FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION

(See section 10 and rulel3)

1. TITLE OF THE INVENTION:
"PREPARATION OF HIGH PURITY LORNOXICAM"
2. APPLICANT
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Miimbai-400059, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of high purity Lornoxicam
[6-Chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-thieno[2,3-e]-l,2-thiazine-1,1-dioxide] of formula (I)

ana'it's potassium or sodium salt or the formula II
0 0

(II) (Where, R=K orNa)

BACKGROUND OF THE INVENTION
Lornoxicam is a new non-steroidal anti-inflammatory drug (NSAID) of the oxicam class
with analgesic, anti-inflammatory and antipyretic properties. It is available in oral and
parental formulation. It is distinguished from established oxicams by relatively short
elimination half time (3 to 5 hours), and therefore Lornoxicam may be better tolerated.
Like other NSAIDS it may be used in relieving symptoms of osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, acute sciatica and low back pain.
Process for the preparation of Lornoxicam has been disclosed in US patent No. 4180662 in which the esters, of 6-chloro-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-l,l-dioxide-3-carboxylic acid (III)

(Where Ri - Methyl, ethyl or isopropyl ester)
is reacted with 2-amino pyridine (hereafter,referred as 2AP) of the formula (IV) at high
temp.

(IV)
*
During the reaction, byproducts with similar chemical structure to Lornoxicam and some

tars are also formed. The process further describes purification by crystallization from
dioxane.
The above mentioned process has the disadvantage of costly and toxic solvent being used
for purification; moreover the solvents are required in high volumes with poor recovery
of the product.


It was found that the above mentioned process led to crude lornoxicam with by products usually in the range of 0.25 to 0.5% by HPLC. Moreover application of recrystallisation from various solvents including dioxane did not reduce the impurity to level of 0.1 %or less. Thus, there were lacunae in the literature to provide Lornoxicam with impurity levels of 0.1 % or less.
OBJECT OF THE INVENTION
The main object of the present: invention is to develop a simple process for the preparation of high purity Lornoxicam with individual and total impurity level below 0.1%, which is suitable for pharmaceutical application.
Another object of the present invention is to provide a process using suitable salt forming inorganic bases and aqueous medium to achieve purification of Lomoxicam.
SUMMARY OF INVENTION
The present invention discloses a simple process for preparation of high purity Lornoxicam and salts thereof, with total impurity level below 0.1% which is suitable for pharmaceutical application. The process for preparation of Lornoxicam comprises of steps which are summarized as follows:
a) Crude Lornoxicam containing impurity 0.2 - 0.5% is treated with inorganic base (either sodium or potassium hydroxide) to form Lornoxicam sodium or potassium salt.
b) The crystallization of Lornoxicam sodium / potassium salt in water.
c) Neutralization of Lornoxicam salt with suitable acids in water or aqueous solvents.
d) Washing the pure Lornoxicam with suitable solvent.

DETAILED DESCRIPTION OF INVENTION
The present invention provides a process for preparation of high purity Lomoxicam which comprises the following steps:
i) reacting 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno-
[2,3-e]-l,2-thiazine-I,l-dioxide [hereafter referred to as CHMTT] with 2
Aminopyridine in Xylene at 140° - 145°C for about 6-8 hrs. The crude
Lomoxicam thus obtained is analyzed for total impurity levels of 0.2 -
0.5% with individual impurity Levels about 0.2 - 0.3% by HPLC,
(probable impurities: 2-AP, CHMTT, N-methyl Lomoxicam)
ii) converting the Crude lomoxicam into its potassium or sodium salt by
treatment with a solution of inorganic base like potassium hydroxide,
sodium hydroxide, sodium carbonates, potassium carbonate, sodium
bicarbonate or sodium methoxide, more preferably potassium hydroxide
in concentration of 0.5% to 5%, more preferably 1%;
iii) heating the reaction mass of step ii at 70°-80°C and charcoalising said
Reaction mass at the same temperature; iv) adding inorganic base solution of the concentration 5% to 10%,
preferably 6% to 7% and more preferably 6.5% to reaction mass of step
Hi; v) cooling the reaction mass of step iv to 35° to 50°C, more preferably 40°C; vi) filtering the Lomoxicam salt from reaction mass of step v; viii) hrating water to the wet filtered Lornoxicam saft of step vi; viii) heating the reaction mass of step vii at about 70° - 80°C to get a clear
reaction mass; ix) Pooling the reaction mass of step viii at 0° to 5°C and isolating the pure
Lomoxicam salt from it; x) Suspending the isolated Lomoxicam salt from step ix in 5 to 10 volume of
water, more preferably in 8 volume of water; (or mixture of water and
Organic solvent)


xi) adjusting the pH of the reaction mass of step x to pH 4.5 to 6.5, with acid
like, hydrochloric acid, sulfuric acid, acetic acid, more preferably acetic
acid; xii) washing the pure Lomoxicam with suitable aqueous solvent selected from
acetone, methanol, isopropyl alcohol etc, xiii) isolating pure Lomoxicam from step xii with 99.96% purity with
individual single impurity NMT 0.01% and total impurity NMT 0.1%;
The purity of Lomoxicam obtained in accordance with present invention was ascertained by HPLC method as described below.
HPLC method:
Column: C1 8, 5μ 150mm X 4.6mm
Wavelength: 264nm
Flow: l.0ml/min
Injection volume: 20u.l
Buffer solution: 6.8045g of monobasic potassium phosphate in 1000ml of
water
Mobile phase: . 57% buffer solution, 33% acetonitrile, 10% methanol
Calculation: Calculate the % of impurities by % area normalization.
REACTION SCHEME:

EXAMPLE-1:
Preparation of Lornoxicam crude
100 gm of 6-chloro-4-Hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e]-l,2-thiazine-l,l-dioxide and 44 gm of 2-AP are refluxed in 7500 ml of Xylene for 8 hours. The reaction mixture is allowed to cool to 0 to 5°C for 2 hrs. The yellow precipitated crystals are filtered under suction to offer 90 gm crude Lornoxicam.
EXAMPLE 2:
Preparation of potassium salt of Lornoxicam
Crude Lornoxicam 85.5gm is dissolved in 1710 ml of 1% potassium hydroxide solution at
the temperature of 75-80°C. To the yellow solution, 4.2gm of activated carbon is added;
stirred for 5 minutes, and filtered. To the filtered solution 1000 ml of 6.5% aqueous
potassium hydroxide solution is added. The potassium salt of Lornoxicam is precipitated
in the form of yellow crystals. The crystal suspension is stirred for 30 min at 35 to 40°C
and filtered; and washed with water to yield 78.66 gm of Lornoxicam potassium salt.
EXAMPLE 3:
Purification of Lornoxicam potassium salt of Lornoxicam
Lornoxicam potassium salt from the example- 2 is dissolved in 630 ml of water at the temperature of 75-80°C. The reaction mixtures is subsequently cooled to 5°C and held for 2 hours, The yellow crystals are filtered off, and washed with water to yield 66.86gm pure Lornoxicam potassium salt.
EXAMPLE-4
PART-A: Preparation of high purity Lornoxicam.
55.28 gm Lornoxicam potassium salt is suspended in 552.80 ml, water at temperature of 30-35°C. Adjust the pH of reaction mass to 5 to 6 with acetic acid. The suspension is stirred for I hr. at 30-35°C temperature, the yellow solid is filtered and the product is washed with water and dried. Yield = 44.22 gm HPLC purity = 99.96 % Individual Impurity =0.023 % Total impurity = 0.04 %


PART B:
55.28 gm.Lornoxicam potassium salt is dissolved in 500 ml water and 500 ml acetone at the temperature of 30-35°C by stirring 10 mints. Adjust the pH of reaction mass 5 to 6 with diluted acetic acid. The suspension is stirred for I hr at 30-35°C temperature, the yellow crystals are filtered and washed with water and dried. Yield = 40.35 gm HPLC purity = 99.93 % Individual Impurity = 0.05 % Total impurities = 0.07 %
Example 5: Second crop recovery from mother liquor
PART A
Mother liquor from example 2 & 3, are cooled to 10 - 15°C. Adjust the pH to 5 to 6 with acetic acid. Stir the slurry for 30 min and filter off yellow colored solid as crude Lornoxicam. Yield = 13 gm
PART B: Purification
Purification of crude Lornoxicam as per process described in example 3 Yield =11.10 gm
PART C: Isolation
Isolation of high purity Lornoxicam as per process described in example - 4 Yield-9.10 gm. HPLC purity = 99.95 % individual Impurity = 0.03 % Total impurities = 0.05 %



We claim,
1) Process for the preparation of Lornoxicam of the formula - I
(1)
of high purity, comprising the steps of;
a) Preparing Lornoxicam potassium / sodium salt of formula II;

(Where, R=K orNa)
b) purifying Lornoxicam potassium / sodium salt from water,
c) suspending pure Lornoxicam potassium / sodium salt in water or mixture of organic solvent and water followed by acidification to yield pure Lornoxicam of formula (I).
2) The process as claimed in claim 1, wherein Lornoxicam salt of formula (II) is prepared by reacting crude Lornoxicam of formula (I) with aqueous solution of potassium hydroxide or potassium carbonate or sodium hydroxide or sodium carbonate followed

3) The Process as claimed in claim 2, wherein the molar ratio of potassium / sodium hydroxide or potassium / sodium carbonate is 1-10 molar equivalent, preferably 4-5 molar equivalent with reference to Lornoxicam.
4) The Process as claimed in claim 1, wherein the crystallization of Lornoxicam potassium / sodium salt is carried out in water.
5) Process as claimed in claim 1,. wherein the acidic treatment of the solution of Lornoxicam potassium / sodium salt in water or mixture of water and organic solvent is carried out by mixing the said solution with acid, such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, preferably with acetic acid.
6) The Process as claimed in claim 5, wherein the treatment with an acid is continued to attain a pH 4.5 to 6.5, preferably 5 to 6.
7) Process as claimed in claim 1, wherein the suitable aqueous solvents for washing of pure Lornoxicam is selected from methanol, isopropanol, acetone.
8) Process for the recovery of additional amount of pure Lornoxicam from the mother liquid comprising its acidification and purification using earlier defined process.
9) Lornoxicam of formula (I) is essentially free of impurities (individual impurity NMT
0.01%and total impurities NMT 0.1%)
10) Process according to above claims that produce highly pure Lornoxicam suitable for
pharmaceutical application.

Dr. Gopakumar G. Nair Agent for the Applicant
Dated this 6th day of October 2008