Title of Invention

PROCESS FOR THE PREPARATION OF HIGHLY PURE CLARITRROMYCIN FORM II

Abstract

A process for direct isolation of pure clarithromycin form II of Formula I 6-O-methylerythromycin A Formula -1 from crude 6-0-methyl-N-demethylerythromycin A of Formula II - 6-O-methyl-N-demethylerythromycin Formula-ll comprising a) providing crude 6-O-methyl-N-demethylerythromycin A; b) purification of said crude 6-O-methyl-N-demethylerythromycin A by at least partial dissolution and/or suspension in an organic solvent system selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, Metahnol:Ethyl Acetate(90:10), Acetone, or mixtures thereof c) N-methylation of thus purified 6-O-methyl-N-demethylerythromycin A (HPLC purity > 95%) in presence of formic acid and atleast one of formaldehyde and paraformaldehyde in water miscible organic solvents; and a) adjusting pH 8-11 with base; b) isolating therefore highly pure 6-O-methylerythromycin A form II.

Full Text

FORM -2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10 ; rule 13) 1. TITLE OF INVENTION A PROCESS FOR THE DIRECT ISOLATION OF PURE CLARITHROMYCIN FORM II FROM CRUDE 6-O-METHYL-N-DEMETHYERYTHROMYCIN A' 2. (a) ALEMBIC LIMITED, (b) Alembic Road, Vadodara-390 003, Gujarat, India, (c) An Indian Company ORIGINAL 748/MUMNP/2003 28/07/03 GRANTED 17-12-2004 The following specification particularly describes the nature of the invention and the manner in which it is to be performed. FIELD OF INVENTION: The present invention relates to a process for direct preparation of highly pure 6-O-methyl erythromycin A (Clarithromycin) Form II from crude 6-O-methyl-N-demethylerythromycin A, key intermediate of Clarithromycin, to obtain highly pure 6-O-methyl erythromycin A form II (Clarithromycin) with purity above 98%.Also disclosed is a simple, safe and cost-effective process for the manufacture of highly pure 6-O-methyl erythromycin A (Clarithromycin) Form II from erythromycin A -9-Oxime derivative. BACKGROUND AND PRIOR ART: 6-O-methyl erythromycin A (Clarithromycin) of_Formula I, is a semi synthetic macrolide antibiotic, which exhibits strong antibacterial activity towards a wid range of bacteria inclusive of gram positive bacteria, some gram negativ bacteria. anerobic bacteria, Mycoplasma, Chlamidia and Helicobacter pylori, and also can be used as a raw material for the synthesis of other antibiotics, and it therefore is a pharmaceutical important material. r*t'y Prior art process for preparing 6-O-methy! erythromycin A from erythromycin A -9-Oxime are disclosed in EP patent document nos. EP 0,158,467, EP 0,195,960 and EP 0,272,110 and U.S. Pat. No. 5,719,272 and WO 97/36913. Separately from the above processes, a process for preparing 6-0-methylerythromycin A from erythromycin A-9-oxime is disclosed in U.S. Pat. document No. 4,672,109 but it has several limitations in obtaining pure 6-0-methylerythromycin A at commercial scales. US 4,672,109 describes selective 6-O-methylation of erythromycin A-9-oxime. However, this process have several drawbacks like it gives lower yield and requires multiple purification of intermediates and final product so as to obtain 6-O-methyl erythromycin A with desired purity. Also, it requires more volume of solvents, involves more time to obtain Clarithromycin of desired purity and also involves wage of increased utility, manpower and cost at commercial production. The method comprises protecting oxime hydroxy group of erythromycin A 9-oxime with an aralkyl group such as O-chloro benzyl group, and protecting the hydroxy group at the 2' position and dimethylamino group at the 3' position with arylalkoxy carbonyl groups such as benzyloxycarbonyl group, and thereafter carrying out alkylation such as methylation of the hydroxy group at the 6' position. The resultant 6-O-methyl-N-demethylerythromycin A of Formula (II) is recrystallized from a mixture of chloroform and diethyl ether. Use of carcinogenic solvents like chloroform and highly flammable solvent like diethyl ether, having low flash point should be avoided at commercial level. Repetition of the process described in US 4672109 revealed at our hand that chloroform does not efficiently reduces the impurities of 6-O-methyl-N-demethylerythromycin A and as a result of this, to obtain Clarithromycin of the desired purity within pharmacopoeial limits number of purifications are required. Also, Chloroform being a class II solvent as per ICH guidelines, a concentration limit of only 60 ppm is allowed in finished good. This shall require excessive drying of the finished good in order to bring down the chloroform content below ICH limits, which will be associated with large energy consumption by way of excessive drying. Hence, it is not desirable to use halogenated class II solvent in penultimate stage because of the lower permissible limit of such solvents in the final drug. Moreover it is anesthetic in nature and inhalation of this may reduce the alertness of the people. Due to this people working in the plant may lead to safety hazards. Accordingly, the prior art processes suffer from inherent difficulties like multiple purification of intermediates and also of final 6-O-methylerythromycin A. Also, It has been reported that clarithromycin exists in at least three distinct crystalline forms, "Form 0", "Form I" and "Form II" (International Publication Nos. WO 98/04573 and WO 98/31699). The crystal forms can be identified by infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectrophotometry. However, the drugs currently available are known to be formulated from the thermodynamically more stable Form II. Preparation of the current commercial entity therefore, requires converting the form I crystals to form II. Typically this is done by heating the form I crystals under vacuum at high temperature of about 70° C which make such processes energy intensive and cost-extensive. OBJECTS OF THE INVENTION : It is, therefore, the basic object of this invention to provide a process for the manufacture of 6-O-methyl-erythromycin A (clarithromycin) with high purity, avoiding the drawback limitations of the prior art processes. Another object of the present invention is to provide a process for the preparation of 6-O-methyl erythromycin A, which would be high yielding, cost effective, easy to operate at industrial scale, be safe to carry out and without not involving carcinogenic, anesthetic and highly explosive solvents and with desired purity as per established Pharmacopoeial limits. Yet another object of the present invention is to provide a process of manufacture of 6-O-methyl erythromycin A, which would avoid unreacted contaminants and side products of the previous steps in the final product and provides the final product with good yield and purity. It is a further object of the present invention to provide a simple, safe and cost-effective method for the purification of 6-O-methyl-N-demethylerythromycin A, a valuable intermediate in the manufacture of 6-O-methyl-erythromycin A (clarithromycin). Whose purity is very important for obtaining highly pure 6-O-methyl erythromycin A (Clarithromycin). Yet further object of the invention is to provide a process for preparation of highly pure Clarithromycin form II that would not require the use of carcinogenic and anesthetic solvent like chloroform and highly flammable diethyl ether, which are hazardous to handle at commercial scale. A further object of the invention is to provide an efficient and robust purification method of intermediates having high levels of impurities and thereby directly isolating highly pure Clarithromycin form II within Pharmacopoeial limit. A further object of the invention is to provide a direct isolation of highly pure Clarithromycin form II that would be industrially favorable in the way that the same would increase the plant capacity and will also require less manpower and less effluent problem. A further object of this invention is to provide the method which would be industrially feasible for large-scale preparation of clarithromycin Form II crystal. SUMMARY OF INVENTION: Thus according to the basic aspect of the present invention, there is provided a process for direct isolation of pure clarithromycin form II of Formula I 6-O-methylerythromycin A Formula - I from crude 6-0-methyl-N-demethylerythromycin A of Formula II 6-O-methyl-N-demethylerythromycin Formula-ll comprising a) purification of crude 6-O-methyl-N-demethylerythromycin A by at least partial dissolution and/or suspension in an organic solvent system selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, Metahnol:Ethyl Acetate(90:10), Acetone, or mixtures thereof; b) N-methylation of thus purified 6-O-methyl-N-demethylerythromycin A (HPLC purity > 95%) in presence of formic acid and atleast one of formaldehyde and paraformaldehyde in water miscible organic solvents ; and c) adjusting pH 8-11 with base; d) isolating therefore highly pure 6-O-methylerythromycin A form II. Following the above process of the invention it is thus possible to obtain highly pure clarithromycin form II from crude 6-O-methyl-N-demethylerythromycin A of any source by way of simple, safe and cost-effective process. The purity of the clarithromycin form II obtained is in the range of 98 to 99.9%. The clarithromycin form II meets desired pharmacopoeia standards including impurity profile. Formula In accordance with another aspect of the present invention there is provided a process for providing pure 6-O-methylerythromycin A form II of Formula I - from erythromycin A-9-oxime derivative of Formula III - 6-O-methyl-N-demethylerythromycin 9-Oxime Formula III comprising- i) converting the erythromycin A-9-oxime derivative (Formula III) to crude 6-O-methyl-N-demethylerythromycin A; ii) purification of crude 6-O-methyl-N-demethylerythromycin A by at least partial dissolution and/or suspension in an organic solvent system selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, Metahnol:Ethyl Acetate(90:10), Acetone, or mixtures thereof.; iii) N-methylation of thus purified 6-O-methyl-N-demethylerythromycin A in presence of formic acid and formaldehyde or paraformaldehyde in water miscible organic solvents and iv) adjusting the pH 8-11 with base; v) isolating therefore highly pure 6-O-methylerythromycin A form II. Following the above process of the invention it is thus possible to obtain highly pure clarithromycin form II from erythromycin A-9-oxime derivative by way of simple, safe and cost-effective process. In accordance with a further aspect of the present invention there is provided a process for direct conversion of pure 6-O-methyl-N-demethylerythromycin A of Formula II 6-0-methyl-N-demethylerythromycin Formula II to pure 6-0 methyl erythromycin A form II of Formula I 6-0-methylerythromycin A Formula I comprising- - treating the pure 6-O-methyl-N-demethylerythromycin A (> 95%) with formic acid and at least one of formaldehyde and paraformaldehyde in water miscible organic solvents and; - adjusting pH 8-11 with base; - cooling, washing, filling and finally drying to obtain the highly pure 6-0-methyl-erythromycin A form II. In the above process of the invention the organic solvent system comprise solvents selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile , Methanol : Ethyl Acetate(90:10), Acetone, or mixtures thereof. In accordance with yet another aspect of the present invention there is provided high purity 6-0- methyl erythromycin A form -II polymorph having the following d-spacing values in powder XRD, 10.37, 9.32, 8.19, 7.74, 7.18, 6.45, 5.85, 5.13, 4.88, 4.65, 4.47, 4.35, 4.12, 4.00, 3.83., 3.58., 3.12. (Figure II), and an endotherm in DSC at 226.61 °C (Figure I) obtained following the above processes. DETAILED DESCRIPTION In the above discussed processes of the invention directed to manufacture of pure 6-O-methylerythrtpmycin form II, the crude 6-O-methyl-N-demethylerythromycin A used can be from any known sources preferably obtained from erythromycin A-9 oxime derivative. In accordance with a preferred aspect the method comprises protecting oxime hydroxy group of erythromycin A 9-Oxime with an aralkyl group such as O-chloro benzyl group, and protecting the hydroxy group at the 2' position and dimethylamino group at the 3' position with arylalkoxy carbonyl groups such as benzyloxycarbonyl group, and thereafter carrying out alkylation such as methylation of the hydroxy group at the 6 position and hydrogenolysis and followed by deoximation of the resultant compound gives crude 6-O-methyl-N-demethylerythromycin A. In accordance with a further preferred aspect the process for the preparation of highly pure 6-O-methylerythromycin A (Clarithromycin) Form II from the crude 6-O-methyl-N-demethylerythromycin A comprises- a) purification of crude 6-O-methyl-N-demethylerythromycin A carried out by at least dissolution and/or suspension in organic solvent preferably selected from group of methanol, ethanol, iso-propanol, n-propanal, ethyl acetate, THF, toluene, acetonitrile , Methanol : Ethyl Acetate(90:10), Acetone, or mixtures thereof. b) N-methylation of thus purified 6-O-methyl-N-demethylerythromycin A (HPLC purity > 95%) in presence of formic acid and formaldehyde or paraformaldehyde in water miscible organic solvents and c) adjusting pH 8-11 with base; d) isolating therefore highly pure 6-O-methylerythromycin A form II. The process of purification of crude 6-O-methyl-N-demethylerythromycin A in accordance with the present invention thus essentially involves the steps of at least partially dissolving and/or suspending the crude 6-O-methyl-N- demethylerythromycin A as prepared by known method, in organic solvent system and initiating the crystallization of pure 6-O-methyl-N-demethylerythromycin A either by cooling or by addition of water or both. The dissolution may be in whole or in part. The organic solvent system can preferably comprise alcohol selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol or mixtures thereof. Preferably, the above purification is carried out at ambient temperature to boiling point of solvent. Further N-methylation of pure 6-O-methyl-N-demethylerythromycin A is carried out in presence of aqueous formaldehyde or paraformaldehyde and formic acid, which directly gives highly pure 6-O-methylerythromycin A (Clarithromycin) form II crystal. In accordance with a preferred aspect, the method of the present invention comprises of dissolving the crude 6-O-methyl-N-demethylerythromycin A at a temperature near to that of the reflux temperature of the organic solvent and then adding water slowly till slight turbidity persisted. Thereafter, the mixture is cooled slowly to room temperature and some more amount of water is added to the reaction mixture. Finally the reaction mixture is cooled to 15-20°C and agitated for approximately 2 hours. The mixture is filtered and the purified solid is dried under reduced pressure to give pure 6-O-methyl-N-demethylerythromycin A. Further N-methylation of pure 6-O-methyl-N-demethylerythromycin A is carried out in aqueous aqueous formaldehyde or paraformaldehyde solution and formic acid and the mixture was refluxed for 2-8 hr. After completion of the reaction more amount of methanol is added at RT to reflux temperature and pH is adjusted to about 10-11. Water is slowly added to the reaction mixture and further refluxed for 30 minutes to 2 hours. The reaction mixture is then cooled ambient to 5-15 °C agitated for 1-4 hrs, filtered and washed with copious amount of water so as to render the neutral pH. The mixture is filtered and the purified under reduced pressure to directly afford the highly pure 6-O-methyl erythromycin A form II. The process of the invention is illustrated in Scheme I: The selective purification method herein described allows reducing in an efficient way, the impurities present in N-demethyl 6-O-methylerythromycin A. The crystal structure of the 6-O-methyl erythromycin A thus prepared has the endotherm in DSC at 226.61 °C (Figure I) and the XRD (Figure II) reported as below d-spacing 10.37, 9.32, 8.19, 7.74, 7.18, 6.45, 5.85, 5.13, 4.88, 4.65, 4.47, 4.35, 4.12, 4.00, 3.83, 3.58, 3.12. The process of the present invention is described hereunder by the following non-limiting examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner. EXAMPLE 1 Crude 6-O-methyl-N-demethylerythromycin A- 9- Oxime (43g) was dissolved in a mixture of ethanol (258 ml) and water (258 ml) and sodium hydrogen sulfite (48.37g) was added. The reaction mixture was refluxed till the end of the reaction. Activated charcoal (4.3 g) was added, refluxed for half an hour and filtered the reaction mixture. Dilute sodium hydroxide solutions (10 % cone.) was added to filtrate and adjust the pH to about 8-11. The solution was cooled ambient ambient to 5-10° C, agitated for 2 hrs, filtered and washed with water till natural pH was obtained to give 27g of crude 6-O-methyl-N-demethylerythromycin A. [HPLC purity: 95.10% Yield: 68.66%] EXAMPLE 2 Crude 6-O-methyl-N-demethylerythromycin A (27g) was added in methanol (135 ml). The reaction mixture was refluxed for half an hour. 50-ml water was slowly added till reaction mixture becomes turbid. The solution was cooled to room temperature, and 31 ml water was added slowly The reaction mass then cooled ambient to 15-20 °C, agitated for 2 hr, and filtered to give 25g of pure 6-O-methyl-N-demethylerythromycin A. [ HPLC purity : 99.70%, Yield : 95.59% j EXAMPLE 3 Crude 6-0-methyl-N-demethylerythromycin A (27g) was added in a mixture of methanol (125 ml) and ethylacetate (15 ml). The reaction mixture was refluxed for half an hour. 50-ml water was slowly added till reaction mixture becomes turbid. The solution was cooled to room temperature, and 31 ml of water was added slowly. The reaction mass then cooled ambient to 15-20 °C, agitated for 2 hr, and filtered to give 25g of pure 6-O-methyl-N-demethylerythromycin A. [ HPLC purity : 99.70%, Yield : 95.59% ] EXAMPLE 4 Crude 6-O-methyl-N-demethylerythromycin A (5g) was added in ethylacetate (65 ml). The reaction mixture was refluxed for half an hour and recovered upto half volume of ethyl acetate. The solution was cooled to 0-10 °C, agitated for 1 hr, and filtered to give 4.57g of pure 6-O-methyl-N-demethylerythromycin A. [ HPLC purity : 99.50%, Yield : 95.00% ] EXAMPLE 5 Crude 6-O-methyl-N-demethylerythromycin A (27g) was added in ethanol (130 ml). The reaction mixture was refluxed for half an hour. 50-ml water was slowly added till reaction mixture becomes turbid. The solution was cooled to room temperature, and 31 ml of water was added slowly. The reaction mass then cooled to 15-20 °C, agitated for 2 hr, and filtered to give 24.7g of pure 6-O-methyl-N-demethylerythromycin A. [ HPLC purity : 99.70%, Yield : 94.50% ] EXAMPLE 6 15.84 ml of 37 % aqueous formaldehyde solution and 2.78 ml of formic acid were added in a solution of 24 g of pure 6-O-methyl-N-demethylerythromycin A in 120 ml methanol and the mixture was refluxed for 4 hr. After completion of the reaction, 360-ml methanol was added at reflux temperature and pH was adjusted to about 8-11 by adding 28 ml of 10 % aqueous sodium hydroxide solution. In the reaction solution was added 48 ml of water slowly and refluxed for half an hour. The reaction mixture was cooled ambient to 5-10 °C. agitate for 2 hrs, filtered and washed with water till neutral pH was obtained to give 18.5 g of 6-O-methyl erythromycin A Form II. [HPLC purity : 99.74%, Yield = 78.59% ] EXAMPLE 7 15.84 ml of 37 % aqueous formaldehyde solution and 2.78 ml of formic acid were added in a solution of 24 g of pure 6-O-methyl-N-demethylerythromycin A in 120ml acetonitrile and the mixture was refluxed for 4 hr. After completion of the reaction, 360-ml acetonitrile was added at reflux temperature and pH was adjusted to about 8-11 by adding 28 ml of 10 % aqueous sodium hydroxide solution. In the reaction solution was added 48 ml of water slowly and refluxed for half an hour. The reaction mixture was cooled to 5-10 °C. agitate for 2 hrs, filtered and washed with water till neutral pH to give 18.2 g of 6-O-methyl erythromycin A Form II. [HPLC purity : 99.59%, Yield = 76.5% ] EXAMPLE 8 15.84 ml of 37 % aqueous formaldehyde solution and 2.78 ml of formic acid were added in a solution of 24 g of pure 6-O-methyl-N-demethylerythromycin A in 60 ml methanol and 60 ml ethanol. The mixture was refluxed for 4 hr. After completion of the reaction, 360-ml methanol : ethanol [1:1] mixture was added at reflux temperature and pH was adjusted to about 10-10.5 by adding 28 ml of 10 % aqueous sodium hydroxide solution. In the reaction solution was added 48 ml of water slowly and refluxed for half an hour. The reaction mixture was cooled to 5-10 °C. agitate for 2 hrs, filtered and washed with water till neutral pH was obtained to give 18.4 g of 6-O-methyl erythromycin A Form II. [HPLC purity: 99.73%, Yield = 76.6% ] Further studies were carried out for a comparative analysis of the yield and purity achieved of pure 6-0-methyl erythromycin following the process of the invention and that following the process described in U.S. patent 4672109 . The results obtained are provided in Table-1. Table -1 (% Assay & % HPLC purity comparison) Starting material: 6-O-methyl-N-demethylerythromycin A 9-Oxime (% Purity = 88.82%) The Table-1 clearly reveals that the process as defined in patent no. US 4,672,109, is inadequate to give 6-O-methylerythromycin A of the desired purity. Also that the selective crystallization of 6-O-methyl-N-demethylerythromycin A by the selected solvent like methanol, ethanol, iso~ propanol, n-propanol, ethyl acetate, THF, toluene, acetonitrile, Methanol . Ethyl Acetate(90.10), Acetone, or mixtures thereof, is capable of removing all impurities to the desired extent and give 6-O-methylerythromycin A of high purity as per the pharmacopoeial limits. The process of the invention is thus clearly directed to improvement in preparation of 6-O-methylerythromycin A in terms of effective removal of impurities and isolation of form II crystals. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. WE CLAIM : 1. A process for direct isolation of pure clarithromycin form II of Formula I 6-O-methylerythromycin A Formula -1 from crude 6-0-methyl-N-demethylerythromycin A of Formula II - 6-O-methyl-N-demethylerythromycin Formula-ll comprising a) providing crude 6-O-methyl-N-demethylerythromycin A; b) purification of said crude 6-O-methyl-N-demethylerythromycin A by at least partial dissolution and/or suspension in an organic solvent system selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, Metahnol:Ethyl Acetate(90:10), Acetone, or mixtures thereof c) N-methylation of thus purified 6-O-methyl-N-demethylerythromycin A (HPLC purity > 95%) in presence of formic acid and atleast one of formaldehyde and paraformaldehyde in water miscible organic solvents; and a) adjusting pH 8-11 with base; b) isolating therefore highly pure 6-O-methylerythromycin A form II. 2. A process as claimed in claim 1, wherein said crude 6-O-methyl-N-demethylerythromycin A is provided by converting erythromycin A-9-oxime derivative of Formula III to said crude 6-O-methyl-N-demethylerythromycin A. 6-O-methyl-N-demethylerythromycin 9-Oxime (Formula III) 3. A process as claimed in claim 2, wherein said conversion of erythromycin A-9-oxime derivative of formula III to said crude 6-O-methyl-N-demethylerythromycin A comprises: I. protecting oxime hydroxy group of erythromycin A 9-oxime with an aralkyl group preferably O-chloro benzyl group II. protecting the hydroxy group at the 2' position and dimethylamino group at the 3' position of step I with aralkyloxy carbonyl groups preferably benzyloxycarbonyl group; III. reacting the product of step II with a methylating agent; IV. deprotection and deoximination the product of step III to form said crude 6-0- Methyl-N-demethylerythromycin A. 4. A process as claimed in anyone of claims 1 to 3 wherein the said organic solvent system preferably comprise alcoholic solvent system selected from group of methanol, ethanol, iso-propanol, n-propanol and mixtures thereof preferably methanol. 5. A process as claimed in anyone of claims 1 to 4 wherein the crude 6-0-methyl-N-demethylerythromycin A is at least partially dissolved or suspended in organic solvent system and the purified 6-O-methyl-N-demethylerythromycin is obtained by adding water. 6. A process as claimed in anyone of claims 1 to 5 wherein the impure 6-O-methyl-N-demethylerythromycin A is at least partially dissolved and suspended in said organic solvent system with heating and the purified product obtained by cooling the mixture. 7. A process as claimed in anyone of claims 1 to 6 wherein the purification of crude 6-O-methyl-N- demethylerythromycin A comprise crystallisation initiated by cooling off and/or by addition of water. 8. A process as claimed in anyone of claims 1 to 7 wherein the purification of crude is carried out at ambient temperature to boiling point of solvent. 9. A process as claimed in anyone of claims 1 to 8 comprising of dissolving the crude 6-O-methyl-N-demethylerythromycin A at a temperature near to that of the reflux temperature of said organic solvent system, and then adding water slowly or the mixture is cooled slowly or both and there after the solution is filtered and finally, the said purified solid is dried at a temperature between 40 and 60 °C. 10. A process as claimed in claim 9 wherein said step of cooling is carried out at ambient to 15°C. 11. A process as claimed in anyone of claims 1 to 10 wherein the methylation of 6-0-methyl-N-emethylerythromycin A is carried out with aqueous formaldehyde or paraformaldehyde and formic acid in presence of an organic solvent selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, Methanol :Ethyl Acetate(90:10), Acetone, or mixtures thereof. 12 . A process for direct conversion of pure 6-O-methyl-N-demethylerythromycin A of Formula II to pure 6-0 methyl erythromycin A form II of Formula I comprising- - providing an organic solvent purified 6-O-methyl-N-demethylerythromycin A and treating the same with formic acid and at least one of formaldehyde and paraformaldehyde; - cooling, washing, filling and finally drying to obtain the highly pure 6-0-methyl-erythromycin A form II. 13. A process as claimed in claim 12 wherein said step of treating of purified 6-0- methyl-N-demethylerythromycin A is also carried out in the presence of an organic solvent. 14.A process as claimed in claim 13 wherein said organic solvent used is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol ethyl acetate, THF, toluene, acetonitrile, MethanoI.Ethyl Acetate(90:10), Acetone, or mixtures thereof. 15.A process as claimed in anyone of claims 1 to 14 wherein said form II of clarithromycin of desired purity is obtained upon isolation and even after desired drying. 16. A process as claimed in anyone of claims 12 to 15 wherein the final power is dried above 70°C to get form II of clarithromycin. 17. A process as claimed in anyone of claims 1 to 16 wherein the final solid of 6-O- methyl erythromycin A form -II polymorph have the following d-spacing values in powder XRD, 10.37, 9.32, 8.19, 7.74, 7.18, 6.45, 5.85, 5.13, 4.88, 4.65, 4.47, 4.35, 4.12, 4.00, 3.83, 3.58, 3.12. (Figure II) and an endotherm in DSC at 226.61°C(Figure l).

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