HK1017611B - Pharmaceutical preparations of cilansetron stabilized against racemization - Google Patents

Description

Stable pharmaceutical formulation of cilansetron against racemization

The invention relates to solid and liquid pharmaceutical formulations containing Cilansetron (Cilansetron) as active substance, which contain a sufficient amount of a physiologically tolerated water-soluble acidic additive to confer stability against racemisation of Cilansetron. The invention further relates to the use of such an acidic additive for the anti-racemization stabilization of cilansetron in pharmaceutical preparations.

Cilancetron is known from EP-B0297651 as the generic name for R- (-)5, 6, 9, 10-tetrahydroxy-10- [ (2-methyl-imidazol-1-yl) methyl ] -4H-pyrido- [3, 2, 1-jk ] carbazol-11 (8H) -one. The compounds can be prepared according to known methods described in this patent or analogously thereto. Furthermore, a process for obtaining enantiomers from cilansetron is known from EP-A0768309. Cilansetron has 5 HT-antagonistic properties and can be used as a pharmaceutical active substance. Celancetolone is known from EP-B0601345 for the treatment of lower gastrointestinal diseases.

Cilansetron is an optically active compound. In pharmaceutical preparations, cilansetron can be partially racemized over time, in particular when stored open, by environmental influences, so that optically active isomers in addition to cilansetron are present in the pharmaceutical preparation. It is therefore desirable for pharmaceutical preparations that the active substances contained therein are present in a sustained, uniform form.

The object of the present invention is to prepare a pharmaceutical formulation in liquid or solid form containing cilansetron or its physiologically tolerated acid addition salts as active substance, wherein cilansetron is stable against racemization.

The object of the present invention is a pharmaceutical preparation containing active cilansetron or its physiologically tolerated acid addition salts in conventional therapeutically effective doses, characterized in that the preparation also contains at least one physiologically tolerated water-soluble acidic additive in a suitable dose for stabilizing the cilansetron against racemization. The object of the present invention is also the use of the acidic additive to make cilansetron or its acid addition salts stable against racemization, especially in pharmaceutical formulations.

According to the invention, cilansetron or its physiologically tolerated salts are subjected to a stabilization treatment against racemization. Suitable acid addition salts are those of cilansetron with inorganic acids, for example sulfuric acid or hydrohalic acids, in particular hydrohalic acids, or with physiologically tolerated organic acids. The acid addition salt preferably used is cilansetron-hydrochloride, which is usually present in solid form as the monohydrate.

For the anti-racemization stabilization of cilansetron or its acid addition salts in solid or liquid pharmaceutical preparations, the compounds are suitablePhysiologically tolerated water-soluble acidic additives having a first pK with 2 to 12 carbon atoms_SMonobasic or polybasic organic acids with values between 1.1 and 4.8, acid salts of the aforementioned polybasic organic acids and their first possible pK_SAcid salts of polybasic inorganic acids with values between 1.5 and 7.5, and mixtures of these compounds. In solid pharmaceutical formulations, solid water-soluble acidic additives are used. In liquid pharmaceutical formulations, solid or liquid water-soluble acidic additives may be used.

As solid acidic additives, for example, malonic acid, mandelic acid, oxalic acid, lactic acid, lactobionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid or physiologically tolerated acidic salts of these acids can be used. Also contemplated are acid salts of inorganic acids such as phosphoric acid or sulfuric acid, and mixtures of these compounds, preferably acid salts of phosphoric acid such as the physiologically tolerated dihydrogen phosphate salts. In liquid pharmaceutical preparations, the solid acidic additives mentioned above can be used, in addition to physiologically tolerated liquid organic acids, such as acetic acid.

Acidic salts of mostly polybasic acids come into consideration, for example, their physiologically tolerated alkali metal or alkaline earth metal salts, especially their sodium, potassium or calcium salts or their ammonium salts.

The pharmaceutical formulation of cilansetron of the invention contains a usual pharmaceutically effective dose of cilansetron. For example, a solid pharmaceutical formulation may contain between about 10mg and about 250mg of cilansetron per gram of formulation, while a liquid formulation typically contains between about 1mg and about 10mg of cilansetron per milliliter of formulation.

The stabilised preparation according to the invention preferably comprises an acid addition salt of cilansetron, especially cilansetron-hydrochloride. It has been shown that the dosage of acid necessary to form the acid addition salt of cilansetron is often not sufficient in itself to effectively protect cilansetron from racemization. Thus, the pharmaceutical preparation contains, as water-soluble acidic components, the acids necessary for forming acid addition salts of cilansetron and acidic additives. Only the pharmaceutical formulation by formulating a physiologically tolerable water-soluble acidic additive according to the invention gives cilansetron a satisfactory and reliable stability against racemization.

Provided that its first pK is applied in a solid pharmaceutical formulation_SAn organic acid having a value of between 1.1 and 4.8 as acidic additive, the molecular ratio of water-soluble acid component to cilansetron being approximately between 1.02: 1 and 5.0: 1, preferably between 1.15: 1 and 3.0: 1. As long as an acid addition salt of cilansetron is present, the acid content of the formulation is provided by the presence of the acidic moiety in the acid addition salt. Thus in solid pharmaceutical preparations of the acid addition salt of cilansetron, the molecular ratio of the added water-soluble acidic additive to the cilansetron-acid addition salt is advantageously between about 0.02: 1 and about 4.0: 1, preferably between about 0.15: 1 and 2.0: 1. Thus in the usual 150mg tablet form with a cilansetron-hydrochloride monohydrate content of 4.68mg, the cilansetron is effectively stabilized against racemization, for example by containing about 0.05mg to 10.0mg of citric acid, preferably about 0.3mg to 4.0mg of citric acid. Preferably, the first pK is applied in a solid pharmaceutical preparation_S-a solid organic acid with a value between 1.1 and 4.8. Ascorbic acid and/or citric acid may be used in particular.

If applied in solid pharmaceutical preparations with a higher pK_SAn acidic additive having a value, for example, between 4.8 and 7.5, the molecular ratio of the water-soluble acid component to cilansetron is suitably between about 4: 1 and 10: 1, preferably between about 5: 1 and 8: 1. The use of the weakly acidic additive in solid pharmaceutical preparations of cilansetron makes it possible to stabilize the active substance markedly against racemization, especially in the presence of moisture.

If a solid pharmaceutical formulation contains a cilansetron acid addition salt, the higher the content of cilansetron-acid addition salt in the formulation observed, the more stable the cilansetron in the formulation is against racemization. Thus, depending on the content of the cilansetron-acid addition salt in the solid preparation, it is possible to add the acidic additive in higher or lower doses within the given dosage range. Thus, for example, in solid preparations having a higher content of the cilansetron-acid addition salt, for example in a 150mg tablet containing 18.72mg of cilansetron-hydrochloride monohydrate, a better stability of the active substance against racemization can be achieved by adding acidic additives.

In general, the content of the acidic additive should not exceed 50% by weight of the solid preparation in order to ensure good handleability of the mixture, for example for better compression into tablets.

Preference is given to solid preparations according to the invention which, by dissolving in 2500 times by weight of water, based on the amount of cilansetron contained in the preparation, form aqueous solutions or suspensions having a pH of between 2.5 and 4.5, preferably between 3.0 and 4.0. If a typical tablet of the compositions 1 to 4 according to the invention as illustrated in Table 1 with a weight of 150mg and a content of cilansetron of 4mg is disintegrated in 10.0ml of water and the pH-value is determined in accordance with known methods after the water-soluble ingredients have dissolved sufficiently, such a pH-value is for example 3.8 to 4.0. If, instead of tablets 1 to 4 according to the invention, unstable comparative compositions, for example tablets 1a to 4a from Table 1, are determined under identical conditions, the pH values are from 5.0 to 5.3.

In order to stabilize the cilansetron against racemization in solid pharmaceutical preparations, the total content of water-soluble acidic components is in most cases about 5.10 per gram of solid preparation^-5Mol to 2.5.10^-3Between mols, preferably 6.0^-5Mol to 8.10^-4Molar ratios are sufficient. Likewise, the content of acidic additives can also be increased, but this generally no longer increases the stability effect.

Solid pharmaceutical preparations are, for example, oral pharmaceutical preparations such as tablets, dragees, capsules, powders or granules.

The solid pharmaceutical preparations according to the invention may furthermore contain customary adjuvants and/or carrier substances, such as, for example, fillers, binders, disintegrants, flow regulators or separating agents, which are known per se.

As fillers there may be used sugars such as lactose, sugar substitutes such as mannitol or xylitol, cellulose or cellulose derivatives such as microcrystalline cellulose, optionally modified starches such as optionally gelatinized maize starch, or customary inorganic fillers such as bentonite.

As further adjuvants such as binders, disintegrants, flow control agents and/or separating agents which may be used, transversely crosslinked polymers of starch derivatives, such as Crossscarmelose-sodium, or polyvinylpyrrolidone derivatives, such as mutually crosslinked polyvinylpyrrolidone, preferably cross-PVP (polyvinylpyrrolidone), colloidal silicon dioxide or long-chain amphiphilic organic compounds, such as stearic acid or glycerates, may be mentioned. Preferably, only the adjuvant and/or carrier substance(s) which are predominantly neutral-reacting are included in the solid pharmaceutical agent of the invention.

According to the invention, cilansetron or its acid addition salts are included in a solid medicament together with at least one physiologically tolerated water-soluble acidic additive and at least one adjuvant and/or carrier substance as specified above. The active substances can be mixed and formulated with acidic additives and pharmaceutical adjuvants and/or carrier substances according to known methods. The solid pharmaceutical preparation can be prepared by mixing cilansetron with the other listed ingredients and granulating them in a usual manner, wet or dry, to prepare granules. If pK is applied_SAn acidic additive with a value between 4.8 and 7.5, which is advantageous for the preparation of wet granules. Granules or powders can be directly filled into capsules or compressed into tablet cores in the usual manner. These may be formulated in known manner into sugar-coated pills or film-coated tablets, if desired.

In the preparation of the solid pharmaceutical preparations according to the invention, it is advantageous to first premix cilansetron or its acid addition salts with only a portion of the adjuvant and/or carrier material, preferably about 5 to 50% by weight of the total amount required for the preparation of the solid preparations, and with at least one acidic additive in a known manner to prepare granules; the other remaining adjuvant and/or carrier materials are then added to the premix separately or as premixed granules, respectively. Thereby reacting cilansetron withThe acidic additive is uniformly mixed and directly contacted in the solid preparation, and thus the stability of the cilansetron against racemization is more enhanced. In this way, it is particularly advantageous to prepare solid pharmaceutical preparations, in particular tablets, with a smaller content of active substance, for example 150mg tablets containing 2mg of cilansetron; or preparing a composition containing pK alone_S-a solid pharmaceutical formulation of an acidic additive having a value between 4.8 and 7.5.

As liquid preparations, aqueous solutions, suspensions or emulsions of cilansetron are conceivable, with which usual liquid pharmaceutical forms, for example ampoules, can be filled. The active ingredient and the acidic ingredient are naturally and uniformly distributed in such a liquid preparation.

The acid addition salt of cilansetron, preferably its hydrochloride, is generally used to prepare liquid pharmaceutical formulations. If cilansetron is used as base, a correspondingly higher dose of acidic adjuvant is required in order to achieve stability of the active substance against racemization according to the invention. The pH of the liquid preparation should be adjusted to the desired value, i.e. between pH2.5 and 4.5, preferably between pH3.4 and pH 4.0. Particularly suitable for this purpose are known physiologically tolerable buffer systems such as citrate buffers, phosphate buffers and/or acetate buffers which can be adjusted to a pH of between 2.5 and 4.5. Preferably, a citric acid buffer is used.

To form a suitable buffer system, a physiologically tolerable water soluble acidic additive, preferably a base, can be used in a dosage sufficient to form a physiologically tolerable buffer system. Suitable bases are, for example, weak bases and weak base salts of organic acids which can be used according to the invention. A strong base such as an alkali metal hydroxide, e.g. sodium hydroxide, may also be applied in suitable dosages to form the base salt or the physiological buffer system in situ. If, for example, citric acid is used as an acidic additive for the preparation of liquid pharmaceutical preparations, physiologically tolerated buffer systems can be formed by adding suitable doses of sodium hydroxide or of sodium citrate.

The total amount of acidic additives in the liquid preparations stabilized according to the inventionThe amount and the ratio of acidic additive to cilansetron may vary within relatively wide ranges. For example, the acidic additive may be included in an amount of about 2.5.10 per microliter of the formulation^-6Mol to 10.0.10^-5Molar, preferably 7.5.10^-6Mol to 1.5.10^-5And (3) mol. The ratio of the acidic additive to the acid addition salt of cilansetron may for example be between 0.15: 1 and 8.0: 1. Thus, the molecular ratio of the dissolved acidic component to cilansetron in the liquid preparation was 1.15: 1 and 9.0: 1. Liquid formulations may be preferred due to their better physiological tolerability, wherein the ratio of acid additive to acid addition salt of cilansetron is between 0.3: 1 and 2.0: 1.

The liquid preparations may contain, as necessary, usual diluents such as water, oils, emulsions and/or suspending agents such as polyethylene glycol and the like. If necessary, other adjuvants and/or additives such as storage agents, flavoring agents and the like may also be added. If necessary, the liquid preparation can also be sterilized before or after the infusion of the medicament. The liquid pharmaceutical preparation is preferably prepared under protection from light.

The following examples further illustrate the invention but are not intended to be limiting thereof.

In the examples purified water was used according to the german pharmacopoeia (═ DAB). The pH of the water used was determined before each experiment according to the rules in the corresponding United States Pharmacopeia (USP), which in all examples was between 6.0 and 7.0. The pH of the water used is generally 6.5.

The content of the (R) -and (S) -enantiomers of the active substance was determined by high performance liquid chromatography (═ HLPC) on chiral column material (chiralex, Merck). Table 1: compositions of solid pharmaceutical preparations with or without acidic additives

Example No. 2	Tablet granules
												Composition by weight (mg)	1	2	3	4	5	6	1a	2a	3a	4a	7a
Bronstone HCl & H2O	4.68	4.68	4.68	4.68	4.68	4.68	4.68	4.68	4.68	4.68	4.68
												Pearlitol 300DC	80.52	80.52	0	0	80.82	78.52	81.52	81.52	0	0	225.32
Corn starch	0	0	0	0	49.5	0	0	0	0	0	130.0
												Starch 1500	53.6	0	0	53.6	0	46.6	53.6	0	0	53.6	0
Microcrystalline cellulose pH200	0	53.6	53.6	-	0	0	0	53.6	53.6	0	0
												Lactose	0	0	80.52	80.52	0	0	0	0	81.52	81.52	0
Polyplasdone XL	5.1	5.1	5,1	5.1	3.0	5.1	5.1	5.1	5.1	5.1	13.0
												Kollidon 25	0	0	0	0	4.9	0	0	0	0	0	13.5
Aerosil 200	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	2.5
												Stearic acid	4.1	4.1	4.1	4.1	4.1	4.1	4.1	4.1	4.1	4.1	11.0
Citric acid	0	0	0	0	2.0	0	0	0	0	0	0
												Ascorbic acid	1.0	1.0	1.0	1.0	0	0	0	0	0	0	0
NaH2PO4·2H2O	0	0	0	0	0	10.0	0	0	0	0	0
												Total amount [ mg]	150.0	150.0	150.0	150.0	150.0	150.0	150.0	150.0	150.0	150.0	400

Examples 1, 2, 3, 4, 5 and 6 are compositions according to the invention. Examples 1a, 2a, 3a, 4a and 7a are comparative compositions not according to the invention.Examples 1-4 and 6 and comparative compositions 1a-4 a:by direct compression, tablets with and without acidic component are prepared

The tablet dosage forms 1 to 4, 1a to 4a and 6 illustrated in table 1 were prepared by direct compression. For this purpose, the active substance or a premix containing the active substance and an acidic additive is mixed with mannitol (Pearlitol 300 DC) as the adjuvant given above^Roquette corporation), lactose in fine powder form, Starch, gelatinized corn Starch (Starch 1500)^Colorcon corporation) and/or microcrystalline cellulose (Avicel PH 201)^FMC corporation). Then mixed and added to highly dispersed silica (Aerosil 200)^Degussa), stearic acid and cross-linked polyvinylpyrrolidone (PolyplasdoneXL)^GAF chemical company) and the resulting mixture is compressed on a rotary compressor into tablets weighing 150mg each, so that each tablet contains 4mg of pure active substance.Examples 5 and 7 a:tablets and capsules with and without acidic additives by granulation

The tablet formulation 5 and granules 7a illustrated in table 1 were prepared by a granulation method. For this purpose, the active substance is mixed with mannitol and corn starch in a mixer, and the mixture formed is thoroughly moistened in the case of example 5 with citric acid, which is dissolved in the necessary amount of polyvinylpyrrolidone (Kollidon 25)^BASF corporation) in demineralized water. Demineralized water was added in both examples, i.e. 5 and 7a, if necessary. The wetted mixture is granulated in a high-speed mixer (Diosna Corp.), the coarse granules formed are dried to a mass at 40 ℃ and sieved. Followed by the addition of highly dispersed silica, stearic acid and polyvinylpyrrolidone with mixing. Will be provided withThe finished granules were filled in 400mg aliquots into hard gelatin capsules of size 0 by means of an automatic capsule machine, each capsule containing 4mg of pure active substance (granules 7 a); alternatively, the finished granules were compressed on a rotary tablet press into 150mg tablets containing 4mg of cilansetron per tablet (tablet 5).Example 8Preparation of liquid pharmaceutical preparations (ampoules) with acidic additives

A liquid formulation of the following composition was prepared with cilansetron and citric acid buffer as an acidic additive: bronstone HCl & H₂O234 mg of citric acid monohydrate 60 mg of NaCl 900 mg of NaOH 5mg of demineralized water 99.296 g. The pH of the solution was about 3.6. For this purpose, the active substance and the adjuvant are dissolved in water under protection from light, while the solution is constantly aerated with nitrogen. The solution was then filtered through a membrane filter with a pore size of 0.2 μm and filled into 2 ml-sized ampoules in 2ml aliquots with the aid of an automatic ampoule filling device, so that each ampoule contained 4mg of cilansetron-base.Example 9:the pH of aqueous solutions or suspensions of various solid pharmaceutical formulations with and without acidic additives were compared.

The solid pharmaceutical formulations 1 to 6 according to the invention and the non-inventive comparative compositions 1a to 4a and 7a given in table 1 were each added to 10.0ml of water at room temperature (pH 6.5). The formulation of example 7a was formulated in 25.0ml of water under the same conditions. When the preparation is dissolved and the water-soluble components are completely dissolved, the pH of the resulting aqueous solution or suspension is measured using a glass electrode. The measured pH values are given in table 2 below.

Table 2:

solid pharmaceutical preparation number	1	2	3	4	5	6	1a	2a	3a	4a	7a
												pH value	4.0	4.0	3.9	3.9	3.3	4.8	5.3	5.0	5.2	5.1	5.2

The active substance dose of the above-described dosage form, i.e. the amount corresponding to 4.68mg of cilansetron-hydrochloride-monohydrate, was dissolved in 10.0ml of water under the conditions specified above. The pH of the resulting solution was determined to be 5.45.Stability test I:the racemization rates of cilansetron with and without the acid component are compared in the tables

The tablet formulations listed in table 3 with (relating to tablets 1 to 4) and without (relating to tablets 1a to 4a) the acidic additive were subjected to storage tests. The increase in the S- (+) -isomer content of cilansetron formed by racemization was measured in each dosage form after 4 weeks. The results of the storage test are shown in table 3.Table 3:increase in the S- (+) -isomer content of cilansetron in tablets with and without acidic additive after 4 weeks storage

Storage conditions	Relative temperature [% ]]	Increase in the content of the S- (+) -enantiomer, expressed in%
											Tablet formulation
		1	2	3	4	6	1a	2a	3a	4a
											Sealing at 30 deg.C	60	0.10	0.10	0.10	0.20	--	0.20	0.20	0.20	0.30
Open at 30 ℃	60	0.10	0.10	0.40	0.20	--	1.70	0.20	0.20	0.50
											Open at 40 ℃	75	0.40	0.40	0.40	0.40	0.10	1.70	0.70	0.70	1.70
Sealing at 50 deg.C	Not determined	1.60	1.10	1.60	1.70	--	0.70	3.50	2.30	2.20

As the measured values given in Table 3 show, there is a clear difference in the content of the S- (+) -enantiomer formed as a result of racemization after 4 weeks of storage, in particular when stored open, i.e.when air andmoisture and, in certain cases, elevated temperatures can enter. The increase in the content of the S- (+) -enantiomer in the dosage forms stabilized according to the invention is significantly lower than in the unstabilized comparative dosage forms.Stability test H:racemization speed of cilansetron in liquid formulations with different pH values

A water-soluble, citric acid-buffered stock solution of cilansetron having the following composition was prepared: bronstone HCl & H₂O6.684 g citric acid monohydrate 30.2 g NaCl 9.0 g NaOH 11.5 g1N HCl 1566.0 g. Test solutions with pH values of 2.9, 3.3, 3.6, 3.8 and 4.0 were prepared from the stock solution by adding the required dose of 1N HCl. The reagents were subjected to storage tests at two different temperatures (26 ℃ and 41 ℃) and the content of the S- (+) -enantiomer formed as a result of the racemization of the active substance was determined after a time interval of 8 weeks (storage temperature 26 ℃) and 12 weeks and after a time interval of 12 months (storage temperature 41 ℃). The results of the storage test are shown in table 4.Table 4:speed of racemization of cilansetron in liquid formulations as a function of pH and temperature

pH-Wert	At a certain time (+) -enantiomeric content
							26℃	41℃
	t＝0	8 weeks	For 12 weeks	12 months old
					2.9	1.25	2.72	--	--
3.3	1.26	2.20	1.50	3.63
					3.6	1.21	1.66	1.41	3.55
3.8	1.21	1.92	1.29	3.19
					4.0	1.13	1.76	1.44	--

As can be seen from the measured values given in Table 4, in the measured pH-range, cilansetron is most effective in preventing racemization between pH3.6 and pH 4.0.Stability test III:effect of pH and temperature on racemization Rate of Bronstone in liquid formulations

Cilansetron-hydrochloride monohydrate was dissolved at a concentration of 1% in 0.065 molar phosphate buffer. Test solutions having pH values of 2, 3, 4, 5 and 6 were prepared from this stock solution by adding a necessary amount of 1/15 molar aqueous sodium hydroxide solution. The test solutions were stored at 61 ℃ for 1, 7, 14 and 28 days, respectively, and the racemization rate of cilansetron was determined in a known manner using first order kinetics. The test results are shown in Table 5.Table 5:racemization rate constant of cilansetron in liquid formulations at different pH values and temperatures of 61 deg.C

pH value	2	3	4	5	6
						K*10-3[l/d]	8.86	3.00	2.21	7.18	21.05

From the measured values reported in Table 5, it can be seen that the racemization rate of cilansetron is significantly lower at pH values above 2 and below 5, preferably between pH3 and 4, compared to the other pH values.Stability test IV:storage stability of cilansetron in liquid formulations

Liquid preparations of cilansetron buffered with citric acid were prepared as described in example 8 with an active substance content of 2mg/ml and filled into ampoules of two different sizes, 2ml and 4 ml. The pH values of the solutions were 3.7, respectively. Storage testing of the ampoules was performed. The content of S- (+) -enantiomer in the ampoule was determined after 6 and 24 months, respectively. The measured values are shown in Table 6.Table 6:verification of the storage stability of cilansetron in liquid pharmaceutical dosage forms stabilized according to the invention

Product of	pH value	Content of (+) -enantiomer [% ]]
									t＝0	6 months old		24 months
		40℃	K10-3[l/d]	25℃	K10-5[l/d]
						Ampoule 4mg/2ml	3.7	1.6		4.0	1.37	3.7	3.0
Ampoule 8mg/4ml	3.7	1.5	3.8	1.31	3.9				3.4

From the calculated rate constant k, it is clear that the S- (+) -enantiomer content of the active substance doses in ampoules does not exceed a value of 5% within 3 years at an average storage temperature of 25 ℃.

Claims (16)

1. Pharmaceutical preparation containing a therapeutically effective dose of the active substance cilansetron or a physiologically tolerated acid addition salt thereof, characterized in that the preparation also contains at least one physiologically tolerated water-soluble acidic additive which stabilizes the cilansetron against racemization.

2. The pharmaceutical formulation according to claim 1, wherein the water-soluble acidic additive is selected from the group consisting of having 2 to 12 carbon atoms and a first pK_S-mono-or polybasic organic acids having a value between 1.1 and 4.8, the aforesaidAcidic salt of polybasic organic acid and first-usable pK thereof_S-an acid salt of a physiologically tolerated polybasic inorganic acid with a value between 1.5 and 7.5.

3. Pharmaceutical preparations according to claim 2, which contain as acidic additive ascorbic acid, citric acid, fumaric acid, lactobionic acid, maleic acid, malonic acid, mandelic acid, lactic acid, oxalic acid, tartaric acid and/or acidic salts of the above mentioned polybasic organic acids and/or physiologically tolerated dihydrogen phosphate and/or hydrogen sulphate, and if the preparation is in liquid form, physiologically tolerated liquid organic acids.

4. A pharmaceutical preparation according to any one of claims 1 to 3, which comprises cilansetron-hydrochloride as an acid addition salt of cilansetron.

5. A solid pharmaceutical formulation according to any one of claims 1 to 3 wherein the molecular ratio of the water-soluble acid component to cilansetron in the formulation is 1.02: 1 and 10: 1 and wherein the acidic additive is present in an amount not exceeding 50% by weight of the formulation.

6. Solid pharmaceutical preparation according to one of claims 1 to 3, which contains as acidic additive a compound having 2 to 12 carbon atoms and a first pK_S-mono-or polybasic organic acids with a value between 1.1 and 4.8.

7. A solid pharmaceutical formulation according to claim 6 wherein the molecular ratio of the water soluble acid component to cilansetron in the formulation is between 1.02: 1 and 5.0: 1 and wherein the acidic additive component does not exceed 50% by weight of the formulation.

8. The solid pharmaceutical preparation according to one of claims 1 to 3, which is obtained by dissolving the solid preparation in 2500 times by weight of water based on the amount of cilansetron contained in the preparation to form an aqueous solution or suspension having a pH value of between 2.5 and 4.5.

9. Solid pharmaceutical preparations according to claim 8, which contain 0.15 to 2.0 mol of ascorbic acid and/or citric acid and other customary pharmaceutical adjuvants and/or carrier substances per 1 mol of cilansetron-hydrochloride.

10. A liquid, predominantly aqueous pharmaceutical formulation according to any of claims 1 to 3, which contains the acidic additive in such a dosage that the pH of the formulation is between 2.5 and 4.5.

11. Liquid pharmaceutical formulations according to claim 10, containing a physiologically tolerable buffer system for adjusting the pH to between 2.5 and 4.5.

12. The liquid pharmaceutical preparation according to claim 11, which contains at least one buffer system selected from the group consisting of citrate buffer, phosphate buffer and acetate buffer.

13. The liquid pharmaceutical formulation according to claim 10, wherein the molecular ratio of the dissolved acid component to cilansetron in the formulation is between 1.15: 1 and 9.0: 1.

14. The liquid pharmaceutical preparations according to claim 13, which contain 0.3 to 2.0 moles of ascorbic acid and/or citric acid and/or physiologically tolerated salts thereof and, if desired, customary pharmaceutical adjuvants and/or additives per 1 mole of cilansetron-hydrochloride.

15. Use of a physiologically tolerable water soluble acidic additive selected from the group consisting of compounds having 2 to 12 carbon atoms and a first pK_SMono-or polybasic organic acids having a value between 1.1 and 4.8, acid salts of the aforementioned polybasic organic acids and their first possible pK_S-an acid salt of a physiologically tolerable polybasic inorganic acid having a value between 1.5 and 7.5 for use in the treatment of cancerAnti-racemization stabilization of cilansetron in pharmaceutical formulations.

16. Process for the preparation of a solid pharmaceutical preparation containing as active substance cilansetron or a physiologically tolerated acid addition salt thereof and at least one physiologically tolerated solid water-soluble acidic additive selected from the group consisting of those according to claim 1 having from 2 to 12 carbon atoms and a first pK_SMono-or polybasic organic acids having a value of between 1.1 and 4.8, acid salts of the above polybasic organic acids and their first possible pK_SAcid salts of physiologically tolerated polybasic inorganic acids with a value of between 1.5 and 7.5, characterized in that cilansetron or one of its acid addition salts is first mixed with at least one acid additive and about 5 to 50% by weight, based on the total amount required for the preparation of the solid preparation, of an adjuvant and/or carrier substance to form a premix, and the premix obtained is granulated if necessary, and then the remaining adjuvant and/or carrier substance is added, and the granules or powders obtained in this way are compressed if necessary into tablets or cast into the usual pharmaceutical form.