Ondansetron (chemical name: 1, 2,3, 9-tetrahydro-9-methyl-3-/ (2-methyl-lH- imidazol-1-yl)-methyl/-4H-carbazol-4-one) is the active ingredient of pharmaceutical compositions with highly efficient antiemetic activity. These compositions are especially important for chemotherapeutically treated patients.

Several chemical processes are known from the literature for the synthesis of ondansetron. GB-Pat. 2 153 821 and 2 192 885 describe syntheses starting from carbazolone derivative, and EP-Pat. 595 111 as well as a Hungarian patent application (P 00-01287) give detailed information about some different chemical procedures.

According to the above literature the ondansetron base is transformed into ondansetron hydrochloride dihydrate with hydrochloric acid in aqueous isopropanol in the final step.

Furthermore, there is a known procedure described in the EP-Pat.

Specification 415 522, in which the ondansetron hydrochloride dihydrate is prepared from dried anhydrous ondansetron hydrochloride by rehydration.

According to this description the main advantage of the above procedure is that the average size of the granules of the active ingredient can be kept at considerably low value (< 63 um min. 80 %; < 250 um 100 %).

After reproduction of the above procedures we found that the obtained products do not fulfill the high colour requirements measured by objective experiments, they rather belong to the beige colour category. The more rigorous colour requirements, which are prescribed since then (for example the white or almost white colour; see European Pharmacopoeia, shortly Ph.

Eur. Vol. 4.3, page 3101) can not be fulfilled by using these above mentioned, known technological processes, even after repeated application.

The aim of our invention is to elaborate a process for the synthesis of high purity, white (or almost white) coloured active pharmaceutical ingredient, which has the appropriate crystal size.

The basis of our invention is the following : if the crude ondansetron base is dissolved in water in the presence of equivalent amount of hydrochloric acid (pH=5-6.5), the so obtained solution is clarified with charcoal, the charcoal is filtered off, then a colourless, transparent aqueous filtrate is obtained, from which after adjusting the pH to maximum 1 with further addition of hydrochloric acid, the high purity ondansetron hydrochloride dihydrate, which fulfils the highest colour requirements as well, can be prepared in good yield.

Surprisingly it was found, that the product prepared by the above process contains maximum 0.1 % individual impurity, this very high chemical purity was not to be expected at all.

According to the process of our invention, which is carried out in the knowledge of this observation, the crystal size of the obtained crystalline product can also be determined by the appropriate rate of cooling of the crystallization from water. Namely, fast cooling results in very fine crystal size (< 63 um min. 95 %), while with slow cooling crystal size above 250 urn can safely be obtained.

According to the above mentioned facts, the invention relates to such ondansetron hydrochloride dihydrate (chemical name: 1, 2,3, 9-tetrahydro-9- methyl-3-/(2-methyl-lH-imidazol-l-yl)-methyl/-4H-carbazol-4- one hydrochloride dihydrate), which contains not more than 0.10 w/w % of chemical impurity.

The invention also relates to the process for the synthesis of the above product, which is the following : the ondansetron base obtained by known chemical synthesis (impurity content: 0.5-10 w/w % ; colour: from gray to dark brown) is treated with hydrochloric acid solution in water at 95-100 °C, the pH is adjusted to 5.8-6. 2, then the solution is clarified at this temperature, the impurities are removed by filtration, the pH of the obtained filtrate is adjusted to 1-2 by addition of aqueous hydrochloric acid solution, and the so obtained solution is cooled at a rate of 0. 1-1 °C/min to 20-25 °C to give the desired product, which is isolated.

Furthermore the invention relates to pharmaceutical compositions, which contain the above defined and prepared product as active ingredient, as well as known auxiliaries.

The main advantage of the invention is that high purity ondansetron hydrochloride dihydrate-which fulfils the colour requirements and can be used as active ingredient in pharmaceutical compositions as well-can be obtained in good yield-in aqueous solution without liberation of the free base - from such ondansetron hydrochloride dihydrate, which does not fulfil the colour requirements and is prepared by known method (for example EP-Pat.

595 111) from isopropanol solution.

The invention is illustrated by the following not limiting examples:

Example 1 Preparation of ondansetron hydrochloride dihydrate from crude ondansetron base Under nitrogen, 10 g of crude ondansetron base (prepared according to the method described in example 3b of the HU-Pat. 212 785, and in example 3 of the Hungarian patent application Number of P-00-01287; impurity content measured by HPLC: 3.8 %, colour brownish red) is suspended in 150 ml of desalinated water, the pH is adjusted to 6 with concentrated hydrochloric acid at 95-100 °C, 2 g of charcoal is added to the solution, and the mixture is stirred at this temperature for 1 h. The charcoal is filtered off at 95-100 °C, the pH of the filtrate is adjusted to 1-2 with concentrated hydrochloric acid and the solution is cooled slowly, at a rate of not more, than 0. 3 °C/min to 20- 25 °C, then after cooling to 0-5 °C the product is filtered off, washed with cooled (0-5 °C) desalinated water (2x5 ml), and dried below 35 °C.

The obtained dried ondansetron hydrochloride dihydrate is 10.8 g (87 %) (water content: 9.5 %, which is equivalent to 2 mol of water).

Additional measured data: the purity of the product is 99.90 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.10 w/w %, they are 0.03 w/w % (RT 6.76), 0.02 w/w % (RT 7.10) and 0.05 w/w % (RT 8. 65), respectively.

Colour: white, AE = 0.5 on the range of colours Granule size results: <63 pm 36 % <150um 72% <250 urn 95 % The above results were obtained by the following analytical methods:

A. HPLC measurements: Type of the apparatus: Spectra System/TSP (manufacturer: Thermo Separation Products, USA) Column: LICHROCART 250-4, LICHROSPHER 100 CN (5 urn) Eluent : 70 % of 0.02 M KH2PO4 30 % of acetonitrile Flow rate: 1.00 ml/min Wavelength: 216 nm Temperature: 25 °C Dissolution of samples: in the eluent B. Colour measurement: Type of the apparatus: Minolta chromometer with CR-200 measuring head.

Before measuring the sample the apparatus is calibrated to standard white CR- A43.

Measured parameters: L lightness factor a)<BR> chromaparameter b AE, the colour deviation from the standard, is calculated from the measured data according to the following equation: AEab = [(dL) 2 + (da) 2 + (db) 2 % 2 If AEab value is between 0-0.5, the deviation from the white colour is not visible; if tE value is between 0.5-1. 5, in some cases the deviation can be visible to good eyes, this value fulfils a very good colour requirement.

C. Granule size: the granule size was determined by sieve analysis, using Alpine airjct sieve.

Example 2 Preparation of ondansetron hydrochloride dihydrate from hydrochloride salt by purification Under nitrogen, 10 g of ondansetron hydrochloride dihydrate of beige colour (AE = 4.2 on the range of colours) is dissolved in 150 ml of ion- exchanged water at 75-80 °C. 2 g of charcoal is added to the homogeneous solution. After 1 h stirring the mixture is filtered and the pH of the filtrate is adjusted to 1-2. The solution is cooled slowly (at a rate of not more, than 0.3 °C/min) to 5-10 °C, stirred at this temperature for 1 h, the product is filtered off, washed 2x5 ml of desalinated water at 5-10 °C, and dried below 35 °C.

Dried weight: 9.6 g (96 %) The colour of the product is white, AE = 0.55 on the range of colours The amount of the impurities in the product: The purity of the product is 99.92 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.08 w/w %, they are 0.01 w/w % (RT 2. 08), 0.01 w/w % (RT 2.43), 0.02 w/w % (RT 6.51), 0.01 w/w % (RT 6.83) and 0.03 w/w % (RT 7. 74), respectively.

Granule size results: <63 um 31 % <150 llm 71 % <250 um 97 % These results were obtained according to the methods described in example 1.