. Charged 2% activated charcoal to it and continued stirring for 20 minutes. The reaction mass was filtered hot through filter aid at 70-75 °C. The filtrate was cooled gradually UP t0 10-15 °C and stirred for 1 hour. It was unloaded and dried in vacuum oven at 120 °C to get Lornoxicam form-II; 34 gm.

WE CLAIM
1. A process for preparing a crystalline Form-I of Lornoxicam comprising
a. Dissolving Lornoxicam in a organic solvent, cooling and filtration of resultant
reaction mass
b. Heating the product of a) in an organic solvent, refluxing and filtration of cooled
mass.
c. Drying of the product to get Lornoxicam Form-I.
2. The process of claim 1 a), wherein the organic solvent for dissolution are selected from xylene, monochlorobenzene and N, N- dimethyl formamide. preferably N, N-dimethyl formamide.
3. The process of claim 1 b), wherein the organic solvent used for heating the product is selected from methanol, ethyl acetate, acetonitrile and acetone, preferably methanol.
4. Crystalline Lornoxicam Form-I prepared in accordance with the process of claim 1.
i
5. Crystalline Lornoxicam Form-I according to claim-1 having a powder X-ray diffraction pattern substantially in accordance with Figure-1.
6. Crystalline Lornoxicam Form-I according to claim-5 having powder X-ray diffraction pattern characterized by the peaks at 8.80, 13.08, 13.50, 13.93, 14.35, 15.14, 17.08,

17.65, 18.29, 18.93, 20.55, 21.56, 22.62, 22.99, 24.71, 25.43, 25.59, 26.30, 26.98, 27.18, 27.47, 27.62, 28.05, 30.52, 31.00, 32.34, 34.32, 37.43, 39.66 ± 0.2° 29 values
7. Crystalline Lomoxicam Form-I according to claim-6 having characteristic XRPD peaks at 13.08, 13.50, 14.35, 18.93, 21.56, 24.71, 25.43, 25.99, 28.05, 32.34, 39.66 ± 0.2° 29.
8. Crystalline Lornoxicam Form-I, prepared according to claim-1, having IR spectrum substantially in accordance with Figure-2.
9. Crystalline Lornoxicam Form-I according to claim-8 having IR peaks at 3468, 3134, 3101, 3067, 2926, 2876, 1732, 1647, 1621, 1594, 1536, 1501,1452, 1424, 1381, 1326, 1236, 1186, 1173, 1145, 1122, 1083, 1035, 982, 950, 905, 886, 869, 828, 791, 764, 736, 716, 688, 639, 628, 612, 576, 543, 521, 499, 488 cm0.
10. Crystalline Lornoxicam form-I according to claim-9, characterized by an IR spectrum having absorption bands at 3067, 1732, 1621, 1452, 1326, 1186, 1173,791 cm"
11. A process for the preparation of crystalline Lornoxicam Form-II, comprising
a. Dissolving Lornoxicam in a organic solvent, cooling and filtration of resultant
reaction mass
b. With or without washing of the product of a) in organic solvent;
c. Drying of the product to get Lornoxicam Form-II.

12. The process of claim 11 a), wherein the suitable organic solvent used for dissolution are xylene, monochlorobenzene and N. N- dimethyl formamide preferably N, N-dimethyl formamide
13. The process of claim 11 b), wherein the organic solvent used for washing the product is selected from methanol or tetrahydrofuran, preferably methanol.
14. Crystalline Lornoxicam Form-II prepared in accordance with the process of claim 11.
15. Crystalline Lornoxicam Form-II according to claim- 11 having a powder X-ray diffraction pattern substantially in accordance with Figure-3.
16. Crystalline Lornoxicam Form-II according to claim-15 having X-ray powder diffraction pattern characterized by the peaks at 9.4, 12.17, 14.03, 15.08, 15.42, 15.97, 16.95, 18.45, 19.36, 20.18, 20.89, 21.12, 21.51, 22.51, 23.13, 24.06, 26.41, 26.98, 27.80, 28.31, 29.37, 29.83, 30.45, 31.10, 32.00, 35.54, 37.11, ±0.2° 29.
17. Crystalline Lornoxicam Form-II according to claim-16 having characteristic XRPD peaks at 9.4,12.17, 19.36, 20.89, 21.12, 22.51, 23.13, 28.31 ± 0.2° 28
18. Crystalline Lornoxicam Form-II according to claim-11 having IR spectrum substantially in accordance with Figure-4
19. Crystalline Lornoxicam Form-II, according to claim-18, characteristic IR peaks at 3451, 3090, 2978, 2931, 2357, 2065, 1846, 1643, 1597, 1557, 1538, 1500, 1427, 1387, 1354,

1336, 1317, 1294, 1240, 1202, 1157, 1145, 1125, 1098, 1080, 1040, 999, 933, 868, 847, 827, 779, 766, 736, 725, 719, 689, 640, 626, 614, 583, 549, 523, 505, 490, 459, 429, 417, 404 cm-1
20. Crystalline Lornoxicam Form-II, according to claim-19, characterized by an IR spectrum having absorption bands at 3090, 2065, 1846, 1557, 1354, 1336, 1294, 1157, 1098, 999, 933, 847, 779, 725 cm"1
21. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.