Title of Invention

PROCESS FOR PREPARING CRYSTALLINE GLUCOSAMINE SULPHATE METAL SALTS

Abstract

A method for the preparation of compounds of formula I, which comprises the steps of: i. reacting glucosamine hydrochloride and a metal hydrogen sulphate selected from sodium hydrogen sulphate and potassium hydrogen sulphate in stoichiometric ratio in a solvent; ii. precipitating the resulting glucosamine sulphate metal salt in the presence of a water miscible organic solvent; iii. filtering the reaction mass to obtain the compound of formula I.

Full Text

FORM -2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION ( See Section 10 ) 1. TITLE OF INVENTION A Process for the Preparation of Crystalline Glucosamine Sulphate Metal Salts 2. NICHOLAS PIRAMAL INDIA LIMITED, a Company incorporated under the Companies Act, 1956, of 100 Centrepoint, Dr. Ambedkar Road, Parel, Mumbai - 400 012, State of Maharashtra, India, an Indian company The following specification particularly describes the nature of the-invention and the manner in which it is to be performed. Field of the invention : The present invention relates to a process for preparing novel crystalline glucosamine sulphate metal salts for use in the treatment of acute and chronic forms of rheumatic and arthritic diseases and of all the pathological conditions originating from metabolic disorders of the osteoarticular tissues. More particularly, the present invention relates to process for preparing novel crystalline glucosamine sulphate metal salts having low metal content wherein the metal may either be sodium or potassium. Background of the invention: Both acute and chronic forms of rheumatic and arthritic diseases are associated with joint pain and inflammation and hence cause a lot of distress to patients suffering from such a disease. Osteoarthritis, a degenerative joint disease, is the most common form of arthritis. This disease is mostly prevalent in older people. The standard therapy for the treatment of osteoarthritis mostly includes the use of aspirin, corticosteroids, non-steroidal anti-inflammatory drugs (NSAID's) e.g. ibuprofen, naproxen etc. and the most recent COX-2 inhibitors e.g. rofecoxib, celecoxib. However, all these drugs are associated with one or more side effects which may also be long term in some cases. An ideal treatment of osteoarthritis must effectively control pain as well as slow down or reverse the degeneration of joints and also cause fewer side effects. In the early 1970's it was discovered that a naturally occurring substance namely glucosamine can slow down the progression of osteoarthritis and also alleviate the pain associated with this disease [Kurtz J. F. et. al.: Z. Allgemeinmed 46(21): 1090-1095 (1970); Vinel P. et. al.: Therapeutique, 47(10): 839-843 (1971)1. Glucosamine (an amino saccharide) helps in strengthening the joint structure thereby improving mobility. So far four main sources of glucosamine are reported namely glucosamine hydrochloride, glucosamine hydroiodide, glucosamine sulphate and N-acetyl glucosamine. Of these, glucosamine sulphate is the most preferred form of glucosamine and is widely used in the treatment of osteoarthritis and other acute and chronic forms of rheumatic and arthritic diseases. The benefits of using glucosamine sulphate in the treatment of osteoarthritis and other arthritic diseases as well as the safety and efficacy of this drug are well proven [Dormant A. et. al. : Clin. Ther. 3(4): 260-272 (1980); Vaz. A.L.: Curr. Med. Res. Opin.; 8(3): 142-149 (1982); Tapadinhas M. J. : Pharmaceutica 3: 157-168(1982); Reichelt A. et. al.: Arzneim Forschung 44: 75-80 (1994) ]. Although highly effective, glucosamine sulphate is unstable in its free form due to its highly hygroscopic nature and also the amino group gets oxidised readily. Hence, oral formulations such as capsules, tablets of this drug contain anti-oxidants. However, this does not solve the problem of its hygroscopic nature. To overcome this problem glucosamine sulphate is usually combined with metal salts preferably sodium or potassium salts. Mixed salts of glucosamine hydrochloride with alkali metals or alkaline earth metal sulphates such as sodium or potassium sulphates are well known in the literature. Usually glucosamine sulphate metal salts are prepared starting from either glucosamine hydrochloride or the glucosamine free base. Preparation of glucosamine sulphate is described in GB Patent No. 1056331, U.S. Patent No.3683076 and Swiss Patent No. 525861. Preparation of mixed salt of glucosamine sulphate and sodium chloride is described in U. S. Patent No. 4642340 wherein previously prepared glucosamine sulphate is treated with sodium chloride solution followed 2 by addition of liquid precipitant to precipitate the mixed salt. This process involves direct use of glucosamine sulphate which has to be strictly maintained in an environment with a relative humidity not greater than 30 % and a temperature not more than 15°C, thus one has to take proper precautions in this case. EP 214642 describes a process for the preparation of mixed salt of glucosamine sulphate and potassium chloride starting from glucosamine free base wherein solution of the glucosamine free base in water is treated with concentrated sulphuric acid and to the resulting solution potassium chloride is added. The metal salt is precipitated out from the solution by adding liquid precipitant. This is a lengthy process since it first involves liberation of free glucosamine base from glucosamine hydrochloride followed by the subsequent reaction steps. Also this process results in low yield. U.S. Patent No. 5841707 teaches a process for preparing crystalline form of mixed glucosamine sulphate salts wherein glucosamine hydrochloride is treated with a metal sulphate e.g. sodium sulphate in an aqueous solvent and the stable crystalline form of glucosamine sulphate is precipitated from the solution by adding a liquid precipitant. U.S. Patent Nos. 5843923 and 5902801 follow the same method for the preparation of glucosamine sulphate metal salts, however, in these cases the process avoids addition of liquid precipitating agent but involves freeze drying of the solution resulted from the reaction of glucosamine hydrochloride and metal sulphate. Although, the mixed glucosamine sulphate metal salts, the products described in U. S. Patent Nos. 5847107 and 5902801, are suitable for treatment of rheumatic and arthritic diseases, they have proportionately high metal content e.g. sodium or potassium. Rheumatic and arthritic 3 diseases are mostly prevalent in older people who are also at higher risk of other diseases such as hypertension and cardiovascular diseases. Hyperkalemia (high potassium level) is also a serious electrolyte disorder which appears to develop more commonly in the aged patients. In such cases the patients are advised a restricted sodium or potassium intake depending on the case history. Also people suffering from renal dysfunction require low sodium intake. Therefore, administration of glucosamine sulphate mixed salts having proportionately high sodium or potassium content may not be advisable to those rheumatic or arthritic patients who are also having history of hypertension, cardiovascular diseases, renal dysfunction, hyperkalemia and other diseases which require restricted sodium or potassium intake. Taking into account the proven safety and efficacy of glucosamine sulphate over other conventional drugs for arthritic diseases, there is a need to develop a specific form of glucosamine sulphate which can also be safely administered to sodium or potassium sensitive patients. The present inventors have found a process for preparing novel crystalline glucosamine sulphate metal salts having low metal content, wherein the metal may be either sodium or potassium. The use of the crystalline glucosamine sulphate sodium or potassium salt prepared by the process employing the present invention, is not only an efficacious treatment for all arthritic patients but also a safer remedy for those patients who are also having history of diseases which require restricted sodium or potassium intake. Our copending Indian patent application number 1088/MUM/2000, claims "Crystalline glucosamine sulphate metal salts and pharmaceutical compositions comprising said salts". 4 Objects of the invention: The primary object of the invention aims at providing a process for the preparation of novel crystalline glucosamine sulphate metal salts having low metal content, useful in the treatment of acute and chronic forms of rheumatic and arthritic diseases and of all the pathological conditions originating from metabolic disorders of the osteo-articular tissues. Another object of the present invention is to provide a process for preparing novel crystalline glucosamine sulphate metal salts having low metal content, wherein the metal may be either sodium or potassium, as efficacious and safer remedy to sodium or potassium sensitive arthritic patients. Summary of the Invention Thus in accordance with the present invention there is provided a method for the preparation of compounds of formula I, which comprises the steps of: 5 i. reacting glucosamine hydrochloride and a metal hydrogen sulphate selected from sodium hydrogen sulphate and potassium hydrogen sulphate in stoichiometric ratio in a solvent; ii. precipitating the resulting glucosamine sulphate metal salt in the presence of a water miscible organic solvent; iii. filtering the reaction mass to obtain the compound of formula I. In the above process the solvent used in the reaction in step (i) can be water. Also, the said steps of precipitating the resulting glucosamine sulphate metal salt can comprise either adding the resulting solution of step (i) to a water-miscible organic solvent or the water-miscible organic solvent to the resulting solution of step (i), followed by stirring the resulting solution obtained for a predetermined period of time. This well stirred reaction mass is then filtered to obtain the desired compound of formula I. According to another aspect of this invention, prior to the step of filtering the reaction mass in step (iii) the reaction mass is allowed to cool for a predetermined period of time and then filtered to obtain the desired compound of Formula I. The term stoichiometric ratio refers to 2:1 ratio of glucosamine hydrochloride to the metal hydrogen sulphate. The solvent used can be water. The water-miscible organic solvent may be selected from ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide and the like. The most preferred solvent is isopropanol. The water-miscible organic solvent is taken in a proportion of four to ten parts by volume with respect to solution of step (i). Preferably solution of step (i) is added to six times its volume of the water-miscible solvent. 6 The time period required for the addition might vary from five minutes to four hours, preferably one hour. The addition of the resulting solution of step (i) to the water-miscible organic solvent or the addition of the water-miscible organic solvent to the resulting solution of step (i) is carried out at room temperature ranging from 17°C to 35°C preferably 20-25°C. The resultant mixture containing the precipitate is stirred for a period of about 2 to 6 hours preferably 4 hours at room temperature ranging from 17°C to 35°C preferably 20-25°C. This well stirred reaction mass is then filtered under vacuum. The product is washed to obtain glucosamine sulphate salt as white solid and is further dried at about 25°C under vacuum. According to another aspect of this invention, this well stirred reaction mass may be cooled to 0-20°C, preferably 0-10°C, more preferably 0-5°C, and maintained at this temperature for about 1-24 hrs preferably 1-20 hours more preferably 1-16 hours. The reaction mass is then filtered under vacuum. The product is washed to obtain glucosamine sulphate salt as white solid and is further dried at about 25°C under vacuum. The present invention provides a process for the preparation of compounds of formula I, wherein the products are stable at ambient temperature and humidity. The yield of the product is between 75% to 85%: The above process provides for the preparation of compounds of formula I, which are suitable for use in the treatment of both acute and chronic forms of rheumatic and arthritic diseases, in particular osteoarthritis and generally, of all pathological conditions originating from metabolic disorders of the osteo-articular tissues. 7 The above process provides for the preparation of compounds wherein the compounds may be administered preferably in the form of oral formulations such as tablets or capsules or in injectable form. Other forms of formulations containing the compounds prepared by following a process according to the present invention are also included within the scope of this invention. The following examples further illustrate the invention but are not to be considered as limiting the scope of the invention. Example 1 : Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.6 g Melting Point : > 300°C [ Sodium content : 4.22 % Example 2 : Preparation of glucosamine sulphate potassium salt (low potassium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and potassium hydrogen sulphate (2.040 g, 0.015 mol) were taken in a flask and dissolved in 8 water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.94 g Melting Point : > 300°C [a]D25° : +58.5° (c 2, water) Potassium content: 7.16% Example 3 ; Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was vigorously stirred and to this isopropanol (150 ml) was added dropwise at 25°C (room temperature) over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.34 g Melting Point : > 300°C [CC]D25° : +60.0° (c 2, water) 9 Example 4 : Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and the precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield :6.35g Melting Point : > 300°C [CC]D25° : +60.6° (c 2, water) Example 5 ; Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 2 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.86 g 10 Melting Point : > 300°C [CC]D25° : +60.4° (c 2, water) Example 6 ; Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 4 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.9 g Melting Point : > 300°C 25° [CC]D : +59.5° (c 2, water) Example 7 ; Preparation of glucosamine sulphate sodium salt (low sodium content) Glucosamine hydrochloride (6.45 g, 0.03mol) and sodium hydrogen sulphate (1.8 g, 0.015mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added to vigorously stirred isopropanol (150 ml) at room temperature over a period of five minutes. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm 11 Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.68 g Melting Point : > 300° C [ct]D25° : +60.0° (c 2, water) Estimation of metal content in the mixed glucosamine sulphate metal salt: The sodium content in the mixed glucosamine sulphate sodium salt or the potassium content in the mixed glucosamine sulphate potassium salt respectively is estimated using Inductively Coupled Plasma Method. The sodium content was measured at 589.592 nm and the potassium content was measured at 766.491 nm. Instrument : Inductively Coupled Plasma Spectrometer Model : Spectroflame Modula Type FSM 0A 81A 12 We Claim; 1. A method for the preparation of compounds of formula I, which comprises the steps of: i. reacting glucosamine hydrochloride and a metal hydrogen sulphate selected from sodium hydrogen sulphate and potassium hydrogen sulphate in stoichiometric ratio in a solvent; ii. precipitating the resulting glucosamine sulphate metal salt in the presence of a water miscible organic solvent; iii. filtering the reaction mass to obtain the compound of formula I. 2. A method as claimed in Claim 1 wherein said step of precipitating the resulting glucosamine sulphate metal salt comprise either adding the resulting solution of step (i) to a water-miscible organic solvent or the water-miscible organic solvent to the resulting solution of step (i), followed by stirring the resulting solution obtained for a predetermined period of time. 3. A method as claimed in anyone of claims 1 or 2 wherein said step of filtering the reaction mass is carried out immediately after step (ii) to obtain the compound of formula I. 13 . 4. A method as claimed in anyone of claims 1 or 2 wherein said step of filtering the reaction mass comprises cooling the reaction mass, maintaining it for a predetermined period of time and then filtering to obtain the compound of formula I. 5. A method as claimed in anyone of claims 1 to 4 wherein in the compound obtained M is Na (sodium). 6. A method as claimed in anyone of claims 1 to 4 wherein in the compound obtained M is K (potassium). 7. A method as claimed in anyone of claims 1 to 6 wherein the said water-miscible organic solvent is selected from ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide and the like, preferably isopropanol. 8. A method as claimed in anyone of claims 1 to 7 wherein the ratio of the resulting solution of step (i) to the water-miscible organic solvent ranges from 1:4 to 1:10, preferably 1:6. 9. A method as claimed in anyone of claims 2 to 8 wherein the addition of the resulting solution of step (i) to the water-miscible organic solvent or the addition of the water-miscible organic solvent to the resulting solution of step (i) is carried out at a temperature ranging from 17°C to 35°C, preferably 20-25°C. 10. A method as claimed in claim 9 wherein the addition is carried out over a period ranging from 5 minutes to 4 hours, preferably one hour. 14 11. A method as claimed in anyone of claims 2 to 10 wherein the resulting mixture is stirred for a period of 2 to 6 hours, preferably 4 hours. 12. A method as claimed in claim 11 wherein the mixture is stirred at a temperature ranging from 17°C to 35°C, preferably 20-25°C. 13. A method as claimed in anyone of claim 3 to 12 wherein the mixture is cooled to 0-20°C, preferably 0-10°, more preferably 0-5°C. 14. A method as claimed in claim 13 wherein the mixture is maintained at the said temperature for a period of 1-24 hours, preferably 1-20 hours, more preferably 1-16 hours. 15. A method as claimed in anyone of claim 1 to 14 wherein the solvent used is water. 16. A method for the preparation of a compound of Formula I substantially as hereindescribed and illustrated with reference to the accompanying examples. 15 FORM -2 THE PATENTS ACT, 1970 (39 OF 1970) PROVISIONAL SPECIFICATION (See Section 10) 1. TITLE OF INVENTION Process for preparing Crystalline Glucosamine Sulphate Metal Salts 2. NICHOLAS PIRAMAL INDIA LIMITED, a Company incorporated under the Companies Act, 1956, of 100 Centerpoint, Dr. Ambedkar Road, Parel, Mumbai - 400 012, State of Maharashtra, India, an Indian company The following specification describes the nature of the invention : Process for preparing crystalline Glucosamine sulphate metal salts Field of the invention: The present invention relates to process for preparing novel crystalline glucosamine sulphate metal salts for use in the treatment of acute and chronic forms of rheumatic and arthritic diseases and of all the pathological conditions originating from metabolic disorders of the osteo-articular tissues. More particularly, the present invention relates to process for preparing novel crystalline glucosamine sulphate metal salts having low metal content wherein the metal may be either sodium or potassium. Background of the invention: Both, acute and chronic forms of rheumatic and arthritic diseases are associated with joint pain and inflammation and hence, cause a lot of distress to patients suffering from such a disease. Osteoarthritis, a degenerative joint disease, is the most common form of arthritis. This disease is mostly prevalent in older people. The standard therapy for the treatment of osteoarthritis mostly includes the use of aspirin, corticosteroids, non-steroidal anti-inflammatory drugs (NSAID's) e.g. ibuprofen, naproxen etc. and the most recent COX-2 inhibitors e.g. rofecoxib, celecoxib. However, all these drugs are associated with one or more side effects which may also be long term in some cases. An ideal treatment of osteoarthritis must effectively control pain as well as slow down or reverse the degeneration of joints and also cause fewer side effects. In the early 1970's it was discovered that a naturally occurring substance namely glucosamine can slow down the progression of osteoarthritis and also alleviate the pain associated with this disease [Kurtz J. F. et. at: Z. Allgemeinmed 46(21): 1090-1095 (1970); Vinel P. et. al.: Therapeutique, 47(10): 839-843 (1971)]. Glucosamine (an amino saccharide) helps in strengthening the joint structure thereby improving mobility. So far four synthetic sources of glucosamine are reported namely glucosamine hydrochloride, glucosamine hydroiodide, glucosamine sulphate and N-acetyl glucosamine. Of these, glucosamine sulphate is the most preferred form of glucosamine and is widely used in the treatment of osteoarthritis and other acute and chronic forms of rheumatic and arthritic diseases. The benefits of using glucosamine sulphate in the treatment of osteoarthritis and other arthritic diseases as well as the safety and efficacy of this drug are well proven [ Dormant A. et. al. : Clin. Ther. 3(4): 260-272 (1980); Vaz. A.L.: Curr. Med. Res. Opin.; 8(3): 142-149 (1982); Tapadinhas M. J. : Pharmaceutica 3: 157-168(1982); Reichelt A. et. al.: Arzneim Forschung 44: 75-80(1994)]. Although highly effective, glucosamine sulphate is unstable in its free form due to its highly hygroscopic nature and also the amino group gets oxidised readily. Hence, oral formulations such as capsules, tablets of this drug contain anti-oxidants. However, this does not solve the problem of its hygroscopic nature. To overcome this problem glucosamine sulphate is usually combined with metal salts preferably sodium or potassium salts. Mixed salts of glucosamine hydrochloride with alkali metals or alkaline earth metal sulphates such as sodium or potassium sulphates are well known in the literature. Usually glucosamine sulphate metal salts are prepared starting from either glucosamine hydrochloride or the glucosamine free base. Preparation of glucosamine sulphate is described in GB Patent No. 1 056 331, U.S. Patent No. 3 683 076 and Swiss Patent No. 525, 861. Preparation of mixed salt of glucosamine sulphate and sodium chloride is described in U. S. Patent No. 4 642 340 wherein previously prepared glucosamine sulphate is treated with sodium chloride solution followed 2 by addition of liquid precipitant to precipitate the mixed salt. This process involves direct use of glucosamine sulphate which has to be strictly maintained in an environment with a relative humidity not greater than 30 % and a temperature not more than 15°C, thus one has to take proper precautions in this case. EP 214 642 describes a process for the preparation of mixed salt of glucosamine sulphate and potassium chloride starting from glucosamine free base wherein solution of the glucosamine free base in water is treated with concentrated sulphuric acid and to the resulting solution potassium chloride is added. The metal salt is precipitated out from the solution by adding liquid precipitant. This is a lengthy process since it first involves liberation of free glucosamine base from glucosamine hydrochloride followed by the subsequent reaction steps. Also this process results in low yield. U.S. Patent No. 5 847 107 teaches a process for preparing crystalline form of mixed glucosamine sulphate salts wherein glucosamine hydrochloride is treated with a metal sulphate e.g. sodium sulphate in an aqueous solvent and the stable crystalline form of glucosamine sulphate is precipitated from the solution by adding a liquid precipitant. U.S. Patent Nos. 5 843 923 and 5 902 801 follow the same method for the preparation of glucosamine sulphate metal salts, however, in these cases the process avoids addition of liquid precipitating agent but involves freeze drying of the solution resulted from the reaction of glucosamine hydrochloride and metal sulphate. Although, the mixed glucosamine sulphate metal salts, the products described in U. S. Patent Nos. 5 847 107 and 5 902 801, are suitable for treatment of rheumatic and arthritic diseases, they have proportionately high metal content e.g. sodium or potassium. Rheumatic and arthritic 3 diseases are mostly prevalent in older people who are also at higher risk of other diseases such as hypertension and cardiovascular diseases. Hyperkalemia (high potassium level) is also a serious electrolyte disorder which appear to develop more commonly in the aged patients. In such cases the patients are advised a restricted sodium or potassium intake depending on the case history. Also people suffering from renal dysfunction require low sodium intake. Therefore, administration of glucosamine sulphate mixed salts having proportionately high sodium or potassium content may not be advisable to those rheumatic or arthritic patients who are also having history of hypertension, cardiovascular diseases, renal dysfunction, hyperkalemia and other diseases which require restricted sodium or potassium intake. Taking into account the proven safety and efficacy of glucosamine sulphate over other conventional drugs for arthritic diseases, there is a need to develop a specific form of glucosamine sulphate which can also be safely administered to sodium or potassium sensitive patients. The present inventors have now found novel crystalline glucosamine sulphate metal salts having low metal content, wherein the metal may be either sodium or potassium. The use of the crystalline glucosamine sulphate sodium or potassium salt of the present invention, is not only an efficacious treatment for all arthritic patients but also a safer remedy for those patients who are also having history of diseases which require restricted sodium or potassium intake. In our copending application No. that is disclosed and claimed "Crystaline glucosamine sulphate metal salts ". 4 Objects of the invention: The object of the invention is to provide a process for the preparation of the crystalline glucosamine sulphate metal salts having low metal content. Summary Of The Invention: Thus the present invention relates to a process for the preparation of compounds of formula I: wherein M represents Na or K, the process comprising: i. reacting glucosamine hydrochloride and a metal hydrogen sulphate selected from either sodium hydrogen sulphate or potassium hydrogen sulphate in stoichiometric ratio in an aqueous solvent such as water; ii. precipitating the resulting glucosamine sulphate metal salt by either adding the resulting solution of step (i) to a water-miscible organic solvent or the water-miscible organic solvent to the 5 resulting solution of step (i), followed by stirring the resulting solution obtained for a predetermined period of time. The term stoichiometric ratio refers to 2:1 ratio of glucosamine hydrochloride to the metal hydrogen sulphate. The water-miscible organic solvent may be selected from ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide and the like. The most preferred solvent is isopropanol. The water-miscible organic solvent is taken in a proportion of four to ten parts by volume with respect to solution of step (i). Preferably solution of step (i) is added to six times its volume of the water-miscible solvent. The time period required for the addition might vary from half an hour to four hours, preferably one hour. The addition of the resulting solution of step (i) to the water-miscible organic solvent is carried out at a temperature ranging from 17°C to 30°C preferably 25°C. Compounds I according to present invention are stable at ambient temperature and humidity. The yield of the product is between 75% to 85%. The compounds of formula I of the present invention are suitable for use in the treatment of both acute and chronic forms of rheumatic and arthritic diseases, in particular osteoarthritis and generally, of all pathological conditions originating from metabolic disorders of the osteo-articular tissues. The compounds of the present invention may be administered preferably in the form of oral formulations such as tablets or capsules or in 6 injectable form. Other forms of formulations containing the compounds of the present invention are also included within the scope of this invention. In compound I (M=Na), the amount of sodium content is only 4.22 % as against 8 % of sodium that is present in the mixed glucosamine sulphate sodium salt, the product described in the prior art (U. S. Patent Nos. 5 847 107 and 5 902 801). Also the potassium content in compound I (M=K) is only 7.16 % as against 12.9 % of potassium that is present in the product described in U. S. Patent Nos. 5 847 107 and 5 902 801. Thus, the compounds of formula I of the present invention are significantly advantageous over those reported in the prior art with respect to their usefulness specifically in the treatment of arthritic patients who are sodium and potassium sensitive. The following examples further illustrate the invention but are not to be considered as limiting the scope of the invention. Example 1: Preparation of glucosamine sulphate sodium salt flow sodium content) Glucosamine hydrochloride (6.45 g, 0.03M) and sodium hydrogen sulphate (1.8 g, 0.015M) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.6 g 7 Melting Point : > 300°C 25° [a]D : +59° (c 2, water) Sodium content : 4.22% Example 2: Preparation of glucosamine sulphate potassium salt (low potassium content) Glucosamine hydrochloride (6.45 g, 0.03M) and potassium hydrogen sulphate (2.040 g, 0.015 M) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0°C-5°C for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol). Glucosamine sulphate salt was obtained as white solid and was further dried at 25°C under vacuum (2mm Hg). Yield : 6.94 g Melting Point : > 300°C 25° [a]D : +58.5° (c 2, water) Potassium content: 7.16% Estimation of metal content in the mixed glucosamine sulphate metal salt : The sodium content in the mixed glucosamine sulphate sodium salt or the potassium content in the mixed glucosamine sulphate potassium salt 8 respectively is estimated using Inductively Coupled Plasma Method. The sodium content was measured at 589.592 nm and the potassium content was measured at 766.491 nm. Instrument : Inductively Coupled Plasma Spectrometer Model : Spectroflame Modula Type FSM OA 81A Dated this 29th day of November 2000. 9

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1088-mum-2000-correspondence-rceived-270204.pdf

1088-mum-2000-correspondence-rceived-290304.pdf

1088-mum-2000-correspondence-rceived-310106.pdf

1088-mum-2000-correspondence-rceived.pdf

1088-mum-2000-descripiton (complete).pdf

1088-mum-2000-descripiton (provisional).pdf

1088-mum-2000-form 1(1-1-2001).pdf

1088-mum-2000-form 1(1-12-2000).pdf

1088-MUM-2000-FORM 16(3-10-2012).pdf

1088-mum-2000-form 19(15-12-2003.pdf

1088-mum-2000-form 2(granted)-(3-12-2001).doc

1088-mum-2000-form 2(granted)-(3-12-2001).pdf

1088-mum-2000-form 3(1-12-2000).pdf

1088-mum-2000-form 5(3-12-2001).pdf

1088-mum-2000-form-1.pdf

1088-mum-2000-form-19.pdf

1088-mum-2000-form-2-complete.doc

1088-mum-2000-form-2-complete.pdf

1088-mum-2000-form-2-provisional.doc

1088-mum-2000-form-2-provisional.pdf

1088-mum-2000-form-26.pdf

1088-mum-2000-form-3.pdf

1088-mum-2000-form-5.pdf

1088-mum-2000-form-pct-ipea-408.pdf

1088-mum-2000-form-pct-isa-210(1-12-2000).pdf

1088-mum-2000-form-pct-isa-220.pdf

1088-MUM-2000-HIGH COURT BOMBAY(3-10-2012).pdf

1088-mum-2000-other documents(27-1-2006).pdf

1088-mum-2000-pct-search report.pdf

1088-mum-2000-power of attorney(1-1-2001).pdf

1088-mum-2000-power of attorney(1-12-2000).pdf