This invention relates to an improved process for the preparation of crystalline form -1 of N-[2-[[[5-[(dimethylamino)methyl]2-furanyl]methyl]thio]ethyl] N-methyl-2-nitro-l, 1-ethenediamine hydrochloride, designated as ranitidine hydrochloride.
Hitherto the process for the preparation of the crystalline form 1 of ranitidine hydrochloride employs a mixture of ethanol and ethyl acetate.
Ranitidine hydrochloride is used as an antiulcerative drug. Two forms of ranitidine hydrochloride are reported till now, namely 'form 1' and 'form 2'. These two forms differ in their infrared (IR) spectral analysis and x-ray diffraction analysis. The data is given below.
IR Spectra fin solid stated : The spectra exhibited considerable differences, especially with respect to bands in the region above 3000 cm"', (bonded NH absorption), between 2700-2300 cm"' region (protonated dimethyl amino group) and between 1620-1570 cm"' region (stretching vibration of the C==N double bound). [Ref Journal of Chemical Society. Perkin transaction.II 1984. PP. 1765-1766].
X-ray diffraction :The X-ray powder diffraction data recorded for forms 1 and 2 are presented in tables I and II here under. [Ref Analytical profiles of Drug Substances, Vol. 15,P.549-553].

Eventhough they differ in their crystalhne forms both have been reported to be bioequivalent.
The known process of preparing the crystalhne form-1 "ranitidine hydrochloride" involves the use of ethylalcohol (or methylated spirit), (US.Pat.No. 4,128,658). It is very well known that ethylalcohol is not freely available, as in many places, there is government control for its supply and usage. Due to the restricted availability and usage of ethylalcohol, the process for the preparation of "crystalline form-1" of ranitidine hydrochloride on a commercial scale using ethylalcohol has become difficult. At the same time, the demand of "ranitidine hydrochloride form-1", as an anti-ulcerative drug, is increasing. There is an increasing need to develop a simpler process for the preparation of 'form 1' of ranitidine hydrochloride using easily available solvents and chemicals.
The main objective of the present invention is therefore to provide an improved process for the preparation of crystalline 'form-1' of ranitidine hydrochloride to meet the above said requirements.
Another objective of the present invention is to provide a synergestic solvent system which is useful for the preparation of crystalline form-1 of ranitidine hydrochloride.
The present invention is based on our finding that when methanol and isopropyl alcohol are mixed, in certain specific ratios the resultant mixture acquires unexpected properties which can be capitalised for the preparation of the crystalline form-1 of ranitidine hydrochloride. The property of the resulting mixture is unexpected because either methanol or isopropylalcohol, as such, does not possess such properties.

This property results due to a synergestic effect when the solvents are mixed. The solvent used in the process of the present invention is a combination of methanol, isopropylalcohol and ethyl acetate. In a preferred embodiment of the present invention the ratio of methanol and isopropylalcohol used may be 1:1 to 1:6. The amount of ethyl acetate used may range from 1 to 6 times that of the total mixture of the solvents.
Accordingly, the present invention provides an improved process for the preparation of a crystalline form-1 of ranitidine hydrochloride which comprises dissolving ranitidine base in a solvent comprising methanol and isopropylalcohol in the ratio ranging from 1:1 to 1:6, adjusting the pH of the resulting solution to the range of 3to5 by using hydrochloric acid gas and adding ethylacetate in an amount of I to 6 times of the above said solvent mixture to effect precipitation of the crystalline fonn-l, filtering the resulting precipitate and washing the precipitate with the above said solvent mixture and drying.
The dissolution of ranitidine base in the solvent is effected by stirring the mixture for a period ranging from 30 minutes to 3 hours. The drying of the crystalline form-1 of ranitidine hydrochloride may be effected by drying it at a temperature in the range of 40 to 70"C under reduced pressure. It is to be noted that the process of the present invention has to be effected in anhydrous conditions.
The details of the invention are given in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the present invention.
EXAMPLE-! N-[2-[[[5-[(Dimethylamino)methyl]2-furanyl]methyl]thio]ethyl]N'-methyl
-2-nitro-l,l-ethenediamine(ranitidine base)(10g) is dissolved in a mixture of methanol

(10ml) and isopropylalcohol (30ml). The pH of the solution is adjusted to 4.0 by using dry hydrochloric acid gas. Then ethyl acetate (60ml) is added to the reaction mass. The crystallisation is initiated by seeding with crystalline form-1 ranitidine hydrochloride crystals. The mixture is stirred at ambient temperature for 30 minutes. The form-1 of ranitidine hydrochloride which got precipitated is filtered and washed with the above said solvent mixture and dried. Yield 10 g.
EXAMPLE 2
N-[2-[[[5-[(Dimethylamino)methyl]2-furanyl]methyl]thio]ethyl]N'-methyl -nitro-l,l-ethenediamine(ranitidine base)(20g) is dissolved in a mixture of methanol(18ml) and isopropylalcohol (42ml). The pH of the solution is adjusted to 4.5 by using hydrochloric acid gas. To the resulting solution ethyl acetate (100ml) is added and crystallisation is initiated by seeding with form-1 crystals of ranitidine hydrochloride. The mixture is stirred at ambient temperature for 30 minutes. The crystalline form-1 of ranitidine hydrochloride precipitated from the above solution is filtered and washed with the same solvent mixture, as used for dissolution in this example and dried. Yield : 19.5g.
EXAMPLE 3
N-[2-[[[5-[(Dimethylamino)methyl]2-furanyl]methyl]thio]ethyl]N'-methyl -nitro-l,l-ethenediamine(ranitidine base)(40g) is dissolved in a mixture of methanol (40ml) and isopropylalcohol( 160ml). The pH of the reaction mass is adjusted to 4.2 by using dry hydrochloric acid gas. Ethyl acetate (320ml) is then added and the crystallisation is initiated by adding form-1 crystals of ranitidine hydrochloride. The mixture is stirred at ambient temperature for 30 minutes. The precipitated crystals of ranitidine hydrochloride (form-1) are filtered and washed with the above said solvent mixture and dried. Yield 40.6 g.

We Claim
1. An improved process for the preparation of the crystalhne form-1 of ranitidine hydrochloride which comprises dissolving ranitidine base in a solvent comprising methanol and isopropylalcohol in the ratio ranging from 1:1 to 1:6, adjusting the pH of the resulting solution to the range of 3 to 5 by passing hydrochloric acid gas through the mixture and adding ethylacetate in an amount of 1 to 6 times that of the above said solvent mixture to effect precipitation of the crystalline form-1, filtering the resulting precipitate and washing the precipitate with the above said solvent mixture and drying.
2. An improved process as claimed in claim-1 wherein the solution is mixed by stirring which is effected for a period ranging from 30 minutes to 3 hours.
3. An improved process as claimed in claims 1 and 2 wherein crystalline form-1 of ranitidine hydrochloride crystals are added to the solution to initiate crystallization.
4. An improved process as claimed in claims 1 to 3 wherein the drying of the crystalline form-1 of ranitidine hydrochloride is effected by heating it to a temperature in the range of 40°C to 70°C under reduced pressure.
5. An improved process for the preparation of the crystalline form-1 of ranitidine hydrochloride substantially as herein described with reference to the examples.