MXPA97008122A - A process for preparing ranitidine hydrochloride form - Google Patents

Abstract

A process for preparing N- [2 - [[[5- [dimethalamino] -methyl-2-furanyl] -methyl] -2-furanyl] methyl] thio] etuK-N'-methyl-2-nitro-1 hydrochloride , Pure 1-ethyldiamine, designated ranitidine hydrochloride Form 1, from ranitidine in methylene chloride with the addition of hydrochloric acid. The ranitidine hydrochloride Form 1 asóobtenido is stable and therefore useful to produce commercial scale amounts of ranitidine hydrochloride Form

Description

A PROCESS TO PREPARE RANITIDINE HYDROCHLORIDE FORM 1 FIELD OF THE INVENTION The present invention relates to the hydrochloride salt of the H2 antagonist N- [2 - [[[5- [dimethylamino] -methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1 , 1-ethyldiamine, also known as ranitidine. More specifically, the present invention relates to a novel process for the production of ranitidine hydrochloride form 1.

BACKGROUND OF THE INVENTION The patent of E. U.A. No. 4, 128,658, issued Dec. 5, 1978 to Price et al., Discloses various aminoalkyl furan derivatives including ranitidine. Example 32 of the patent of E. U.A.

No. 4, 128,658 in particular describes the preparation of ranitidine hydrochloride Form 1, by dissolving ranitidine in an industrial methylated spirit (a solvent made mostly of ethanol) containing hydrogen chloride gas, and crystallizing with the addition of ethyl acetate. This process is unsatisfactory due to the instability of ranitidine hydrochloride in the solvent crystallization system described, which contains ethyl acetate and ethanol. In particular, the process is inadequate for large-scale production. The patents of E. U.A. Nos. 4, 521, 431 and 4,672, 133, issued to Crookes on January 4, 1985 and January 9, 1987, respectively, describe a crystalline form of ranitidine hydrochloride, which is designated as Form 2 and which supposedly has more favorable filtration and drying characteristics than the ranitidine hydrochloride Form 1 obtained from the process using hydrogen chloride gas in industrial methylated spirit and ethyl acetate, as described in Example 32 of the E patent. U .A. No. 4, 128,658. The ranitidine hydrochloride Form 2 of Crookes can be prepared by treating a solution of ranitidine in a hydroxylic solvent, v. gr. , a lower alkanol, with hydrochloric acid followed by crystallization at elevated temperatures by adding additional amounts of solvent. Alternatively, ranitidine hydrochloride Form 2 can be prepared from ranitidine hydrochloride Form 1 or Form 2 previously isolated by dissolving the salt, v. gr. , heating in an organic solvent, such as methanol or ethanol, followed by cooling to cause crystallization of the Form 2 salt, optionally accompanied by the addition of an anti-solvent or by the addition of seeds of form 2 to induce crystallization. The differences between Form 2, as described in the patents of E. U.A. Nos. 4, 521, 431 and 4,672, 133, and Form 1, which is the product of Example 32 of the E patent. U .A. No. 4, 128,658, are characterized by infrared spectra and X-ray powder diffraction patterns. The patent of E. U.A. No. 5, 338,871 to Ngooi et al., Is directed to the preparation of ranitidine hydrochloride Form 1 pure, forming a solution of ranitidine hydrochloride in a solvent mixture comprising at least one lower aliphatic alcohol, preferably ethanol, and a aromatic hydrocarbon, preferably toluene, and initiating crystallization by seeding with pure form 1 ranitidine hydrochloride crystals. Ranitidine hydrochloride Forms 1 and 2, both have histamine H2 block activity. However, due to the progression of difficulties experienced with Form 1, v. gr. , its sensitivity to moisture and the inability to produce it in commercial quantities, Form 2 has been produced exclusively and used as the active ingredient in the treatment of conditions where there is hypersecretion of gastric acid, such as gastric or peptic ulceration, and in the treatment of allergic conditions where histamine is a known mediator. Form 2 is also used in the treatment of allergic and inflammatory conditions. So that Form 1 can also be used to treat these conditions, there is a need for a process that will consistently produce pure and stable ranitidine hydrochloride Form 1 without any co-production of, or conversion to, Form 2.

OBJECTS AND COMPENDIUM OF THE INVENTION It is therefore an object of the present invention to provide a process for preparing ranitidine hydrochloride Form 1, which will remain stable for an extended period. It is also an object of the present invention to provide a process for preparing a seed material of ranitidine hydrochloride Form 1 pure for use in the large scale production of ranitidine hydrochloride Form 1. The present invention is thus directed to a process for the preparation of pure form 1 ranitidine hydrochloride comprising dissolving ranitidine in a solvent, mixing the solution thus obtained with hydrochloric acid to form a reaction mixture, and crystallizing the hydrochloride from ranitidine Form 1 of the reaction mixture. Ranitidine, which is employed herein, is described in the patent of E.U.A. No. 4, 128,658 mentioned above. More particularly, the process of the present invention comprises the steps of dissolving ranitidine in methylene chloride, adding hydrochloric acid, with or without cooling, to the solution thus obtained, mixing the solution to form a reaction mixture, heating the reaction mixture under reflux and while heating, separate the water under azeotropic conditions to produce crystals of ranitidine hydrochloride Form 1. The crystals of ranitidine hydrochloride Form 1 which are thus produced are then filtered, washed with ethanol and dried. These crystals can be used as seeds to induce additional crystallization which will result in large scale production quantities of ranitidine hydrochloride Form 1 pure, (See Example 6 below), without any co-production of, or conversion to, hydrochloride. of ranitidine Form 2. The present invention is also directed to pure form 1 ranitidine hydrochloride produced through processes described herein and characterized by its infrared spectrum.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 is an infrared spectrum of ranitidine hydrochloride Form 1 of the present invention in a KBr pellet, where the ordinate is the transmittance in% and the abscissa is the wave number in cm "1.

DETAILED DESCRIPTION OF CURRENTLY PREFERRED MODALITIES The present invention provides a process for the preparation of ranitidine hydrochloride Form 1. More particularly, the present invention provides a process for preparing pure form 1 ranitidine hydrochloride, which among other uses, can be used as a seed material to produce large-scale quantities of ranitidine hydrochloride Form 1 in a second process. The seed material of pure ranitidine hydrochloride Form 1 can be prepared by dissolving ranitidine in a solvent, preferably methylene chloride, at room temperature (20 ° to 25 ° C), wherein the ratio of ranitidine to methylene chloride is about 1: 1 to 1: 5, preferably 1: 4, treating the solution thus obtained with concentrated aqueous hydrochloric acid (eg, from 35 to 38% w / w). The hydrochloric acid and ranitidine can be mixed without cooling to form a reaction mixture. Preferably, however, hydrochloric acid and ranitidine are mixed with cooling from -5 ° C to 10 ° C. The reaction mixture is then heated under reflux and during heating, the water is separated under azeotropic conditions. Preferably, the reaction mixture is heated under reflux for at least 4 hours, most preferably for about 6.5 hours. Alternatively, the reaction can be carried out under mild reaction conditions, such as, for example, from 0 ° C to 10 ° C to 20 ° C to 25 ° C for about 6.5 hours. The crystals of ranitidine hydrochloride Form 1 that are formed, are then filtered from the crystallization medium, washed with ethanol and dried. Alternatively, the planting material of pure rantidine hydrochloride Form 1 can be prepared by first introducing a solvent, preferably methylene chloride, in preferably a first oxygen-free reactor (1) at 20 ° -25 ° C. Then the ranitidine is added to the solvent and the solution thus obtained was stirred for about 10 minutes and then cooled to about 0o at -5 ° C. Preferably, in a second oxygen-free reactor (2), a solvent, preferably methylene chloride, is introduced and cooled to about -5 ° C. After loading the reactor (2) with hydrogen chloride gas at -5 ° C, the ranitidine solution of the reactor (1) was slowly added to the reactor (2) to form a reaction mixture, the temperature of the mixture remaining stable. about -5 ° to 0 ° C, and the pH to about 6 to 6.8. (It is important to maintain the acidic pH in order to avoid co-production of ranitidine hydrochloride Form 2). After stirring the reaction mixture for several hours, the crystallization of pure form 1 ranitidine hydrochloride occurred. The crystals of ranitidine hydrochloride Form 1 which were formed, and then filtered by centrifugation, for example, and dried under vacuum at a maximum of 40 ° C for about 2 to 3 hours. Among the uses for these crystals of ranitidine hydrochloride Form 1 is as a seed material in the large-scale production process that will be described later. When production quantities of pure Form 1 ranitidine hydrochloride are desired, a preferred method is first to first introduce oxygen-free, pure ethanol into a reactor instead of solvents such as, for example, toluene and ethyl acetate. At 15 ° to 20 ° C, ranitidine was added to the ethanol and stirred for about 15 minutes to dissolve ranitidine. The ratio of ranitidine to ethanol is from about 1: 2 to 1: 4, preferably about 1: 3.6. Then, aqueous hydrochloric acid (35%) was added to the solution thus obtained, until a pH of 6 + about 0.2 was reached at about 30 ° C. While maintaining this acid pH and a temperature of about 30 ° to 35 ° C, the seed material of ranitidine hydrochloride Form 1 (as produced by the process described above) was added to the solution at a concentration of about 3% to 20% by weight. Preferably, the concentration of the seed material in the solution is about between about 4% to 7% by weight. For one hour, the crystallization of ranitidine hydrochloride Form 1 occurs. The crystals of ranitidine hydrochloride Form 1 which are formed, are then filtered by centrifugation, for example, and dried under vacuum at a maximum of 40 ° C for about 2 to 3 hours. The stability test results of the ranitidine hydrochloride compound Form 1 and the tablets containing the ranitidine hydrochloride Form 1 confirm the retention of the polymorph of Form 1 for at least six months of storage at 40 ° C / 75% RH. The present invention also provides pure Form 1 ranitidine hydrochloride produced through the processes described herein and characterized by its infrared spectrum as shown in Figure 1. Ranitidine hydrochloride Form 1 may be formulated to be administered in any convenient manner, and the invention includes, within its scope, pharmaceutical compositions comprising ranitidine hydrochloride Form 1 adapted for use in humans or veterinary medicine. Said compositions may be presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient and may also contain, if required, other active ingredients, v. gr. , H i-antagonists. In this way, the hydrochloride salt according to the invention can be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred, particularly in the form of tablets and capsules. For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For buccal administration, the compositions may be in the form of tablets or troches formulated in a conventional manner. Ranitidine hydrochloride Form 1 can be formulated for parenteral administration through bolus injection or continuous infusion. Formulations for injection may be presented as a dose unit in ampoules or in multi-dose containers, with an added preservative. The compositions may have forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Ranitidine hydrochloride Form 1 can also be formulated in rectal compositions, such as suppositories or retention enemas, v. gr. , containing conventional suppository bases such as cocoa butter or other glycerides. For topical application, ranitidine hydrochloride Form 1 can be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner. For internal administration, the dose should be adjusted to the individual needs of each patient. In general, the manufacturer's specifications for any drug or drug combination are useful administration guides. You can also check the Physician's Desk Reference or other publication to find out the appropriate levels of the drug. However, the typical dose for adults can vary from 100 mg daily to as much as 6 g daily, depending on the severity of the symptoms being treated. For example, for the treatment of active duodenal ulcer, the usual dose for an adult is 150 mg twice a day. For the treatment of pathological hypersecretory conditions, the usual dose for an adult is 150 mg twice a day, but it can be administered more frequently if necessary, for the treatment of erosive esophagitis, the usual dose for an adult is of 150 mg four times a day. The present invention is more particularly described and explained through the following examples. However, it should be understood that the embodiments and preferred examples described are for purposes of illustration only, and are not construed as limiting the scope of the present invention, which is properly delineated only in the appended claims.

EXAMPLE 1 50 g (0.16 moles) of ranitidine were dissolved in 250 ml of methylene chloride at room temperature. Without cooling, 14.9 ml (0.167 mol) of the concentrated aqueous HCl solution was added. The temperature of the emulsion was increased to 6 ° C and the pH of the oil phase varied from 2.5 to 3. The reaction mixture was then heated under reflux for 6. 5 hours. During the heating of the mixture, 10.5 ml of water were separated under azeotropic conditions. Ranitidine hydrochloride Form 1 crystallized. After filtration, washing with absolute ethanol and drying, 53.4 g of ranitidine hydrochloride were obtained Form 1.

EXAMPLE 2 50 g (0.16 mole) of ranitidine were dissolved in 250 ml of methylene chloride at room temperature. Without cooling, 15.6 ml (0.175 moles) of a concentrated aqueous HCl solution was added. The temperature of the emulsion was increased by up to 6 ° C. The pH of the oil phase varied from 2 to 2.5. Refer to Example 1 for the remaining steps of the process. 52.6 g of ranitidine hydrochloride Form 1 were obtained.

EXAMPLE 3 100 g (0.32 mole) of ranitidine were dissolved in 500 ml of methylene chloride at room temperature. Without cooling, 34 ml (0.382 mole) of the concentrated aqueous HCl solution was added. The temperature of the emulsion was increased by up to 12 ° C. The pH of the oil phase was 2. Refer to Example 1 for the remaining steps of the process. 1 1 1.2 g of ranitidine hydrochloride Form 1 was obtained.

EXAMPLE 4 18.86 g (0.32 mol) of HCl in 1000 ml of methylene chloride were introduced at room temperature. To this solution was added 130 g of ranitidine dissolved in 390 ml of methylene chloride at 20 ° C, without cooling. The pH of the oil phase was 2. After sowing with a ranitidine HCl Form 1, the oil phase crystallized. Refer to Example 1 for the remaining steps of the process. 103.5 g of ranitidine hydrochloride Form 1 were obtained.

EXAMPLE 5 120 liters of methylene chloride were introduced into an oxygen-free reactor (1) of 600 liters at room temperature. 40 kg of ranitidine was added to this solvent. After stirring for 10 minutes, the solution was cooled to 0 ° -5 ° C. In a second oxygen-free reactor (2), 200 liters of methylene chloride were introduced and cooled to -5 ° C. 4.5 kg of HCl gas was charged at -5 ° C. While maintaining the temperature from -5 ° C to 0 ° C, a sufficient quantity of the ranitidine solution of the reactor (1) was added slowly until the pH ranged from about 6 to 6.8. After stirring the reaction mixture for several hours, the ranitidine hydrochloride Form 1 crystallized. Ranitidine hydrochloride Form 1 was dried under vacuum at a maximum of 40 ° C for 2-3 hours. 42 kg of ranitidine hydrochloride Form 1 were obtained.

EXAMPLE 6 1080 liters of ethanol were introduced into an oxygen-free reactor. At 15-20 ° C, 300 kg of ranitidine was added to the solvent. This solution was stirred for 15 minutes to dissolve ranitidine. Through a spout, 85 liters of a 35% aqueous hydrochloric acid solution were added, until a pH value of 6 + 0.2 was reached at 30 ° C. To this solution was added, at 30 ° -35 ° C, 17 kg of the seed crystals of ranitidine hydrochloride Form 1 (produced in Example 5). The pH value was 6 ¿0.2. After one hour, the pure form 1 ranitidine hydrochloride was crystallized. After centrifugation, the ranitidine hydrochloride was dried under vacuum at 40 ° C. 350 kg of ranitidine hydrochloride Form 1 were obtained. It should be understood that the embodiments and preferred examples described are for purposes of illustration only and have been constructed to limit the scope of the present invention, which is suitably delineated only by the appended claims.

Claims (8)

1. - A process to prepare ranitidine hydrochloride Form 1 pure, which comprises: dissolving ranitidine in a solvent comprising methylene chloride; mixing the solution thus obtained with hydrochloric acid to form a reaction mixture; and crystallize the ranitidine hydrochloride Form 1 from the reaction mixture.

2. The process according to claim 1, wherein further includes the steps of heating the reaction mixture under reflux, and while heating, separating the water under azeotropic conditions.

3 - The process according to claim 2, wherein the reaction mixture is heated under reflux for at least 4 hours.

4. The process according to claim 3, wherein the reaction mixture is heated under reflux for about 6.5 hours.

5. The process according to claim 1, wherein ranitidine and hydrochloric acid are mixed with cooling from -5 ° to 10 ° C.

6. - The process according to claim 1, wherein the ranitidine is dissolved in said solvent at room temperature.

7. The process according to claim 7, wherein the ratio of ranitidine to methylene chloride is from about 1: 1 to 1: 5.

8. - The process according to claim 8, wherein the ratio of ranitidine to methylene chloride is about 1: 4. 9. - A process for preparing ranitidine hydrochloride Form 1, which comprises: dissolving ranitidine in ethanol at 15 ° to 20 ° C, the ratio of ranitidine to ethanol being from about 1: 2 to 1: 4; mixing the solution thus obtained with hydrochloric acid to form a reaction mixture having a pH of from 6 + to about 0.2; and while maintaining this acid pH and a temperature of about 30 ° to 35 ° C, add the seed material of ranitidine hydrochloride Form 1 to the reaction mixture in a concentration of 3% to 20% by weight, so that the crystallization of ranitidine hydrochloride Form 1 occurs. 10. The process according to claim 10, wherein the ratio of ranitidine to ethanol is about 1: 3.6. 1 - The process according to claim 10, wherein the seed material is added in a concentration of 4% to 7% by weight. 12.- Ranitidine hydrochloride Form 1 prepared by dissolving ranitidine in methylene chloride, the ratio of ranitidine to methylene chloride being from about 1: 1 to 1: 5, mix the solution thus obtained with hydrochloric acid to form a mixture of In the reaction, heat the reaction mixture under reflux, and while heating, separate the water under azeotropic conditions to form crystals of ranitidine hydrochloride Form 1 without any co-production of, or conversion to ranitidine hydrochloride Form 2. 13. - The ranitidine hydrochloride Form 1 according to claim 13, wherein the ratio of ranitidine to methylene chloride is about 1: 4. 14.- Ranitidine hydrochloride Form 1 prepared by dissolving ranitidine in ethanol from 15 ° C to 20 ° C, the ratio of ranitidine to ethanol being from about 1: 2 to 1: 4, adding aqueous hydrochloric acid to the solution thus obtained until a pH of 6 + about 0.2 is reached at about 30 ° C, and while maintaining this acidic pH and a temperature of about 30 ° C to 35 ° C, add the seed material of ranitidine hydrochloride Form 1 to the solution in a concentration of about 3% to 20% by weight, whereby the crystallization of ranitidine hydrochloride Form 1 occurs. 15. The ranitidine hydrochloride Form 1 according to claim 15, wherein the ratio of ranitidine to ethanol is about 1: 3.6. 16. A process for preparing ranitidine hydrochloride Form 1 pure, which comprises: dissolving ranitidine in a solvent consisting essentially of methylene chloride; Mix the solution thus obtained with hydrochloric acid to form a reaction mixture; and crystallize the ranitidine hydrochloride Form 1 from the reaction mixture. 17. The process according to claim 16, wherein further includes the steps of heating the reaction mixture under reflux, and while heating, separating the water under azeotropic conditions. 18. The process according to claim 17, wherein the reaction mixture is heated under reflux for at least 4 hours. 19. The process according to claim 18, wherein the reaction mixture is heated under reflux for about 6.5 hours. 20. The process according to claim 16, wherein ranitidine and hydrochloric acid are mixed with cooling from -5 ° to 10 ° C. 21. The process according to claim 16, wherein the ranitidine is dissolved in said solvent at room temperature. 22. The process according to claim 21, wherein the ratio of ranitidine to methylene chloride is from about 1: 1 to 1: 5. 23. - The process according to claim 22, wherein the ratio of ranitidine to methylene chloride is about 1: 4. 24. - A process to prepare ranitidine hydrochloride Form 1 pure, which includes: dissolving ranitidine in a solvent; mixing the solution thus obtained with hydrochloric acid to form a reaction mixture; heating the reaction mixture under reflux and while heating, separating the water under azeotropic conditions; crystallize ranitidine hydrochloride Form 1 from the reaction mixture. 25 - The process according to claim 24, wherein the reaction mixture is heated under reflux for at least 4 hours. 26. - The process according to claim 25, wherein the reaction mixture is heated under reflux for about 6.5 hours. 27. The process according to claim 24, wherein the ranitidine and the hydrochloric acid are mixed with cooling from -5 ° to 10 ° C. 28. The process according to claim 24, wherein the solvent is methylene chloride. 29 - The process according to claim 28, wherein the ranitidine is dissolved in said solvent at room temperature. 30. The process according to claim 29, wherein the ratio of ranitidine to methylene chloride is approximately 1: 1 to 1: 5. - The process according to claim 30, wherein the ratio of ranitidine to methylene chloride is about 1: 4. SUMMARY A process for preparing pure N- [2 - [[[5- [dimethylamino] -methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1, 1-ethyl-iamine hydrochloride, designated ranitidine hydrochloride Form 1, from ranitidine in methylene chloride with the addition of hydrochloric acid. The ranitidine hydrochloride Form 1 thus obtained is stable and therefore useful for producing commercial scale quantities of ranitidine hydrochloride Form 1.