SU1704631A3 - Method for preparation polymorphous form of famotidine - Google Patents

Abstract

Improvements to patent number 8702020 for a new process for the preparation of famotidine polymorphs. The preparation of crystalline structures of the Famotidine polymorph having a low melting point which have high and low bulk density is described. From a solution of a salt of Famotidine in methanol the desired crystalline structures are precipitated or crystallised out by the incorporation of a tertiary organic base and subsequent dilution with a chlorinated hydrocarbon. Seeding with high-density crystals encourages the formation of the corresponding polymorph; rapid precipitation at low temperatures encourages formation of the low-density polymorph.

Description

This invention relates to a method for producing a new polymorphic form of famotidine.

Famotidine is N-sulfamoyl-3- (2 guand-n-thiazol-1-yl) methylthiopropionamidine of the formula

H, N

/ Ј

 N CH, CH,

S CH2 NH2 ///

 cm

H, N

xsox

NH,

317

 Jro (cpn is active in inhibiting the secretion of acid and pepsin and can be used to treat gastric and duodenal ulcers, for example, Pollyger-Ellison syndrome and other disorders of the upper digestive tract.

A known method for the preparation of famotidine is that methyl 3 g (2-guanidino-thiazol-4 yl) methyl tyr - propionimidate is reacted with sulfamide in alcohol at room temperature, followed by evaporation of the solvent and purification of the target product by silica gel column chromatography to obtain the target product with so pl. 163-164 ° C (after recrystallization from methanol).

There is also known a method for producing famotidine by reacting α-methyl J3- (2-guanidinothiazole 4 yl) methyl (propionimidate with sulfamide in methyl alcohol and separating the precipitated crystals of the target product, which after washing with methanol, mp 157.6 ° C and after recrystallization from DMF-water, conversion of the product to acetate by treatment with an equimolar amount (with acetic acid and then again by transferring the salt to the free base by treatment with an equimolar amount of sodium hydroxide, get the desired famotidine p. 163-164 (.

There is also known a method for producing famotidine, in which S- (2-guanidino-thiazol-4-ylmethyl) isothiourea dihydrochloride is reacted with N-sulfamyl-3-chloropropionamidine hydrochloride in an aqueous-alcoholic medium in the presence of sodium hydroxide solution, the isolation filtering target product has a pl. from (159) -1 (up to 162 G ,, and decomposes at 1650C.

,- 50

These variations of thermal properties and different infrared spectra for a product with the same chemical structure confirm the presence of polymorphic forms associated with different physical forms, with the characteristic properties of the chemical structure that are associated with the purity of the material, apparent density and activity. Therefore, it is of interest polymorphic form

Jq j jq

25,

." ., - 50

: i4

ma with special characteristics more acceptable for pharmaceutical use.

The aim of the invention is to create a polymorphic form of famotidine with high anti-ulcer activity1.

This goal is achieved by adding hydrochloric acid to a suspension of famotidine in methanol, which forms hydrochloride as a solution of famotidine and is reacted with a tertiary organic base, such as triethylamine or c 1, azobicyclo (5.4, 0) undec-7-en, pop- | The resulting solution at a temperature of 50-65 ° C is diluted with chlorinated hydrocarbon selected from methylene chloride and chloroform, cooled and recovered by filtration at a temperature of 0-15 ° C a new polymorphic form of famotidine, having an apparent density of 0.20-0.30 g / cm and so pl. 158-161 ° C and characterized by an X-ray diffraction grating, removed on copper radiation with nickel FILTER (Cu: Ni) with a wavelength of 5405 A with the following interplanar spacings d in Angstroms and. relative intensities J / J 4 d (X). J / J ,, 14,68 0,28

7,620,58

7.150.14

5,870.12

5,610,41

5,030,20

4,920,38

4,570,41

4,421,00

4,310,20

4,250,64

3,950,52

3,890,41

3,810,82

3.69 0.68

3,610,33

3,470.09

3,400,19

3,370.20

3,270,21

3.180, P6

3,090.08

2,950,28

2,910.12

2,850,13

2,770.36

2.72 0.05

0.06 O, 19 0.14 0.0 O ,, 7 0.09 0.10 0.06 0.11 0.07 0.05 0.06 0.11 0.08 0.07 0.05 0 , 06 0.06 0.06 0.07 0.05 0.05 0.13

I

Nova polymorphic form famotidine

It is a crystalline structure in the form of short and miniature needle-like prisms. I

A density of 0.20-0.30 g / cm3 is low density. Such a material does not have a static charge and its characteristics allow it to be directly used in some pharmaceutical compositions.

Example 1. Obtaining the polymorphic form of famotidine. I

143.0 g of famotidine with an IR spectrum (KVg) -3 cm: 3430 and 3380 (doublet, singlet), 3300 (singlet), 3220 (singles years), 1660 and 1635 (doublet, singlet) and 1535 (singlet), suspended in 2000 ml of methanol and adjusting the temperature in the range. 22-22 ° C. Concentrated hydrogen chloride (35.0%, 85.0 ml) is added. To the resulting solution, 147.5 g of biline amidine (DNU) are added all at once. The temperature at the same time reaches 35 ° C. After about 10-15 minutes, the solution becomes cloudy. It is immediately heated to the temperature of reflux to give a colorless solution at a temperature of 50-55 ° C. It is diluted with 5000 ml of chloroform and a precipitate begins to form at a temperature of 35-36 ° C. After cooling and keeping at a temperature

specified- t.t. 159-161 ° С, nratura 1P-1:) ° (; it is filtered for 3 hours, washed with successive methanol, dichloromethane and dried. As a result, 107.2 g of compound are obtained and the density is 0.20.

Research using a Kiov stereoscopic microscope

The SDZ-PL, equipped with a device for quickly moving the lens, showed the presence of short prisms in a homogeneous mixture and of a white color. When regenerating solvents from

 the remainder of the septum gives 25.0 g of the compound, which is recycled to the conversion reaction.

Example 2 is carried out similarly to Example 1, but replacing the TLD with M-methylmorpholOH. Obtain the desired polymorphic form of famotidine with the same yield and characteristics as in Example 1.

5P rm. 3. 3. 150 g of famotidine with so pl. 1L, 5 ° 0 and a visible density of 0.78 is dissolved in 2250 ml of methanol with hydrogen chloride (36, OX, 90 ml) and with the aid of

Neither triethylamine (155.0 ml), the possible precipitate is dissolved again by heating to reflux temperature. Methylene chloride is added to the solution at elevated temperature.

(2000 ml), which leads to precipitation. After 4 h (5-10 (), 113.6 g of the title compound were isolated; mp.

157-159 C and apparent density of 0.29, Nova is a polymorphic form of famotidine, having a density of 0.20, and so on.

158-161 C, was studied for antiseptic action in comparison with other polymorphic forms and the known antiulcer drug, cimetidine.

The study of antiulcer activity of substances was carried out on groups of male Wistar rats weighing 202-230 g, in total, six groups were used.

The preparations were administered orally, both forms of famotidine at a dose of 6 mg / kg, and cimetidine at a dose of 100 mg / kg.

Into a solution of carboxymethylcellulose (0.5%) in distilled water, substances were suspended for appropriate treatment and used in a volume of 10 ml / kg.

Ai fiir, a beginner of the LCP, - INDOMR. T .: qing, was applied 30 minutes after the appropriate treatment (.) Of 0 mg / Yu ml / kg orally and used, and then euthanized (after that the stomachs and the formed gastric damage was assessed in millimeter lengths.

The prototypical activity of the test substances was evaluated by inhibition (as a percentage) calculated on the average length of each treated group and averaged over the control group. The results obtained in different groups were compared by a statistical method using correlation analysis and Duncan-Kramer testing. The results are collected in the table.

Thus, the test data presented in the table shows that the polymorphic form of the family, obtained by the proposed method, possesses the highest antioxidant activity and is more preferable for therapeutic use in medicine and in the preparation of pharmaceutical compositions, in particular, such does not change the crystal structure.

jg jf

20

25

thirty

Claims (1)

Invention Formula The method of obtaining the polymorphic form of famotidine with an apparent density of from 0.20 to 0.30 g / cm 5 and melting point 158-161 ° C, characterized by an X-ray diffraction grating, taken on copper radiation with a nickel filter (Cu: Ni) with a wavelength of 1, 5405 A with tracked interplanar spacings d in Angstroms and relative intensities J / J: d (a) j / j , B "7.62 7.15 5.87 5.61 5.03 4.92 4, 57 4.4. A, 31 O, M 0.1 + 0.12 11.41 0.20 0.38 0., 1, 110, 0.20 35 40 characterized in that hydrochloric acid is added to a suspension of famotidine in methanol; the hydrochloride formed as a solution of famotidine is reacted with a tertiary organic base, such as triethylamine, or with 1,8-diazabicyclo 5,4, (G undec-7-ene the resulting solution at a temperature of 50-H5 G is diluted with a chlorinated hydrocarbon selected from methylene chloride and chloroform, cooled and the whole product is isolated by filtration at 0-1 ° C (,. Tplotg / cm3 T „L plotg / cm3 Tpd plotg / cm3 plotg / cm3 100 218.7 ± 2, S4 70, ii7.89 212.8 ± 2.02 7.0+ 2.33 90.0 212.64: 2,200100.0 218, Ј1,952,5 ± 1,1296,4 214.2 ± 1.9413.2t4.7781.3 211, 2222.0i5.1768.8