FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR PURIFICATION OF LORNOXICAM"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b) NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
3.EAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

FILED OF INVENTION:
The present invention relates to a process for purification of Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without the use of toxic and hazardous materials.

Lornoxicam BACKGROUND AND PRIOR ART:
Lornoxicam (chlortenoxicam) is a non-steroidal anti-inflammatory drug (NSAID) of oxicam class with analgesic, anti-inflammatory and antipyretic properties. It is also effective in relieving symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute sciatica and low back pain. Lornoxicam binds closely to plasma proteins, and inhibits prostaglandin biosynthesis by blocking the enzyme cyclooxygenase (COX). It inhibits both isoforms of COX in the same concentration range, i.e.COX-1 inhibition : COX-2 inhibition = 1. Lonoxicam's chemical name is 6-chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno-[2,3-e]-1,2-thiazine-3 -carboxymide-1,1 -dioxide, and its molecular structure is represented as follows.


Lornoxicam is available in oral and parenteral formulations. Lornoxicam readily penetrates into the synovial fluid, and is absorbed rapidly and almost completely from the gastro-intestinal tract. Its bioavailability is 90-100%. It is distinguished from established oxicams by a relatively short elimination half-life (3 to 5 hours). NSAID drugs of the oxicam class include Lornoxicam, Tenoxicam, Meloxicam, Piroxicam and Droxicam.
US 4180662 discloses preparation of Lornoxicam by refiuxing methyl-6-chloro-4-hydroxy-2-inethy I-2H -thieno[2,3-e][ 1,2]-thiazine-3-carbaldehyde-1, \ -dioxide and 2-aminopyridine in absolute xylene for 16 hrs, and subsequently recrystallizing crude Lornoxicam with dioxane.
Chinese Patent application 101619070 discloses method of preparing tenoxicam with high yield and purity by mixing methyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylate 1,1-dioxide with 2-aminopyridine in alkylbenzene, and adding activated alkali metal carbonate, wherein molar ratio of the thienothiazine compound, 2-aminopyridine and alkali meta! carbonate is 1 : 1 to 1-4 : 1 to 3, the resulting crude tenoxicam was dissolved in mixture of methanol/ethanol, water and inorganic alkali and then treated with activated carbon. The resulting solution was filtered and adjusted to pH 2.5-3.5 to get pure tenoxicam.
US 6967248 discloses preparation of crystalline form I of Meloxicam by heating a mixture of crude meloxicam, ethanohwater (1:1) and NaOH scales to 50°C ; slowly adding acetic acid and cooling to 0-5°C; filtering and washing the resulting precipitate with water to obtain Meloxicam with 94% yield. The patent also discloses preparation of crude meloxicam by reacting isopropyl-4-hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate-1,1-dioxide (or other derivatives of carboxylic acid) and 2-amino-5-methyfthiazole in xylene at reflux with partial distillation.
None of the aforementioned prior arts discloses a process for purification of Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without the use of toxic and hazardous materials. Hence, there is a need to develop an industrially viable method for purification of Lornoxicam.

OBJECT OF THE INVENTION:
The main objective of the present invention is to provide a process for purifying Lornoxicam with increased efficiency, in a simple and easy manner, without using hazardous and toxic solvents such as dioxane.
Yet another objective of the present invention is to provide industrially viable and cost effective process for purification of Lornoxicam.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention provides a process for purification of Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without the use of toxic and hazardous materials.
Increased purity of Lornoxicam was obtained by performing acid /base purification of crude Lornoxicam specifically at 50-55°C instead of crystallization from hazardous and toxic solvents such as dioxane. The process produces highly-pure Lornoxicam in simple and easy manner without the use of toxic and hazardous materials.

Lornoxicam
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

It is known in the prior art that crude Lornoxicam is purified by crystallization using hazardous solvent like dioxane in order to achieve pure Lornoxicam. It is therefore necessary to involve a simple, cost effective and industrially viable purification process which is more efficient and environment friendly.
Accordingly, the present invention provides a process for purification of Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without the use of toxic and hazardous materials.
The crude Lornoxicam in the present invention was prepared from methyl-6-chloro-4-hydroxy-2-methyl-2H-thiev\o[2,3-el[l .2]4hiazine-3-caryate-1, \ -dioxide and 2-aminopyridine using reduced volume of o-xylene.
In a preferred embodiment of the present invention the crude Lornoxicam was added to the solvent mixture of water and alcohol under stirring. Subsequently alkali metal hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr and filtered through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C till the reaction mass reached pH of 2-3, and then stirred for around lhr. The reaction mass was cooled to room temperature, filtered and then washed with 1:1 mixture of alcohol and water.
The solvent mixture comprises water and alcohol in the ratio of 1:1, wherein alcohol is selected from methanol, ethanol or isopropyl alcohol.
Alkali metal hydroxide used in the present invention is selected from but not limited to sodium hydroxide or potassium hydroxide.
To illustrate the process of the invention, the detailed description is provided herein as depicted below in Scheme 1:


Scheme 1
The invention is further illustrated with the following examples and should not be construed to limit the scope of the present invention. The features of the present invention will become more apparent from the following description of the inventive concept and the description of the preferred embodiments.
EXAMPLES:
Preparation of Lornoxicam crude
Example I
To 1200ml o-xylene, 20gm Methyl-6-chloro-4-hydroxy-2-methyl-2//-thieno [2, 3-e] [1, 2] thiazine-3- carboxyate 1,1-dioxide and 6.44gm 2-aminopyridine was added. The reaction mass was stirred under nitrogen atmosphere. Temperature was raised to 140-145°C and maintained for 6hrs. The reaction mass was cooled to 30-35°C and nitrogen was removed. Reaction mass was further stirred for 3hrs- Filtered and washed twice with 50ml of o-xylene. 19.8gm of crude Lornoxicam was obtained.

Purification of Lornoxicam crude
Example 2
19.8gm of crude Lornoxicam was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3, and then stirred for around I hi*. The reaction mass was cooled to room temperature, filtered, and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 19.1 gm of pure Lornoxicam was obtained. (HPLC purity- 99.95%)
Example 3
!7.9gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C till the reaction mass reached pH of 2-3, and then stirred for around Ihr. The reaction mass was cooled to room temperature, filtered and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 17.2 gm of pure Lornoxicam was obtained. (HPLC purity- 99.9%)

clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, till the reaction mass reached pH of 2-3, and then stirred for around lhr. The reaction mass was cooled to 30-35°C, filtered and then washed with 1:1 mixture of isopropyl alcohol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.85 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 5
5 gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and ethanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3 and then stirred for around lhr. The reaction mass was cooled to 30-35°C and filtered, washed with 1:1 mixture of ethanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.8 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 6
19.4 gm of crude Lornoxicam (prepared as per example I) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 20% activated charcoal was further added. The reaction mass was stirred for around lhr at room temperature followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added till the reaction mass reached pH of 2-3 and then stirred for around 1 hr. The reaction mass was * filtered and washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 18.9 gm of pure Lornoxicam was obtained. (HPLC purity- 99.3%).

We claim,
\. A. process for purification of Lornoxicam comprises of the following steps
a. adding crude Lornoxicam to a solvent mixture of water and alcohol under
stirring followed by addition of alkali metal hydroxide and activated
charcoal;
b. heating the reaction mass to 50-55cC under stirring and followed by
filtering;
c. adding a mixture of hydrochloric acid and water to the filtrate at 50-55° C
till the reaction mass reaches pH of 2-3;
d. Cooling the reaction mass to room temperature, filtering and then washing
with a mixture of alcohol and water; and optionally
e. Drying purified Lornoxicam
2. The process for purification of Lornoxicam as claimed in claim 1 wherein the solvent mixture comprises water and alcohol in the ratio of 1:1
3. The process for purification of Lornoxicam as claimed in claim ] wherein the alcohol is methanol, ethanol or isopropyl alcohol.
4. The process for purification of Lornoxicam as claimed in claim 1 wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.
5. The process for purification of Lornoxicam as claimed in claim 1 wherein the mixture of hydrochloric acid and water is in the ratio of 1:1.