SK279173B6 - Complex ranitidine salts, a method of preparation thereof and pharmaceutical agents containing these salts - Google Patents

Abstract

Ranitidine salts with complex tartaric acid or citric acid compound with bismuth, and a solvate of such salts and a method of preparation thereof. The salts are useful in the treatment of gastrointestinal disorders, particularly gastroduodenal conditions. The salts show the antisecretory activity ascribed to ranitidine together with antibacterial activity against Campylobacter pylori and they possess cytoprotective properties as well.

Description

Technical field

The invention relates to complex salts of ranitidine acting on histamine receptors, to a process for the preparation of these salts, to pharmaceutical compositions containing them, and to their use in medicine. In particular, the present invention relates to ranitidine salts of bismuth-carboxylic acid complex compounds.

BACKGROUND OF THE INVENTION

Ranitidine is the commonly used name for N - [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine, which is described, together with its physiologically acceptable salts with inorganic and organic acids, in British Pat. 1,565.966. These salts include hydrochlorides, hydrobromides and sulfates and salts formed with aliphatic monocarboxylic and dicarboxylic acids such as acetates, maleates and fumarates.

Ranitidine is a potent antagonist of the histamine H ₂ receptors, which in the form of its hydrochloride is widely used in the treatment of conditions in which it is advantageous to reduce gastric acidity. These include duodenal and stomach ulcers, reflux esophagitis and Zollinger-Ellison syndrome. Ranitidine can also be used prophylactically in surgical procedures and for the treatment of allergic and inflammatory conditions where histamine is a known mediator.

Bismuth salts and bismuth-containing compositions such as bismuth citrate, bismuth citrate, bismuth sodium tartrate, bismuth acid tartrate, bismuth acid solution, bismuth concentrated solution, and bismuth and ammonium citrate solutions described in, e.g. They have long been used as antacids in the treatment of hyperacidity and dyspepsia. In addition, prior to the introduction of H ₂ -receptor histamine antagonists at which they have now practically emerged, such bismuth agents have also been used to treat gastrointestinal ulcers.

In recent years, there has been a link between Campylobacter pylori and histological gastritis, non-ulcer dispepsia and hypochlorohydria, and this bacterium may be a contributing factor to gastric and duodenal ulcers.

Campylobacter pylori is susceptible to bismuth compounds such as bismuth subcitrate (e.g., tripotassium dicitranobismuthate) and bismuth subsalicylate.

A number of said bismuth compounds are acid complex compounds formed from bismuth and a carboxylic acid such as citric acid or tartaric acid, or salts thereof with ammonia or an alkali metal. It has now been found that a basic ranitidine H ₂ -receptor antagonist forms salts with such complex compounds and that the resulting products have a useful and advantageous activity profile.

SUMMARY OF THE INVENTION

The invention thus provides novel ranitidine salts with complexes of bismuth and carboxylic acids selected from the group consisting of tartaric acid and especially citric acid, as well as solvates of these salts.

In the case of tartaric acid, optical and / or geometric isomers may occur, and the invention therefore encompasses all optical isomers including racemates and / or geometric isomers. Solvates including hydrates are also within the scope of the invention.

In particular, the salts according to the invention are: N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt , formed with a complex compound of triple bismuth with 2-hydroxy-1,2,3-propanetricarboxylic acid, also known as ranitidine bismuth citrate and N- [2 - [[[[5 - [(dimethylamino) methyl] -2] methyl] -2 -furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine formed with a complex of trivalent bismuth compound with [R- (R ⁺ R ⁺ )] - 2,3-dihydroxybutanedioic acid, known also as ranitidine-bismuth-tartrate.

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

The salts of the invention have a particularly advantageous combination of properties for the treatment of gastrointestinal diseases, in particular ulcers resulting from digestive juice and other gastroduodenal diseases such as gastritis and non-ulcer dyspepsia.

The salts of the invention have H ₂ -antagonistic antisecretory properties as well as ranitidine, together with antibacterial activity against Campylobacter pylori. In addition, the salts of the invention have a protective effect on the cells. They also have activity against human gastric pepsins, in particular they inhibit pepsin 1, i.e. the pepsin isozyme causing ulcer resulting from digestive juice.

The antisecretory activity of the compounds of the invention against histamine-induced gastric acid secretion has been demonstrated in in vivo experiments on a dog (Heindenhain cam). The antibacterial activity of these salts against Campylobacter pylori and their ability to inhibit human peptins has been demonstrated by in vitro experiments. In addition, the antibacterial activity of these salts against Campylobacter-like organisms has been demonstrated in vitro on ferrets. The protective effect on cells has been demonstrated in vivo by the ability of these salts to inhibit ethanol-induced gastric lesions in rats.

Another advantageous feature of the salt of the invention is that they are water-soluble and provide stable aqueous solutions. Normally, many salts and complex bismuth compounds, including those formed with carboxylic acids of the type used to produce the salts of the invention, are insoluble. For example, bismuth citrate has a solubility (under neutral aqueous conditions) of only 0.2% w / v, while the water solubility of ranitidine-bismuth citrate is greater than 50% w / v.

Thus, the observed properties of the salts of the invention, such as ranitidine-bismuth citrate, serve to underline the fact that they are distinct chemical individuals that can be clearly distinguished from simple mixtures (e.g. in equimolar proportions) of ranitidine with a complex carboxylic bismuth compound. acid.

The salts of the invention can be distinguished from simple mixtures of ranitidine with a bismuth-carboxylic acid complex compound by infrared spectroscopy. When changing from a simple mixture of ranitidine with a bismuth-carboxylic acid complex compound to the salt according to the invention, larger changes in spectrum are observed. In the infrared spectrum of a simple physical mixture of ranitidine with bismuth citrate, for example, there are larger peaks at v max of 1131, 988 and

603 cm ’· that do not appear in the ranitidine-bismuth-citrate infrared spectrum.

The salts of the invention may be prepared by reacting ranitidine with an appropriate complex of bismuth compound with a carboxylic acid (for example, bismuth citrate or bismuth-ammonium citrate) in a suitable solvent such as water and isolating the resulting salt from the mother liquor.

According to a further aspect of the invention, a salt of ranitidine with a complex of bismuth with tartaric or citric acid, including solvates of such salts, is obtained by reacting ranitidine with a corresponding complex of bismuth with a carboxylic acid.

According to a particularly preferred embodiment of the invention, ranitidine bismuth citrate including solvates thereof is prepared by reacting ranitidine with a complex bismuth compound with citric acid.

The reaction of ranitidine with the appropriate bismuth-carboxylic acid complex compound to obtain the salt of the invention is preferably carried out at an elevated temperature, for example at a temperature in the range of 40 to 100 ° C. Once the reaction is complete (for example, when the reaction mixture reaches a neutral reaction by pH and / or when the reagents are completely dissolved), the resulting suspension or solution is cooled and filtered and the desired ranitidine salt can be recovered from the filtrate by evaporation and subsequent extraction and trituration the resulting residue with an alcohol such as methanol, or a ketone such as acetone, or an ether such as diethyl ether. Alternatively, the reaction mixture can be evaporated directly followed by extraction and trituration of the resulting residue. Other alternative methods for isolating the salt formed include evaporating the filtrate by spraying or adding the filtrate (optionally after dilution with, for example, water) to a suitable displacement solvent (e.g., an alcohol such as ethanol) at elevated temperature (e.g. at reflux temperature of the displacement solvent). .

As a rule, complex compounds of bismuth with a carboxylic acid used as an intermediate can be prepared according to the procedures described in the British Pharmaceutical Code (1949). For example, a suspension of an aqueous bismuth salt (e.g., basic bismuth nitrate) and an appropriate carboxylic acid (e.g., citric or tartaric acid) may be heated at a temperature of, e.g., 90-100 ° C in a solvent such as water. for example, a drop of the reaction mixture gives a clear solution when added to a weak aqueous ammonia solution. The suspension is then optionally diluted with water and the desired bismuth-carboxylic acid complex compound isolated by filtration. For example, bizutito ammonium citrate can be prepared, optionally in situ, by treating bismuth citrate with an appropriate amount of aqueous ammonia solvent.

The salts of the invention may be formulated for administration by any suitable means and within the scope of the invention are pharmaceutical compositions comprising a salt of the invention adapted for use in human or veterinary medicine. Such compositions, especially for oral administration, may be formulated in a conventional manner using at least one pharmaceutically acceptable carrier or excipient. Tablets are a preferred type of formulation.

For oral administration, the pharmaceutical compositions of the invention may take the form of, for example, tablets (including chewing or sucking) or capsules. These compositions can be prepared by conventional procedures with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose or dibasic calcium phosphate), lubricants (e.g., magnesium stearate, talc or silica). disintegrants (e.g. potato starch or sodium starch glycolate) or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by known methods. Liquid compositions for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be dry products for constitution with water or other suitable vehicle before use. Such compositions may be prepared by conventional procedures with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia gum), non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol) or fractionated vegetable oils) and preservatives (e.g. p-hydroxybenzoic acid methyl or propyl ester or sorbic acid). Said compositions may also contain buffers, flavoring, coloring and sweetening agents as appropriate.

The proposed dosage of the salts of the invention for internal administration to humans is 100 mg to 1 g, preferably 100 to 800 mg, and in particular 150 to 600 mg of active ingredient per unit dose. The unit dose can be administered, for example, once or four times a day, preferably once or twice a day. The exact dose will depend on the nature and severity of the disease, and it may also be necessary to vary the dose as appropriate to the age and weight of the patient.

The invention is explained in more detail by the following examples, wherein the temperature is in degrees Celsius. TLC analysis on silica, eluting with dichloromethane / ethanol / 0.88 ammonia 70: 8: 1 (system A) or ethyl acetate / isopropanol / 0.88 ammonia / water ratio 25: 15: 4: 2 (System B) and UV, iodoplatinate, and potassium permanganate are used for detection unless otherwise noted.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1

Complex of 2-hydroxy-1,2,3-propanetricarboxylic acid with trivalent bismuth (1: 1) (bismuth citrate)

A mixture of 22.96 g of basic bismuth nitrate and 33.60 g of citric acid in 80 ml of water is heated with vigorous stirring for 30 minutes in a steam bath. After this time, a drop of suspension, introduced into a weak aqueous ammonia solution, gives a clear solution. The mixture is then diluted with water, filtered and the residue is washed thoroughly with water until it no longer contains nitrate or excess citric acid. The residue was then dried under reduced pressure to give 32.18 g of the title compound.

Analysis for C6H5B10. 0,1 HjO:

calculated: C 18.01 H 1.32 0 28.44 Bi 52.2% found: C 18.08 H 1.34 0 28.80 Bi 52% Water content: 0.49% H 2 O i.e. 0.11 mol.

Preparation 2

Complex compound [R- (R ⁺ R ⁺ )] - 2,3-dihydroxybutyridic acid with trivalent bismuth (2: 1) (bismuth tartrate)

A mixture of (+) - tartaric acid (27 g) and bismuth basic nitrate (8.61 g) in water (50 ml) was heated at 90-100 ° C with stirring for 30 minutes. After this time, a sample of the resulting product was completely dissolved in a weak aqueous ammonia solution. The mixture was then cooled to room temperature, filtered and washed thoroughly with water until water-free. The residue was dried under reduced pressure at 70-80 ° C to give 14.78 g of the title compound.

Analysis for C 8 H 11 BiO 4. 0.43 H2O: calculated: C 18.70 H 1.93 0 38.70 Bi 40.7% found: C 18.44 H 1.81 O 39.04 Bi 40% Water content: 1.54% H 2 O i.e. 0.43 mol.

Example 1

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt with trivalent bismuth (1) : 1: 1) (ranitidine-bismuth-citrate)

A mixture of 2.08 g of bismuth citrate with 1.57 g of N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1 of l-ethanediamine (ie ranitidine) in 15 ml of water is heated at 90-95 ° C until the suspension reaches a neutral reaction to the pH of the paper (approximately 15 minutes). The mixture was then cooled to room temperature and unreacted bismuth citrate (0.657 g) was filtered off. The filtrate was evaporated to dryness under reduced pressure to give a hard gum, to which 50 ml of methanol was added and the mixture was evaporated. 70 ml of methanol are added to the residue, the mixture is heated and then cooled. The turbid supernatant is decanted, the residue is triturated with 50 ml of methanol and the suspension is filtered. The filter residue was washed with methanol and dried to give 1.98 g of the title compound. Thin Layer Chromatography (System A): Rf = 0.35 (ranitidine), Rf = 0 (bismuth citrate).

Analysis for C19H4BÍN4O10S 0.1 C6H5B1O, 0.16 C2H5OH, 0.48 _H2O:

calculated: C 31.14 H 3.86 N 7.29 O 23.65 S 4.17 Bi 29.9% found: C 30.67 H 3.97 N 7.10 O 23.60 S 3.97 Bi 29%

Water content: 1.06% H2O i.e. 0.48 mol. According to the NMR spectrum, the ethanol content is 0.16 mol.

Example 2

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt of complex compound 2- bismuth (1: 1: 1) hydroxy-1,2,3-propanetricarboxylate (ranitidine-bismuth-citrate)

To a mixture of 3.98 g of bismuth citrate and 15 ml of water was added an aqueous solution of 0.88 ammonia in an amount sufficient to dissolve the solids. The resulting solution was filtered through a HYFLO filter aid and the filtrate and the wash water were evaporated under reduced pressure. The resulting residue was re-evaporated after dissolution in water, which was repeated until the vapor above the residue was no longer basic (as determined by pH 1 to 14 indicator paper strips) (water 5 x 70 ml). To a solution of the residue in 30 ml of water is then added 3.14 g of ranitidine and the solution is evaporated to dryness under reduced pressure. The water-soluble residue is then re-evaporated after dissolution in water, which is repeated until the steam no longer shows a basic reaction (16 x 80 ml). The resulting residue is then dried on a rotary evaporator under reduced pressure at 80-90 ° C and the powdered residue is removed with ether. The residue was then ground to a fine powder, which was suspended in ether and filtered. Drying the product yields 6.814 g of the title compound.

Thin Layer Chromatography (System A): Rf = 0.3 (ranitidine), Rf = 0 (bismuth citrate).

NMR Spectrum: δ (DMSO-d 6): 2.57 (2H, d, 1/2 AB of CH ₂ CO), 2.8-2.9 (m, CH ₃ NH, CH ₂ CH ₂ S and 1/2 AB from CH ₂ CO, 2.87 (s, (CH) 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 2 ').

IR spectrum: v max (Nujol) 3454 (OH), 3267 and 3200 (NH) and 1620, 1570 and 1260 (-NHC (= CHNO ₂₎ NH ₂ + CO) cm ^- '

Analysis for C ₁₃ H ₂₂ N 4 O ₃ S. C6H5B1O. 0.34 H ₂ O: calculated: C 31.75 H 3.88 N 7.80 O 23.02 S 4.46 Bi 29.1% found: C 31.54 H 4.04 N 8.02 O 23 , 31 S 4.32 Bi 28%

Water content: 0.85% H ₂ O ie 0.34 mol.

Example 3

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt of 2-hydroxy complex -1,2,3-propanetricarboxylate with trivalent bismuth (1: 1: 1) (ranitidine bismuth citrate)

A mixture of 44.0 g ranitidine and 40.0 g bismuth citrate in 70 ml water was heated at 90-95 ° C for 30 minutes. The cloudy solution is filtered, diluted with 20 ml of water and added to 2.4 liters of industrial alcohol denatured under reflux for 24 minutes with stirring. The resulting suspension was heated for 15 minutes then cooled to room temperature. Filtration gave 63.0 g of the title compound, which was washed twice with 200 ml of industrial alcohol denatured with methanol each time, then dried under reduced pressure at 40 ° C.

Thin Layer Chromatography (System B): Rf = 0.49 (ranitidine), Rf = 0 (bismuth citrate).

Detection: UV, iodine.

Example 4

N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt of 2-hydroxy complex -1,2,3-propanetricarboxylate with trivalent bismuth (1: 1: 1) (ranitidine bismuth citrate)

To a suspension of 55.7 g of bismuth citrate in 56 ml of a 1.0 molar aqueous ammonia solution and 92 ml of water was added 44.0 g of ranitidine. The suspension is then heated at 90 ° C for 5 minutes and the resulting cloudy solution is filtered and diluted with 10 ml of water. Evaporation of the resulting solution by spraying isolated 10.3 g of the title compound.

SK 279173-6

Thin Layer Chromatography (System B): Rf = 0.49 (ranitidine), Rf = 0 (bismuth citrate). Detection: UV, iodine.

Example 5 N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine salt of complex compound [ R- (R ⁺ R ⁺ )] - 2,3-dihydroxybutanedioate with trivalent bismuth (1: 1: 1) (ranitidine-bismuth-tartrate)

To a suspension of 2.02 g of bismuth tartrate in 10 ml of water was added 5.02 g of ranitidine and the mixture was heated gently with stirring until the solids had dissolved. The resulting solution is filtered with the aid of the HYFLO filter aid and the filtrate, together with the washing water, is evaporated under reduced pressure to give a viscous gum which is converted to a foamed solid by further evaporation. This was re-evaporated three times with 50 ml of methanol each time and the gummy residue was extracted three times with 50 ml of hot methanol each time. The semi-solid residue is triturated with 20 ml of methanol until a creamy fine suspension is formed which is filtered. The residue is triturated with 20 ml of methanol to give a fine suspension, which is filtered and the residue is washed first with methanol and then with ether. After drying 1.853 g of the title compound is obtained.

Thin layer chromatography (System A): Rf = 0.35 (ranitidine), Rf = 0 (bismuth tartrate).

IR (KBr) 3600-2000 (complex row of bands, -NH- + -OH), 1750-1500 (row of bands,

-NHC (= CHNO2) NH- + -CO2- + -CO2H) and 1253 (-NHC (= CHNO2) NH-) cm -1

Analysis for C13H22N4O3S C4H3B10. 0.33

C8H9B1O12.0,15 CH3OH:

calculated: C 28.22 H 3.42 N 6.65 O 24.90 S 3.81 found: C 28.03 H 3.59 N 6.84 O 24.85 S 3.87 The NMR spectrum indicates a methanol content of 0 , 15 mol.

Examples A to D below describe pharmaceutical compositions according to the invention wherein the active ingredient is in particular ranitidine bismuth citrate. Other compounds of the invention may be formulated in a similar manner.

Example A

tablets

Tablets can be prepared by conventional methods such as direct compression or wet granulation.

Tablets may be coated with suitable materials, such as hydroxypropylmethylcellulose, by conventional methods.

(i) Direct compression mg / tablet

active ingredient 380 mg lactose 145 mg microcrystalline cellulose 140 mg cross-linked polyvinylpyrrolidone 28 mg magnesium stearate 7 mg the weight of the compressed tablet 700 mg

The active ingredient, microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 µm sieve and mixed in a suitable mixer. The magnesium stearate is sieved through a 250 µm sieve, added to the blend and blended. Tablets are then compressed from the resulting mixture using suitable punches.

(ii) Wet granulation mg / tablet

active ingredient 380 mg lactose 215 mg pregelatinized starch 70 mg cross-linked polyvinylpyrrolidone 28 mg magnesium stearate 7 mg

the weight of the compressed tablet

700 mg

The active ingredient, lactose and pregelatinized starch are mixed together and granulated with water. The wet mass is dried and ground. The magnesium stearate and cross-linked polyvinylpyrrolidone are sieved through a 250 µm sieve and blended with the granulate obtained. Tablets are then compressed from the resulting mixture using suitable punches.

Example B

Chewable / chewable tablets mg / tablet (s) active ingredient polyvinylpyrrolidone sweetener / flavor magnesium stearate mannitol weight of compressed tablet

380 mg mg as needed mg to 700 mg

700 mg

The active ingredient, sweetener / flavor and mannitol are sieved together and granulated with a polyvinylpyrrolidone solution. The wet mass is dried, ground and magnesium stearate, sieved through a 250 µm sieve, is added. Tablets are then compressed from the resulting granulate using suitable punches.

mg / tablet (ii) active ingredient hydroxypropylmethylcellulose magnesium stearate flavor xylitol

380 mg mg mg as necessary up to 700 mg tablet weight 700 mg

The active ingredient, xylitol and the flavoring are mixed together, granulated using a solution of hydroxypropylmethylcellulose in aqueous ethanol and dried. The resulting granulate is ground, magnesium stearate, sieved through a 250 µm sieve, is added, and tablets are compressed using suitable punches.

Example C capsules mg / capsule (i) the active ingredient 380 mg pregelatinized starch 65 mg magnesium stearate 6 mg capsule fill weight 450 mg

The active ingredient and the pregelatinized starch are sieved through a 500 µm sieve, mixed, and magnesium stearate sieved through a 250 µm sieve is added to the mixture. The resulting mixture is filled into hard gelatin capsules of appropriate size.

mg / capsule (ii) active ingredient 380 mg lactose75 mg polyvinylpyrrolidone20 mg cross-linked polyvinylpyrrolidone 20 mg magnesium stearate5 mg capsule fill weight 500 mg

The active ingredient and lactose are mixed together and the resulting mixture is moistened with a solution of polyvinylpyrrolidone. The mass is then dried and ground, then crosslinked polyvinylpyrrolidone and magnesium stearate, sieved through a 250 µm sieve, are added. The resulting mixture is mixed, then filled into hard gelatine capsules of appropriate size.

Example D

Syrup for oral administration

active ingredient 380 mg hydroxypropyl 45 mg hydroxybenzoic acid butyl ester 0.75 mg propyl ester of hydroxybenzoic acid 1.5 mg saccharin sodium 5 mg sorbitol solution 1.0 ml suitable buffers as needed suitable flavorings as needed purified water to 10 ml

Hydroxypropylmethylcellulose is dispersed in a portion of hot purified water along with hydroxybenzoic acid esters and the resulting solution is allowed to cool to room temperature. The saccharin sodium, flavorings and sorbitol solution are added to the bulk of the solution. The active ingredient is dissolved in a portion of the remaining amount of water and the resulting solution is added to the bulk of the solution. Suitable buffers may be added to control the pH in the region of maximum stability. The resulting solution is made up to volume, filtered and filled into suitable containers.

Claims (14)

PATENT CLAIMS A salt formed from ranitidine and a bismuth complex and a carboxylic acid selected from the group consisting of citric acid and tartaric acid, or a solvate of such a salt. The salt of claim 1, wherein the carboxylic acid is citric acid. A salt according to claim 1 which is N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro- 1,1-Ethenediamine with a complex of trivalent bismuth and 2-hydroxy-1,2,3-propanetricarboxylate, as well as solvates of such a salt. A salt according to claim 1 which is N- [2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro- 1,1-ethenediamine with a complex of trivalent bismuth and [(R- (R * R *)] - 2,3-dihydroxybutanedioate, as well as solvates of such a salt. A process for the production of a salt according to any one of claims 1 to 4, characterized in that ranitidine is reacted with a complex of a bismuth compound with a carboxylic acid in a suitable solvent, then the salt thus formed is isolated from the solution. 6. The process according to claim 5, wherein the solvent is water. A process according to claim 5 or 6, characterized in that the reaction is carried out at elevated temperature. Process according to claim 5 or 6, characterized in that the reaction is carried out at a temperature of 40 to 100 ° C. A pharmaceutical composition comprising a salt according to any one of claims 1 to 4 together with at least one pharmaceutically acceptable carrier or diluent. 10. A pharmaceutical composition according to claim 9 which is adapted for oral administration. 11. A pharmaceutical composition according to claim 9, which is in the form of tablets. Pharmaceutical composition according to claim 10 or 11, characterized in that it is in the form of a unit dose containing 100 mg to 1 g of salt per unit dose. Pharmaceutical composition according to claim 10 or 11, characterized in that it is in the form of a unit dose containing 100 mg to 800 mg of salt per unit dose. 14. A pharmaceutical composition according to claim 10 or 11 which is in the form of a unit dose containing 150 mg to 600 mg of salt per unit dose.