Title of Invention

NOVEL PROCESSES FOR THE PREPARATION OF FEXOFENADINE HYDROCHLORIDE FORM-I

Abstract

A process for preparation of crystalline anhydrous fexofenadine hydrochloride Form-I comprising the steps of; a) suspending fexofenadine base or fexofenadine hydrochloride Form C in a suitable organic solvent; b) acidifying the suspension of fexofenadine base with hydrochloric acid dissolved in an organic solvent by adjusting the pH below 2 to obtain a clear solution; c) concentrating the reaction mass by distillation to obtain a residue; d) dissolving the residue in isopropyl alcohol to obtain clear solution and precipitating the anhydrous fexofenadine hydrochloride using ethyl acetate from the said reaction mass at a temperature below 25°C.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION [See section 10; rule 13] "Novel Processes for the synthesis jof Fexofenadine Hydrochloride Form-P (a) CIPLALTD. (b) 289, Bellasis Road, Muitfbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of" this invention and the manner in which it is to be performed: .„«**' 8-12-2004 Technical field of the Invention The present invention relates to a novel process for the synthesis of stable crystalline anhydrous fexofenadine hydrochloride Form-I. More particularly the present invention relates to process for preparation of fexofenadine Form 1 from fexofenadine base. The present invention also relates to process for conversion of fexofenadine Form-C to fexofenadine Form 1. Background of the Invention Fexofenadine is a generic term used to identify a chemical compound 4-[4-[4-hydroxydiphenylmethyl)-l-piperidinyl] - 1- hydroxybutyl] -a, a -dimethyl benzeneacetic acid, a HI receptor antagonist and a useful non-sedative antihistaminic drug used to relieve allergic rhinitis (seasonal allergy) symptoms including sneezing, runny nose, itching, and watery eyes. Fexofenadine has a low permeability into central nervous system tissues and has weak antimuscarinic activity, causing it to have few systemic side effects. Fexofenadine is rapidly absorbed after oral administration with peak plasma concentrations being reached in 2 to 3 hours. It is about 60 to 70% bound to plasma proteins. About 5% of the total dose is metabolised, mostly by the intestinal mucosa, with only 0.5 to 1.5% of the dose undergoing hepatic biotransformation. Fexofenadine is a terfenadine carboxylic acid metabolite and as such has been detected in breast milk after the administration of terfenadine. The antihistaminic activity and synthesis of the fexofenadine was first disclosed in US 4254129. Other methods for the synthesis fexofenadine hydrochloride are discussed in the subsequent U.S. Patents No. 5,578,610, 5,589,487, 5,581,011, 5,663,412, 5,750,703, 5,994,549, 5,618,940, 5,631375, 5,644,061, 5650,516, 5,652,370, 5,656,433, 5,663,353, 5,675,009, 5,375,693 and 6,147,216. US 5,738,872 US 5,932,247 US 5,855,912 incorporated herein by reference, describes four polymorphic forms of fexofenadine hydrochloride which were designated as Form I- 2 IV. According to the '872 and related patents, Form II and IV are hydrates and Form-I and Form-Ill are anhydrous. The '872 patent discusses methods for inter converting Forms-I-IV. This patent discloses a process for preparation of Form-I by water-minimizing recrystallization of Form-II or Form- IV. Fexofenadine hydrochloride was subjected to high temperature under acidic conditions, which leads to the formation of impurities. This patent does not describe any process for preparation of form-I of fexofenadine hydrochloride directly from fexofenadine base. This patent application describes the methods for the conversion of Form- II or III or IV to Form-I and Form-I was characterized by X-ray diffraction and described in this patent. Many subsequent Patents describe synthesis of new polymorphic forms of fexofenadine hydrochloride. WO0071124 discloses amorphous form of fexofenadine hydrochloride and freeze drying technique to prepare the amorphous form. WOO 194313 discloses Form- A crystal modification of fexofenadine hydrochloride, process for preparation and pharmaceutical formulations. WO02002080857 report novel forms of fexofenadine hydrochloride Forms V, VI, VIII through XV and processes for their preparation, preparation of amorphous form and other crystalline forms of fexofenadine hydrochloride, ethyl acetates solvates of form XIV and XV, and pharmaceutical compositions comprising the same. UK Patent Application number 0319935 (Cipla's Co-pending application) discloses a new polymorphic form of fexofenadine hydrochloride Form-C and a process for preparation of the same. Form-1 is the most thermodynamically stable form of fexofenadine hydrochloride hence, Form 1 is ideally suitable for various pharmaceutical formulations. 3 Although many successful attempts have been made to prepare new polymorphic forms and solvates of fexofenadine hydrochloride, none of them have made an attempt to develop a new process for the preparation of stable crystalline anhydrous Form-I of fexofenadine hydrochloride. Object of the Invention The object of the present invention is to provide a novel process for the synthesis of crystalline anhydrous fexofenadine hydrochloride Form-I, by overcoming the shortcoming of the earlier process as described in the prior art. Another object of the present invention is to provide a process for the conversion of Form-C of fexofendine hydrochloride to fexofenadine hydrochloride Form-I. Summary of the Invention The present invention discloses a process for preparation of Form-I of crystalline anhydrous fexofenadine hydrochloride wherein fexofenadine base is converted to fexofenadine hydrochloride Form-I in suitable organic solvent. The present invention has also disclosed a process for conversion of Form-C of fexofenadine hydrochloride to Form-1 of fexofenadine hydrochloride. Detailed description of the invention The present invention describes a novel process for preparation of fexofenadine hydrochloride Form-I. The present invention provides a process for preparation of Form-I directly from fexofenadine base at temperature about 25°C, thereby eliminating the problems associated with the prior art where fexofenadine hydrochloride was subjected to high temperature to prepare Form-I results into the formation of impurities. The present invention eliminates any possibility of such impurity generated due to high temperatures reaction conditions. 4 In one aspect the present invention there is provided a process for preparation of fexofenadine hydrochloride Form-I. Fexofenadine base was suspended in suitable organic solvent such as tetrahydrofuran, acetone or ethyl acetate, preferably in tetrahydrofuran. Further, the pH of the suspended reaction mass was adjusted below 2.0 by adding the solution of hydrogen chloride gas dissolved in solvent like tertiary butanol or tetrahydrofuran at a temperature ranging from 0 to 25 °C, preferably at 10°C to get a clear solution. The more preferable solvent used to dissolve hydrogen chloride is tetrahydrofuran. Person skilled in the art would use dry hydrogen chloride gas instead, but use of hydrogen chloride gas can generate certain impurities in the product. In the present invention formation of these impurities are avoided by using the hydrogen chloride gas dissolved in a suitable solvent. Further, the solvent from the clear reaction mass was distilled to at least 5 volume of the said solvent under vacuum at temperature ranging from 20-35°C, preferably at 25°C. The reaction mass was stripped with additional 5 volume of the said solvent, 5 times at about 25°C and finally distilled to oily residue at the same temperature. The residue was further dissolved in isopropyl alcohol to get clear solution. Further, ethyl acetate was added to the clear solution and precipitated the solid at ambient temperature. The solid was filtered and dried under high vacuum at 90°C to get Form-I of fexofenadine hydrochloride. In another aspect, the present invention provides a method for converting Form-C of fexofenadine hydrochloride to Form-I by refluxing it in an organic solvent or its mixture thereof preferably ethylacetate, toluene, xylene, isopropanol etc. more .pre^ejrabjy a ethylacetate for about 2 - 4 hrs and further subjecting it to distillation at ambient pressure to about 5 volumes of solvent and allowing it to cool to room temperature to get anhydrous Form-I crystals. The crystalline anhydrous Form-I of Fexofenadine Hydrochloride as obtained by the process of the present invention having an X-ray diffraction pattern, or substantially the same X-ray diffraction pattern, as described in '872 patent. 5 The crystalline anhydrous Form-I of Fexofenadine Hydrochloride as obtained by the process of the present invention is characterized by a differential scanning calorimetry thermogram by a melt endotherm with extrapolated onset in the range of about 195.9-203.3. The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Examples Example-1 50 gms (0.099 m) of fexofenadine base was suspended in 500 ml of tetrahydrofuran and stirred. The reaction mixture was cooled to 15°C; approximately 50 ml of Hydrogen chloride dissolved in tetrahydrofuran was added dropwise to the reaction mass till pH of the reaction mass is below 2. The resulting clear reaction mass was filtered through a bed of celite. The clear filtrate was concentrated to approximately 250 ml under vacuum at 35°C and was further stripped 5 times with 250 ml tetrahydrofuran before concentrating it to residue at 35°C under vacuum. 50 ml of isopropyl alcohol was charged to the oily residue and stirred at room temperature to get a clear solution. 450 ml ethyl acetate was added to the clear solution and was allowed to stir at room temperature for approx 16-18 hrs. The resulting solid suspension was filtered and washed with isopropyl alcohol / ethyl acetate mixture in the ratio 1:9. The product was dried at 90°C under vacuum for 8 hour to give 44 gm (82% yield) of fexofenadine hydrochloride Form-I. Example-2 110 gm (0.219 m) Fexofenadine base was suspended in 1100 ml acetone. The reaction mixture was cooled to 15°C and approximately 100 ml of hydrogen chloride dissolved in tetrahydrofuran was added drop wise to the reaction mass till pH of the reaction mass is below 2. The resulting clear reaction mass was filtered through a bed of celite. The clear 6 filtrate was concentrated upto approx 500 ml under vacuum at 35°C and was further stripped 5 times with 500 ml of acetone, and finally concentrating to 500 ml acetone at 35°C under vacuum. The resulting hazy solution was allowed to stir at room temperature for approx 16-18 hrs. The resulting solid suspension was filtered and washed with 250ml acetone. The product was dried at 90°C under vacuum for 8 hours to give 93 gm (80% yield) of Fexofenadine Hydrochloride Form-I. Example-3 Fexofenadine Hydrochloride 100 gm Form C was suspended in 1000 ml of ethyl acetate. The slurry was refluxed for 2 hour at 75-80°C. Further ethyl acetate was distilled from the slurry at ambient pressure and 80° C. to a volume of at least 500 ml . The reaction mixture was allowed to cool to ambient temperature and stirred at ambient temperature for 5-6 hour. The resulting solid was filtered and dried under vacuum at 80°C for approx. 8 hour to give (95 gm) Fexofenadine Hydrochloride Form-I. 7 We Claim 1. A process for preparation of crystalline anhydrous fexofenadine hydrochloride Form-I comprising the steps of; a) suspending fexofenadine base or fexofenadine hydrochloride Form C in a suitable organic solvent; b) acidifying the suspension of fexofenadine base with hydrochloric acid dissolved in an organic solvent by adjusting the pH below 2 to obtain a clear solution; c) concentrating the reaction mass by distillation to obtain a residue; d) dissolving the residue in isopropyl alcohol to obtain clear solution and precipitating the anhydrous fexofenadine hydrochloride using ethyl acetate from the said reaction mass at a temperature below 25°C. 2. The process as claimed in claim 1, further comprising a step of refluxing the reaction mass of suspended fexofenadine Form C for 2 to 4 hrs before distilling the solvent. 3. The process as claimed in claims 1 and 2, further comprising a step of stirring the reaction mixture after distilling the solvent to effect the precipitation of anhydrous fexofenadine hydrochloride form 1. 4. The process as claimed in claim 1, wherein said organic solvent used to dissolve fexofenadine base is selected from tetrahydrofuran, ethyl acetate or acetone. 5. The process as claimed in claims 1 and 4, wherein said organic solvent used to suspend fexofenadine base is tetrahydrofuran. 6. The process as claimed in claims 1 and 2, wherein said organic solvent used to suspend fexofenadine hydrochloride Form C is ethyl acetate. 8 7. The process as claimed in claim 1, wherein said organic solvent used to dissolve hydrochloric acid is selected from tetrahydrofuran or tertiary butyl alcohol. 8. The process as claimed in claim 1, wherein said organic solvent used to dissolve hydrochloric acid is tetrahydrofuran. 9. The processes for preparation of crystalline anhydrous Fexofenadine Hydrochloride Form-I as substantially described herein with reference to the foregoing examples 1 to 3. Dr. Gopakumar G. Nair Agent for the Applicant Dated this 17 DAY of July 2006

Documents:

1309-mum-2004-cancelled pages(8-12-2004).pdf

1309-mum-2004-claims(granted)-(8-12-2004).doc

1309-mum-2004-claims(granted)-(8-12-2004).pdf

1309-mum-2004-correspondence(17-7-2006).pdf

1309-mum-2004-correspondence(ipo)-(13-1-2006).pdf

1309-mum-2004-form 1(8-12-2004).pdf

1309-mum-2004-form 18(26-8-2005).pdf

1309-mum-2004-form 2(granted)-(8-12-2004).doc

1309-mum-2004-form 2(granted)-(8-12-2004).pdf

1309-mum-2004-form 26(8-12-2004).pdf

1309-mum-2004-form 3(8-12-2004).pdf

1309-mum-2004-form 9(16-5-2005).pdf