SI8911427A - PROCEDURE FOR THE PREPARATION OF RANITIDINE SALTS WITH BISMUTE CARBOXYLIC ACID COMPLEXES - Google Patents

Abstract

The present invention relates to salts formed between ranitidine and a bismuth carboxylic acid complex, as well as to solvates of these salts. Examples of suitable carboxylic salts are citric, tartaric and agaricic. The salts are useful in the treatment of gastrointestinal disorders, particularly gastroduodenal conditions. The salts have the antisecretory activity associated with ranitidine, as well as antibacterial activity against Campylobacter pylori, and in particular cytoprotective properties.

Description

GLAXO GROUP LIMITED

Process for the preparation of ranitidine salts with bismuth carboxylic acid complexes

The field of technology

The present invention relates to the field of organic compound synthesis. The codes of the international patent classification are: C 07 D 307/64; C 07 D 307/52; C 07 F 9/94; A 61 K 31/34.

A technical problem

The organic compound, known as ranitidine, is a potent antagonist of histamine H ₂ -receptors and is widely used in the prevention and treatment of conditions in which gastric acidity is desired. Bismuth compounds have long been used in the treatment of over-acidity and dyspepsia, and before the invention of histamine H ₂ antagonists as well as agents for the treatment of gastrointestinal ulcers.

The present invention solves the technical problem of a process for the preparation of novel ranitidine salts with bismuth carboxylic acid complexes that combine the therapeutically advantageous properties of these two active substances.

The state of the art

Ranitidine is a trade name for N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] -methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethendiamine, which is, together with its physiologically acceptable salts, described and protected in English patent specification no. 1565966. This specification describes physiologically acceptable salts with organic and inorganic acids. Such salts include hydrochloride, hydrobromide and sulfate salts as well as salts formed with aliphatic mono- and dicarboxylic acids such as acetates, maleates and fumarates.

Ranitidine is a potent histamine H ₂ antagonist, widely used in the form of its hydrochloride for the treatment of conditions where it is desired to reduce acidity in the stomach. Such conditions include duodenal and gastric ulcer, reflux esophagitis and Colinger-Elison syndrome. Ranitidine can be used both prophylactically in surgical procedures and in the treatment of allergic and inflammatory processes in which histamine is known as a mediator.

Bismuth salts and preparations such as bismuth citrate, bismuth and ammonium citrate, bismuth sodium tartrate, acidic bismuth sodium tartrate, acidic bismuth solution, concentrated bismuth solution and bismuth and ammonium citrate solution, e.g. in the English Pharmaceutical Code (1949), they have long been used as acid neutralizing agents in the treatment of acidity and dyspepsia. In addition, such bismuth preparations, prior to the invention of histamine H ₂ antagonists, which have now been virtually completely replaced, have been used in the treatment of gastrointestinal ulcers.

In recent years, Catnpylobacter pylori has been shown to be associated with histologic gastritis, non-ulcer dyspepsia, and hypochlorhydria, and may participate in the pathogenesis of gastric and duodenal ulcers.

Campylobacter pylori is susceptible to the action of bismuth compounds such as bismuth subcitrate (eg, in the form of tricalcium dicitrato bismuthate) and bismuth subsalicylate.

Many of the bismuth compounds mentioned are acidic complexes formed between bismuth and carboxylic acids such as citric or tartaric acid, or their salts with ammonia or alkali metals. We have found that the base antagonist of the H ₂ -receptor ranitidine forms salts with such complexes as well as that the resulting products have beneficial and improved action.

Description of solution to a technical problem

The present invention thus provides novel salts formed between ranitidine and bismuth complexes with carboxylic acids, as well as solvates of such salts. Suitable carboxylic acids are those that form complexes with bismuth, and these complexes can form salts with ranitidine.

Carboxylic acids capable of forming bismuth complexes to form bismuth-carboxylic acid complexes for use in the present invention may be e.g. carboxylic acids containing at least three functional groups in addition to the carboxylic group available for the formation of salts with ranitidine. Of the three or more remaining functional groups, three must be capable of complexing with trivalent bismuth to form complexes with trivalent bismuth. These are e.g. carboxyl and / or hydroxy groups.

In cases where the carboxylic acid has optical and / or geometric isomers, the present invention includes all optical isomers, including racemates and geometric isomers. Also included within the scope of the invention are solvates such as hydrates.

Examples of suitable carboxylic acids capable of forming bismuth complexes for use in the invention are citric, tartaric and ethylenediaminetetraacetic. Further examples of suitable carboxylic acids are propylcitronic and agaricic. Tartaric acid is preferred and citric acid is particularly preferred. Agaric acid is a further preferred acid for use in the invention.

The particular salts of the invention are:

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- the propantricarboxylate bismuth (3 ⁺ ) complex, also known as bismuth citrate ranitidine;

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-nitro-1, letendiamine [(RR * R *)] - 2,3-dihydroxybutanedioate bismuth (3 ⁺ ) complex, also known as bismuth tartrate ranitidine;

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- nonadecantricarboxylate bismuth (3 ⁺ ) complex, also known as ranitidine bismuth agaricycate; and

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine N, N'-ethanediylbis [N- ( carboxymethyl) glycine] bismuth (3 ⁺ ) complex, also known as bismuth-EDTA ranitidine.

Preferred salts of the invention are:

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- the propantricarboxylate bismuth (3 ⁺ ) complex, also known as bismuth citrate ranitidine;

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-nitro,1,1-ethendiamine [(RR * R *)] - 2,3-dihydroxybutanedioate bismuth (3 ⁺ ) complex, also known as bismuth tartrate ranitidine;

Another preferred salt of the invention is

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- nonadecantricarboxylate bismuth (3 ⁺ ) complex, also known as ranitidine bismuth agaricycate.

Ranitidine bismuth citrate is a particularly preferred compound of the invention.

The salts of the invention have a particularly preferred combination of properties for the treatment of gastrointestinal disorders, particularly peptic ulcers and other gastroduodenal conditions, e.g. gastritis and non-ulcer dyspepsia.

The salts of the invention thus have the anti-secretory properties of the H ₂ antagonist characteristic of ranitidine, together with the antibacterial action against Campylobacter pylori. In addition, the compounds of the invention have cytotoxic properties. They also act against human gastric pepsins, with preferential inhibition of pepsin 1, a pepsin isozyme associated with peptic ulcer. The antisecretory activity of the compounds of the invention is demonstrated in vivo against the secretion of histamine-induced gastric acid in Heidenhain's small dogs. The antibacterial action of salts against Campylobacter pylori and their ability to inhibit human pepsins has been demonstrated in vitro. In addition, antibacterial activity against Campylobacter-like organisms is shown in vivo in weasels. Cytos protective activity has been demonstrated in vivo with the ability of these salts to inhibit gastric lesions in rats induced by ethanol.

Another feature of the salts of the invention is that they are soluble in water and form stable aqueous solutions. Under normal conditions, many bismuth salts and complexes, including those formed with the carboxylic acids of the type used in the present invention, are insoluble. Bismuth citrate has e.g. solubility (under neutral aqueous conditions) of only 0.2 IU wt./vol.%, while the solubility of ranitidine bismuth citrate in water is higher than 50 wt./vol.%.

The perceived properties of the salts of the invention, such as bismuth citrate ranitidine, are also needed to highlight the fact that these salts are novel chemical substances that are clearly different from simple mixtures (eg, equimolar mixture mixtures) of ranitidine and complexes formed between bismuth and carboxylic acids.

The salts of the invention may differ from the simple mixtures of ranitidine and the complex formed between bismuth and carboxylic acids, also by infrared spectroscopy. Thus, with the passage of a simple mixture of ranitidine and the bismuth-carboxylic acid complex on the salts of the invention, significant changes in the spectrum occur. The infrared spectrum of a simple mixture of ranitidine and bismuth citrate, e.g. major peaks at v _max 1131, 988, and 603 cm &^lt; ^-1 &^gt;, but not in the infrared spectrum of ranitidine bismuth citrate.

The salts of the invention can be obtained by reacting ranitidine with a suitable bismuth-carboxylic acid complex (e.g., bismuth citrate or bismuth ammonium citrate) in a suitable solvent such as water, and then the resulting salt is isolated from the solution.

In a further aspect, the present invention provides the salt formed between ranitidine and the bismuth complex with carboxylic acid, including solvates of such salts, the salt being prepared by reaction of ranitidine with the bismuth and carboxylic acid complex.

According to a particular further aspect, the present invention provides ranitidine bismuth citrate, including solvates thereof, prepared by reaction of ranitidine with the bismuth and citric acid complex.

The reaction between ranitidine and a suitable bismuth-carboxylic acid complex to form the salt of the invention is preferably carried out at elevated temperature, e.g. in the range of 40 to 100 ° C. When the reaction is complete (e.g., when the mixture reaches neutral pH and / or when dissolution is complete), the suspension or solution is cooled and filtered and the desired ranitidine salt can be obtained from the filtrate by evaporation, followed by extraction and trituration of the resulting residue with alcohol , e.g. methanol or ethanol, ketone, e.g. with acetone or ether, e.g. diethyl ether. Alternatively, the reaction mixture can be evaporated directly, and the resulting residue is extracted and in

we triturate. Some alternative methods include drying the filtrate by spraying it or adding the filtrate (if necessary by diluting eg with water) to a suitable counter-solvent (eg alcohol such as ethanol) at elevated temperature (e.g., at the counter-reflux temperature), precipitating product.

The bismuth-carboxylic acid intermediate complexes can generally be obtained by the procedures described in the English Pharmaceutical Code (1949). Thus, e.g. a suspension of a suitable bismuth salt (e.g. bismuth oxynitrate) and a suitable carboxylic acid (e.g. citric or tartaric acid) is heated at e.g. from 90 to 100 ° C in a solvent such as water, the reaction being considered to be complete when, after the addition of e.g. One drop of the mixture into a weak aqueous ammonia solution gives a clear solution. The suspension is then diluted with water, if necessary, and the desired bismuth-carboxylic acid complex is isolated by filtration. Bismuth ammonium citrate may e.g. if necessary, prepare in situ by treating bismuth citrate with a suitable amount of aqueous ammonia solution.

The salts of the invention may be formulated for administration by any suitable route, and the invention includes pharmaceutical compositions containing a salt of the invention adapted for use in human medicine and veterinary use. Such preparations, which are primarily intended for oral administration, may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Tablets are the preferred type of preparation.

For oral administration, the pharmaceutical compositions may be in the form of e.g. tablets (including chewing and sucking tablets) or capsules. These preparations may be obtained in the usual way with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (eg magnesium stearate, talc or silica gel); disintegrating agents (eg potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may also be coated according to methods well known in the art of pharmacy. Liquid preparations for oral administration may be e.g. in the form of solutions, syrups or suspensions, and may be made as dry products, which are reconstituted with water or with another suitable carrier before use. Such liquid preparations can be obtained in the usual way with pharmaceutically acceptable additives such as suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (eg lecithin or acacia); non-aqueous vehicles (eg almond oil, oily esters, ethyl alcohol or fractionated!

vegetable oils) and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavors and fragrances, colorants and sweeteners, as appropriate.

The proposed dose of salt of the invention for internal human administration is from 100 mg to 1 g, preferably from 100 to 800 mg, and more preferably from 150 to 600 mg of active substance per dose. A single dose can be administered e.g. once to four times a day, preferably once or twice. The exact dose depends on the nature and severity of the condition being treated, and it is clear that depending on the age and weight of the patient, unavoidable and certain routine variations in dosage may occur.

The present invention is illustrated by the examples in which temperatures are stated in ° C. Thin layer chromatography (TLC) was performed on silica gel eluting with dichloromethane: ethanol: 0.88M ammonia 70: 8: 1 (A) or ethyl acetate: isopropanol: 0.88M ammonia: water 25: 15: 4: 2 (system B ), except for ultraviolet light, iodoplatinate and potassium permanganate, unless otherwise stated.

Preparation 1

2-Hydroxy-1,2,3-propantricarboxylic acid bismuth (3 ⁺ ) complex (1: 1) (bismuth citrate)

A mixture of bismuth oxynitrate (22.96 g) and citric acid (33.60 g) in water (80 ml) was heated in a steam bath, stirring frequently for 30 minutes, after which, after the addition of 1 drop of suspension, a weak aqueous ammonia solution was obtained. solution. The mixture was diluted with water, filtered, and the residue was washed with water until all the nitrate and excess citric acid had been removed. The residue was dried in vacuo to give the title compound (32.18 g).

Analysis: Found: C, 18.08; H, 1.34; 0 28.80; Bi 52

C _fi H ₅ BiO ₇ .O, lH ₂ O requires: C 18.01; H, 1.32; 028,44; Would 52.2%.

Water analysis showed 0.49% H ₂ O = 0.11 mol.

Preparation 2 [R- (R * R *)] - 2,3-dihydroxybutanedioic acid bismuth (3 ⁺ ) complex (2: 1) (bismuth tartrate) σ

The mixture of (+) - tartaric acid (27 g) and bismuth oxynitrate (8.61 g) in water (50 ml) was heated at 90 to 100 ° C with occasional stirring for 30 minutes, after which time a small amount of the product completely dissolves into a weak aqueous ammonia solution. The mixture was cooled to room temperature, filtered, and the filtrate was washed until all water soluble substances had been removed. The residue was dried at 70 to 80 ° C in vacuo to give the title compound (14.78 g).

Analysis: Found: C 18.44; H, 81; 39.04; Bi 40

ΟθΗθΒϊ.0,43H ₂ 0 requires: C 18.70; H l, 93; 0 38.70; Would 40.7%.

Water analysis showed 0.31% H ₂ O = 0.43 mol.

Preparation 3

2-Hydroxy-1,2,3-nonadecantricarboxylic acid bismuth (3 ⁺ ) complex (1: 1) (Bismuth agaricycate)

A mixture of (-) - 2-hydroxy-1,2,3-nonadecantricarboxylic acid (agaric acid, 9.15 g) and bismuth oxynitrate (5.74 g) in water (50 ml) was heated at 90 to 95 ° C for 4 hours. . The acidic mixture was filtered and the residue washed thoroughly with water until the filtrate was neutral. The residue was washed with hot methanol (3 x 50 ml) and then dried to give the title compound (12.286 g).

Analysis: Found: C, 43.52; H, 6.34; 0 18.49; Bi 31

C ₂₂ H _{3 7} B i 0 ₇ .0,1C ₂₂ H _4Q O ₇ .0,11H ₂ O requirement:

C, 43.63; H, 6.24; 0 18.76; Would 31.4%.

Analysis of water: 0.31% H ₂ O = 0.11 mol

Preparation 4

N, N'-1,2-ethanediylbis [N- (carboxymethyl) glycine] bismuth (3 ⁺ ) complex (1: 1) (Bismuth-EDTA)

A mixture of bismuth oxynitrate (20.09 g) and N, N'-1,2-ethanediylbis [N- (carboxymethyl) glycine] (EDTA, 17.57 g) in water (100 ml) was heated at 90 to 95 ° for 2 hours C. The hot suspension was filtered and the residue was heated again at 90 to 95 ° C with water (4 x 70 ml) until almost all the solid had dissolved. After each extraction, the suspension

-y is filtered off and the strongly acidic filtrates are evaporated in vacuo to about 70 ml. The extraction mixture was cooled to 18 [deg.] C. and the precipitated solid was filtered and washed until nitric acid was removed, with cold water, then with ethanol and ether, and then dried to give the title compound (18.52 g).

Analysis: Found: C, 23.27; H, 2.49; N, 5.41; 0 26.43; Bi 41

C ₁₉ H ₁₃ BiN ₂ O ₈ .0.5H ₂ O requires: C 23.68; H, 2.78; N, 5.52; 0 26.81; Would 41.2%.

Water analysis showed 1.819% H ₂ O = 0.5 mol.

Example 1

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- propantricarboxylate bismuth (3 ⁺ ) complex (1: 1: 1) (Ranitidine bismuth citrate)

A mixture of bismuth citrate (2.08 g) and N- [2 - [[[5 - [(dimethylamino-methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, l -etendiamine (ranitidine, 1.57 g) in water (15 ml) is heated at 90 to 95 ° C until the litmus shows that the suspension is neutral (approx. 15 minutes). The mixture is cooled to room temperature and the unreacted bismuth is filtered (0.657 g) The filtrate was evaporated to dryness in vacuo to give a hard gum. decanted and the residue triturated to a powder with methanol (50 ml) and the suspension filtered, the residue was washed with methanol and dried to give the title compound (1.98 g) TLC (System A) R _f 0.35 (ranitidine) and R _f 0 (bismuth citrate).

Analysis: Found: C, 30.67; H, 3.97; N, 7.10; 0 23.60; S, 3.97; Bi 29 C ₁₉ H ₂₇ B i N ₄ O ₁₀ S. 0, lC ₆ H ₅ Bi 0 ₇ .0,16C ₂ H ₅ OH. 0.48H ₂ 0 Requirements:

C, 31.14; H, 3.86; N, 7.29; 0 23.65; S, 4.17; Would 29.9%.

Water analysis showed 1.06% H ₂ O = 0.48 mol.

The NMR shows: 0.16 mol of ethanol.

Example 2

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- propantricarboxylate bismuth (3 ⁺ ) complex (1: 1: 1)

IV (Ranitidine bismuth citrate)

To a mixture of bismuth citrate (3.98 g) with water (15 ml) was added sufficient 0.88M aqueous ammonia to dissolve the solid. The solution was filtered through hyflo and the combined filtrate was evaporated and the liquid was evaporated in vacuo. After addition of water, the solution was evaporated again until the supernatant vapors above the residue were no longer basic (litmus paper, pH 1-14) (water 5 x 70 ml). Ranitidine (3.14 g) was added to a solution of the residue in water and the resulting solution was evaporated to dryness in vacuo. The water-soluble residue was evaporated again with the addition of water until no more base pairs (16 x 80 ml) were detected. The residue was evaporated in a rotary evaporator at 80 to 90 ° C and the powder residue was removed with ether. The residue was ground to a fine powder, which was suspended in ether and filtered. The resulting product was dried to give the title compound (6.814 g). TLC (system A) R _f 0.3 (ranitidine) and R _f 0 (bismuth citrate).

NMR δ (DMSO-d ₆ ) 2.57 (2H, d, 'A AB of CH ₂ CO), 2.8 - 2.9 (m, CH ₃ NH, CH ₂ CH ₂ S and Z 2 AB of CI ^ CO), 2.87 (s, CH ₃ ) ₂ N ⁺ ), 3.47 (2H, t, CH ₂ CH ₂ NH), 3.86 (2H, s, CH ₂ S), 4.35 (2H , s, CH ₂ N ⁺ ), 6.10 and 6.67 (2H, d + d, furan = CH's).

IR ⁱⁿ max ( ^Nu J ^o1 ) ³⁴⁵⁴ (- ° ^H ) ' ^{3267 and 3200} (-NH-), ^and 1620, ^{1570 and 1260} (-NHC (= CHNO ₂ ) NH- + -CO ₂ -) cm ⁴ .

Analysis: Found: C 31.54; H, 4.04; N, 8.02; 0 23.31; S, 4.32; Bi 28 ^C 13 ^H 22 ^N 4 ° 3 ^S · ^C 6 ^H 5 ^Bi0 7- ⁰ ' ^34H 2 ° ^Claim :

C, 31.75; H, 3.88; N, 7.80; 0 23.02; S, 4.46; Would 29.1%.

Water analysis showed 0.85% H ₂ O = 0.34 mol.

Example 3

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3- propantricarboxylate bismuth (3 ⁺ ) complex (1: 1: 1) (Ranitidine bismuth citrate)

A mixture of ranitidine (44.0 g) and bismuth citrate (40.0 g) in water (70 ml) was heated at 90 to 95 ° C for 30 minutes. The cloudy solution was filtered, diluted with water (20 ml) and then added under stirring to industrial methylated spirit (IMS; 2.4 l) under reflux for one minute. The resulting suspension was heated for 15 minutes and then cooled to room temperature. The title compound (63.0 g) was collected by filtration, washed with

IMS (2 × 200 ml) and dried in vacuo at 40 ° C. TLC (system B) R _f 0.49 (ranitidine) and Rf 0 (bismuth citrate); detection: UV light, iodine.

Example 4

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-etenediamine 2-hydroxy-1,2,3- propantricarboxylate bismuth (3 ⁺ ) complex (1: 1: 1) (Ranitidine bismuth citrate)

Ranitidine (44.0 g) was added to a suspension of bismuth citrate (55.7 g), 0M aqueous ammonia (56 ml) and water (92 ml). The suspension was heated at 90 ° C for 5 minutes and then the resulting cloudy solution was filtered and diluted with water (10 ml). The title compound (10.3 g) was isolated by spray-drying the resulting solution (40 ml of a total volume of 195 ml). TLC (system B) R _f 0.49 (ranitidine) and R _{ 0 (bismuth citrate), detection: UV light, iodine.

Example 5

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine [R- (R'R ')] -2,3-Dihydroxybutanedioate bismuth (3 ⁺ ) complex (1: 1: 1) (Ranitidine bismuth tartrate)

Ranitidine (5.02 g) was added to a suspension of bismuth tartrate (2.02 g) in water (10 ml), the mixture warmed gently with stirring until dissolution was complete. The solution was filtered through hyflo and the combined filtrate was evaporated from the rinses in vacuo to give a thick rubber which, by further evaporation, turned into a foamy solid. This substance was re-evaporated with the addition of methanol (3 x 50 ml) and the rubber residue was extracted with hot methanol (3 x 50 ml). The semi-solid residue was triturated with methanol (20 ml) until a fine suspension of the cream color was obtained, which was then filtered. The residue was reduced to a fine suspension by trituration with methanol (20 ml), filtered and the residue washed with methanol, then with ether and finally dried to give the title compound (1.853 g). TLC (system A) R _f 0.35 (ranitidine), R _f 0 (bismuth tartrate).

IR v _max (KBr) 3600-2000 (complex series of bands, -NH- + -OH), 1750-1500 (series of bands, (-NHC (= CHNO ₂ ) NH- + -CO ₂ -) + -CO ₂ H ), and 1233 (-NHC (= CHNO ₂ ) NH-cm- ¹ .

Analysis: Found: C 28.03; H, 3.59; N, 6.84; 0 24.85; S, 3.87;

^C 13 ^H 22 ^N 4 ° 3 ^S - ^C 4 ^H 3 ° 6 ^Bi - 0,33C _a H _g Bi0 ₁₂ .0,15CH ₃ 0H requirement:

C, 28.22; H, 3.43; N, 6.65; O 24.90; S, 3.81.

The NMR shows: 0.15 mol of methanol.

Example 6

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-etenediamine 2-hydroxy 1,2,3-nonadecantricarboxylate bismuth (3 ⁺ ) complex (1: 1: 1) (ranitidine bismuth agaricate)

A mixture of bismuth agaricocite (containing agaric acid, 0.1 mol and water, 0.11 mol) (4.26) and ranitidine (3.77 g) in water (10 ml) was heated at 90 to 95 ° C for 4 hours. The solution was diluted with water (15 ml) and heated for a further 1 hour. The opalescence fluid was filtered hot through hyflo and the filtrate was evaporated to dryness with ethanol. The rubber residue was re-evaporated with ethanol (3 x 30 ml) to give a gummy substance. This material was dissolved in ethanol (50 ml) and the solution filtered through hyflo. The combined filtrate and the rinsing liquid were evaporated in vacuo to give a gummy substance which was mixed with hot acetone (70 ml) and decanted after 10 minutes of heating. This procedure was repeated and the semi-solid residue triturated with acetone (50 ml) to give a fine suspension. It was filtered off and the residue was washed thoroughly with acetone and dried to give the title compound (4.69 g) as a tan solid.

Analysis: Found: C, 45.37; H 6.50; N, 5.36; 017,43; S, 3.01;

C ₃₅ H ₅₉ N ₄ O ₁₀ SBi.0,05C ₂₂ H ₄₀ O ₇ .0,5H ₂ O requirement:

C, 44.85; H, 6.46; N, 5.80; O, 17.96; With 3.32%.

Water analysis showed 1.04% H ₂ O = 0.5 mol.

TLC (system A) R _f 0.35 (ranitidine) and R _f 0 (bismuth agaricycate / agaric acid). TLC (chloroform: methanol: acetic acid: water, 15: 5: 1: 1) _Rf 0.3 (ranitidine); detection: UV light, iodoplatinate, potassium permanganate and bromocresol green dye and R _f 0,6 (agaric acid), detection: bromocresol green dye.

Example 7

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine N, N'-ethanediylbis [N- ( carboxymethyl) -glycine] bismuth (3 ⁺ ) complex in

1,1-ethendiamine N, N'-ethanediylbis [N- (carboxymethyl) -glycine] bismuth (3 ⁺ ) complex (1: 1: 1) (Ranitidine bismuth-EDTA)

Bismuth-EDTA (2.99 g) and ranitidine (2.2 g) were added water (15 ml) and the mixture warmed to dissolve completely. A small amount of the precipitate formed is filtered through hyflo. The solution was evaporated to dryness in vacuo and the residue was re-evaporated with the addition of methanol (2 x 15 ml). The residue was dissolved in warm methanol (20 ml) and the solution filtered through hyflo. The filtrate was evaporated to dryness to give a semi-solid which was dissolved in methanol (10 ml). Cooling causes the oil to precipitate and a white solid forms after 60 minutes of standstill. The mixture was filtered and the residue was washed with methanol. The solid was resuspended in ethanol and filtered and the residue was washed with ethanol. The solid was resuspended in ethanol and filtered, and the residue was washed with ethanol, then with ether and finally dried to give the title compound (3.786 g). TLC (system A) R _f 0.35 (ranitidine) and R _f 0 (bismuth-EDTA).

Analysis: Found: C 33.57; H, 4.45; N, 10.09; S, 3.70; Bi 24;

^C 13 ^H 22 ^N 4 ^O 3 ^S - ^C 10 ^H 13 ^BiN 2 ^O 8 ^H 2 ^Lightening

C, 33.26; H, 4.49; N, 10.12; S, 3.86; Would 25.2%.

Analysis of the water showed: 2.24% H ₂ O = 1.0 mol.

Examples A to D illustrate the pharmaceutical compositions of the invention wherein the active ingredient is ranitidine bismuth citrate. Other compounds of the invention can be formulated in a similar manner.

Example A Tablets

The tablets may be prepared by conventional methods, such as direct compression or wet granulation.

The tablets can be coated using suitable coating materials such as hydroxypropyl methylcellulose in standard ways.

(i) Direct compression mg / tablet active ingredient lactose microcrystalline cellulose cropping irrigated 1 pyrrolidone magnesium stearate

380 mg 145 mg 140 mg 28 mg mg compression mass

700 mg

The active ingredient, microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone were sieved through a 500 μτη sieve and mixed in a suitable mixer. Magnesium stearate was sieved through a 250 μ-m sieve and added to the mixture. The mixture was compressed into tablets using suitable molds.

(ii) Wet granulation mg / tablet lactose active ingredient pregelatinised Starch cross-linked polyvinylpyrrolidone magnesium stearate

380 mg 215 mg 70 mg 28 mg mg compression mass

700 mg

The active ingredient, lactose and pregelatinized starch are mixed and granulated with water. The wet mass is dried and ground. Magnesium stearate and cross-linked polyvinylpyrrolidone are sieved through a 250 μηι sieve and mixed with granules. The resulting mixture is pressed with suitable tablet molds.

Example B Suction / chewable tablets mg / tablet (i) active ingredient polyvinylpyrrolidone sweetener / flavoring

380 mg mg if desired magnesium stearate 7 mg mannitol up to 700 mg compression mass 700 mg

The active ingredient, sweetener / aroma and mannitol are mixed and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried, milled and a magnesium stearate lubricant (sieved through a 250 μ sieve, ιη) is added. The obtained granules are compressed into tablets with suitable molds.

active ingredient mg / tablet 380 mg hydroxypropyl methylcellulose 20 mg magnesium stearate 7 mg aroma Optional xylitol up to 700 mg compression mass 700 mg

The active ingredient, xylitol and aroma is mixed, granulated with hydroxypropyl methylcellulose in aqueous ethanol and dried. Grind the granulate, add the magnesium stearate lubricant (sieved through a 250 μτη sieve) and compress into tablets with convenient molds.

Example C Capsules

active ingredient pregelatinized starch Magnesium stearate mg / capsule 380 mg 65 mg 5 mg filling mass 450 mg

Sift the active ingredient and pre-gelatinised starch through a 500 μτη sieve and add magnesium stearate (sieved through a 250 μτη sieve). Fill the drops of hard gelatin sulphides of suitable size with the mixture.

mg / capsule (s) active ingredient 380 mg lactose 75 mg polyvinyl pyrrolidone 20 mg cross-linked polyvinylpyrrolidone 20 mg magnesium stearate 5 mg fill weight 500 mg

The active ingredient and lactose are mixed and moistened with a solution of polyvinylpyrrolidone. The mass is dried and milled and mixed with cross-linked polyvinylpyrrolidone and magnesium stearate (sieved through a 250 μτη sieve). The resulting mixture is filled with suitable gelatin capsules of suitable size.

Example D Oral Syrup Active Ingredient 380 mg

hydroxypropyl methylcellulose 45 mg propyl hydroxybenzoate 1.5 mg butyl hydroxybenzoate 0.75 mg saccharin sodium 5 mg sorbitol solution 1,0 ml appropriate buffer if necessary appropriate aroma if necessary purified water up to 10 ml

Hydroxypropyl methylcellulose was dispersed in a portion of hot purified water together with hydroxybenzoates and the solution was allowed to cool to room temperature. Saccharin sodium, flavor and sorbitol solution are added to the stock solution. The active ingredient is dissolved in some of the remaining water and added to the solution. Suitable buffers can be added to adjust the pH to the maximum stability range. The solution is adjusted to the desired volume, filtered and filled with suitable containers.

Claims (12)

PATENT APPLICATIONS A process for the preparation of salts formed between ranitidine and the bismuth complex with a carboxylic acid, or a solvate of such a salt, characterized in that it comprises reacting the ranitidine with the bismuth and carboxylic acid complex in a suitable solvent and separating the salt thus obtained from the solution. Process according to claim 1, characterized in that the solvent is water. Process according to claim 1 or 2, characterized in that the reaction is carried out at elevated temperature. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of from 40 to 100 ° C. Process according to one of Claims 1-4, characterized in that the carboxylic acid contains at least three functional groups in the molecule, in addition to the carboxyl group forming salts with ranitidine. Process according to one of Claims 1 - 4, characterized in that the carboxylic acid is citric, tartaric, ethylenediaminetetraacetic, propylcitronic or agaricic. Process according to one of Claims 1 - 4, characterized in that the carboxylic acid is citric or tartaric. Process according to one of Claims 1 - 4, characterized in that the carboxylic acid is citric. Process according to one of Claims 1-4, characterized in that it is obtained N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methylthio] ethyl] -N'-methyl-2-nitro,1,1-etenediamine 2-hydroxy-1,2,3-propanecarboxylate bismuth (3 ⁺ ) complex and its solvates. Process according to one of claims 1 - 4, characterized in that it is obtained N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro,1,1-ethendiamine [(RR * R *)] - 2 , The 3-dihydroxybutanedioate bismuth (3 ⁺ ) complex and its solvates. Process according to one of Claims 1-4, characterized in that N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl is obtained 2-nitro,1,1-ethendiamine 2-hydroxy-1,2,3-nonadecantricarboxylate bismuth (3 ⁺ ) complex and its solvates. A process according to any one of claims 1-4, characterized in that N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl is obtained 2-nitro,1,1-ethendiamine N, N'-ethanediylbis [N-) carboxymethyl) glycine bismuth (3 ⁺ ) complex and its solvates.