HU196184B - Process for producing cimetidine-a modification - Google Patents

Description

FIELD OF THE INVENTION This invention relates to a novel process for the modification of cimetidine (chemically: N-cyano-N'-methyl-N '- [2 - [(5-methylimidazol-4-yl) methylthio] ethyl] guanidine). from cimetidine-H (also known as cimetidine-M-1).

Cimetidine is known to be an excellent histamine H2-receptor blocker and as such a highly potent anti-ulcer agent [J. Int. - Med. 3, 86 (1975)].

It is also known that cimetidine exhibits polymorphism, i.e., has several morphologically distinct variants. The characteristics of the .A variant were first clarified in the literature (see, for example, British Patent Specification No. 1,543,238), but in 1979 there were 4 variants (Gazz. Chim. Ita. 109, 535) and in 1985 7 morphologically well distinguishable {crystalline or non-crystalline) [J. Pharm. Biomed. Anal. 3, 303 (1985)].

In human therapy, cimetidine has the above-mentioned No. 1,543,238. It has been incorporated into the specification of today's state-of-the-art pharmacies. However, in recent times, various chemical syntheses have been carried out to develop the cimetidine molecule. These techniques provided technical advances and simplified synthesis, but often resulted in cimetidine with a morphology other than the. For example, cimetidine-Z (see British Patent No. 2,108,117) or cimetidine H-monohydrate (cf. U.S. Patent No. 2,108,117,116) may be used to synthesize cimetidine (see British Patent No. 2,103,206), depending on the conditions of crystallization. see British Patent No. 2,101,991). Consequently, further modifications of these modifications are required for the preparation of solid cimetidine dosage forms.

No. 1,543,238, mentioned several times. According to British Patents, recrystallization in anhydrous organic solvent, preferably isopropyl alcohol or acetonitrile, leads to cimetidine A form. Cimetidine A was also prepared from the cimetidine-H (also known as cimetidine-M-1) form by recrystallization from isopropyl alcohol (see Examples 3 / a and b of Hungarian Patent No. 185,636). However, it is well known that the above recrystallization with organic solvent has several disadvantages. Of these, it is important to note that this method always leads to significant product losses and that the price of solvents has increased dramatically in the last decade. In addition to the technological difficulties, the toxic, flammable and explosive properties of these solvents must not be overlooked.

It is therefore an object of the present invention to provide a process which allows the preparation of the Cimetidine .A 'form without completely removing the organic solvent.

To substantiate the development of our method, we first underwent extensive thermoanalytical studies in accordance with U.S. Patent No. 2,101,991. The cimetidine monohydrate modification prepared according to British Patent Specification No. 6,198,191 and found that at normal heating rates, the material melts at a temperature in the range of about 70 ° C to about 80 ° C and, after removal of crystalline water, forms an irreversible formulation mixture.

However, it has surprisingly been found in our experiments that, when the heat is carried out with a flow gas of a suitable temperature in the space around the sample, there is an excellent opportunity for a favorable industrial scale conversion of cimetidine H (M-1).

This discovery is unexpected because literature on the realization of dehydration of cimetidine monohydrates gives nothing? teaches. A J.Pharm.Biomed.Anal. 3, 303 (1985) also states that, according to .H or other designation, the M-1 * modification may undergo changes in the infrared spectrum after exposure to light or for several months at room temperature. from the characteristic bands of the .A 'variation. However, it is well known that the crystalline form of imethidine A has been crystallized to date in anhydrous organic solvent (see U. S. Patent No. 1,543,238) or by organic solvent crystallization with little water (see U. S. Patent No. 2,101,991). description) could first be produced.

Thus, the present invention is based on the discovery that cimetidine A from the Cimetidine H (also known as cimetidine-M-1) is very easy to accomplish by dehydration.

The present invention provides a process for the preparation of cimetidine A form (A) from cimetidine H (or cimetidine-M-1) form which comprises starting cimetidine H (or cimetidine-M1) form at a temperature of 40-110 ° C. is preferably dehydrated by heating with flowing gas preheated to 60-100 ° C, preferably maintaining the crystalline state continuously.

In the process of the invention, the gas used for dehydration is air, inert gas, nitrogen. The gas flow is effected by means of overpressure or vacuum. It is advisable to use programmed heating and improve the efficiency of dehydration by mechanical methods (stirring, moving) or fluidization.

The starting material cimetidine-H is disclosed in U.S. Patent No. 2,101,991, supra. It is well-known that it is advantageous to start from a homodispersed or near-homodispersed system to improve the efficiency of the dehydration. .

The process according to the invention can also be carried out in nucleotide or centrifuge wet cimetidine H having a moisture content of water from a crystallization medium. In this case, cimetidine-H is dried at a relatively lower temperature range (40 ° C to 50 ° C) by means of programmed heating, followed by the step of stepwise treatment of the modified process of the present invention.

The advantages of the process according to the invention can be summarized as follows:

1.) We obtain a high quality end product that complies with the requirements of the Pharmacopoeia.

2.) There is no need for expensive flammable and explosive organic solvents, thus avoiding solvent traffic and solvent regeneration.

3.) The implementation of the process does not require any special equipment. Salt, industrial implementation can also be accomplished by disclosing U.S. Pat. The starting and crystallized starting material (cimetidine .H ') prepared according to British Patent Specification is directly dried or dehydrated by filtration or centrifugation.

The invention is illustrated by the following examples:

Example 1

Sieve fractions were obtained from the Cimetidine. we put it in a tube, which is sealed with a dense mesh at the bottom and a suction strainer at the top. A thermometer is mounted in the part of the tube below the mesh fabric, and a heater capable of producing air of sufficient temperature can be connected to it.

The suction nozzle at the top of the column is connected to the mains vacuum line by inserting a cyclone system laboratory dust separator. An aluminum foil cover is applied to the center of the column to reduce heat loss.

The apparatus thus assembled and sealed is then begun to dehydrate 50 grams of cimetidine (M-1), taking care that the air flow is neither too high nor too low. After stabilization of the fluid state, the inlet air temperature is controlled to 70 ° C and maintained at this temperature within ± 3 ° C for one hour. After one hour, the inlet air temperature is adjusted to 80 ° C as described above, and after another hour, the temperature is adjusted to 90 ° C. The temperature of the inlet air to the column is raised to 110 ° C for one hour in isothermal sections, and after another hour, the system is cooled to 70 ° C by passing air at room temperature. Subsequently, the material is extracted from the fluidizing tube, the characteristic bands of the infrared spectrum of which are shown in the following data:

Product Infrared Specifications:

(cm -1): 3401, 3226s, 3142s, 3098, 3051, 3038, 2995, 2943, 2898, 2621, 2298, 2237, 2178s,

1662, 1623s, 1588s, 1502, 1466, 1454s, 1443, 1422, 1403, 1388s, 1347s, 1308, 1283, 1243, 1228, 1204s, 1156s, 1124, 999, 954s, 864, 842, 832, 800, 764, 755, 743, 716, 688s, 667s, 635s, 603, 560, 534, 428, 418. (s = significant peak)

The weight of the product is:

32.7g. It is recovered from the dust separator

11.8 g of material which is not morphologically uniform so that it can be taken back to the beginning of the process.

Example 2

3.4 g (cimetidine .H '(or M1) containing 1.6% water in addition to the crystalline water) are placed in a crystallization bowl in which air is supplied at 62 ° -64 ° C. material is taken out and weighed.

Product: 3.12 g of cimetidine (m.p. 140 DEG -141 DEG C.) having the same IR spectrum as in Example 1.

Claims (5)

PATENT CLAIMS A process for the preparation of cimetidine (chemically known as: N-cyano-N'-methyl-N '- [2- (5-methylimidazol-4-yl) methylthio / ethyl] guanidine). -H (or alias: cimetidine-M-11), characterized in that the starting cimetidine-H (or alias cimetidine-M-1) is 40-110 ° C, preferably 60-100 ° C. It is dehydrated by preheated flowing gas with flowing gas, preferably while maintaining a crystalline state. 2. A process according to claim 1, wherein the dehydrating gas is air, inert gas, nitrogen. Process according to claim 1 or 2, characterized in that the flow of the dehydrating gas is carried out by applying pressure or vacuum. 4. The process of claim 4 wherein the dehydration is carried out with homodisperse starting material. 5. A process according to any one of the preceding claims, wherein the material to be dehydrated is moved by fluidization or agitation.