The invention relates to a process which for the preparation of polymorph I of the terfenadine with an optimum granulometric distribution, by simply heating terfenadine itself in suitable solvents. Terfenadine, of formula I

is a medicament having antihistaminic action, widely used in therapy. Its preparation is disclosed in German patent 2,303,305. Terfenadine exists in three crystalline conditions: a "polymorph III", melting at 142-144°C; a "polymorph II", melting at 146-148°C and a "polymorph I", melting at 149-152°C (see A.A. Badwan et al., "Terfenadine", in Analytical Profiles of Drug Substances, vol. 19, 627-662 (Academic Press, 1990)). Terfenadine used in pharmaceuticals is precisely "polymorph I", which is obtained, according to EP 339,118 is obtained by heat dissolution in aqueous alkanols (preferably ethanol) and slow crystallization of the resulting solution. According to PCT-WO 93/07121, "polymorph I" obtained from alkanols according to EP 339,118, or from acetone according to EP-A-396,100, has an insufficient purity degree, contrarily to the one prepared by

dissolution of the polymorphic mixture in dimethylformamide and reprecipitation with water.

However, the crystals of polymorph I prepared according to the above mentioned processes have average sizes excessive for the pharmaceutical technology requirements, therefore they have to be subjected to micronization to attain the required granulometric characteristics, operations which make the process for the preparation of the active ingredient more complicated, increasing costs, moreover during micronization the compound tends to stick to the apparatuses.

Now it has surprisingly been found that polymorph I of terfenadine can be obtained directly not only in high purity, but also with optimum granulometric characteristics subjecting more low-melting terfenadines to heating, at temperatures from about 50 to about 130°C, for times from about 1 to about 8 hours, in pure solvents or in mixtures of water and at least one solvent selected from the group consisting of compounds of formula

RO-f-CHR ^• -CH ₂ o-)*- _j R« wherein R, R' and R" , which are the same or different, are hydrogen or methyl, whereas n is the integer 1, 2, 3 or 4, then recovering the obtained crystals from the mixture, cooled to room temperature, by filtration or centrifugation.

Particularly suitable for the purpose proved to be ethylene glycol, propylene glycol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl

ether (triglyme) and tetraethylene glycol dimethyl ether (tetraglyme), pure or in admixture with an amount of water ranging up to 70% by volume of the mixture itself. The possibility of preparing polymorph I with the desired characteristics from the mixtures of water and solvents of formula I, particularly glycols, is surprising since, according to literature (A.A. Badwan et al., loc. cit.), "polymorph III" (m.p. 142-144 ^β C) is obtained by crystallization from propylene glycol.

Preferably the heating temperatures are from about 60°C to about 120°C, and the heating times from about 3 to about 6 hours.

Water can be added to solvent either from the beginning of the process, or it can be added to the terfenadine solution or suspension in the solvent or, vice versa, the terfenadine solution or suspension can be poured in water. During the process a recrystallization of terfenadine takes place, said definition not necessarily meaning the traditional process of complete heat dissolution of a compound and the subsequent precipitation of the compound itself by cooling or adding a non-solvent. According to the invention, in fact, highly satisfactorily results are obtained also keeping a suspension of terfenadine in the used solvent mixture at the above stated temperatures and times, without ever attaining a complete dissolution. Anyway, the purpose is reached of converting the undesired polymorph into the high- melting polymorph, in form of very small crystals with such a favourable granulometric distribution to require

no grinding nor sieving steps, the granulometry ranging from 2 to 10 microns, at least for 80% of the crystals.

The following examples illustrate the process according to the invention. Water to solvent ratios should be intended by volume.

Example 1 Preparation of the Amorphous Form: in order to obtain a homogenous product without a crystal habit, to be used in conversion tests into polymorph I, 200 g of terfenadine are melted in oven at controlled temperature of 160 ^β C. An amorphous glass form is obtained by rapid cooling then the ground product is analyzed by optical microscope. It appears made up by big flake of several flat, the melting point is actually a large range between 100-120 ^β C.

Example 2 10 g of amorphous terfenadine are added with 70 ml of ethylene glycol. The suspension is heated under magnetic stirring until complete dissolution is observed (110°C). The temperature is brought down between 90 and 100 ^β C and the mixture, that appears homogeneous and soft, is left under said conditions for 6 hours, then it is cooled to room temperature and left to stand overnight. Finally it is filtered, suspended in H2O, filtered again and dried in oven under vacuum at 100°C until constant weight. Melting point - 150- 151°C. The granulometry of the product is highly satisfactory.

Example 3 50 g of amorphous terfenadine are heated to 70 ^β C with 200 ml of digly e under mechanical stirring until

complete dissolution is obtained. 300 ml of 1^0 are added gradually to re-precipitate terfenadine and mechanical stirring is continued for 4 hours at 80°C. Finally the mixture is left to cool under stirring, then it is filtered, the solid is re-suspended in 200 ml of water to remove diglyme, filtered again and dried in oven at 70°C until constant weight. The microscope analysis of the crystals shows that they are well separated and have a rather narrow granulometry range, from 7 to 25 μ. Melting point - 150-151 ^β C.

Example 4 50 g of amorphous terfenadine are heated to 80°C with 150 ml of triglyme under mechanical stirring until complete dissolution is obtained. 200 ml of H_o are added gradually with care of keeping the temperature not below 70°C in order to re-precipitate terfenadine soft and homogeneous. Mechanical stirring is continued for 4 hours at 80 ^β C. Finally the mixture is left to cool under stirring, then it is filtered, the solid is re-suspended twice in 200 ml of water filtering every time to remove triglyme, filtered again and dried in oven at 70°C until constant weight. The microscope analysis of the crystals shows little circular shape, well separated and with a very narrow granulometry range, from 5 to 10 μ. Melting point ^* = ^** 150-151 ^β C.

Example 5 25 g of amorphous terfenadine are heated with 100 ml of diglyme under mechanical stirring until complete dissolution is obtained (Λ/70°C). This solution is added slowly (in about 1 hour) to 150 ml of 30°C heated water under mechanical stirring. During the addition

the mixture temperature balances at about 40 ^β C and the terfenadine precipitates. Although it is not homogeneous and soft like in the other cases, it does not give any problem in stirring. When the addition is finished a vigorous mechanical stirring is kept until room temperature is achieved. Finally it is filtered, suspended in H ₂ o 100 ml, filtered again and dried in oven under vacuum at 70°C until constant weight. Melting point = 149-151 ^β C. The microscope analysis shows aggregates of little crystals with granulometry range from 2 to lOμ.

Example 6 50 g of amorphous terfenadine are heated with 200 ml of diglyme under mechanical stirring until complete dissolution is obtained (Λ70 ^β C). This solution is added slowly (in about half hour) to 300 ml of 80 ^β C heated water under mechanical stirring. During the addition the mixture temperature balances at about 70°C and the terfenadine precipitates. In this case the first part of precipitation gives a not homogeneous mixture that however amalgamates as the addition goes on. When the addition is finished a vigorous mechanical stirring is kept until room temperature is achieved. Finally it is filtered, suspended in H ₂ 0 100 ml, filtered again and dried in oven under vacuum at 70°C until constant weight. The yielded terfenadine is 48 g. Melting point = 150-15l ^β C.

The microscope analysis shows bladed shape crystals with granulometry range from 3 to 15μ. Example 7

30 g of amorphous terfenadine are added with 120

ml of propylene glycol. The amorphous form totally dissolves at room temperature (while the crystalline form dissolves at about 110 ^β C at the same concentration of propylene glycole) . But in few minutes it re- precipitates as homogeneous suspension. When 120 ml of

H ₂ 0 are added, the mixture becomes slightly thicker without stirring problems. The mixture is heated until

100°C and stirred for 3 hours. Then it is cooled until room temperature and filtered. The filtration is slow because of propylene gl-lcol viscosity. The solid product is re-suspended 3 times in 120 ml of water, filtering every time to remove completely the propylene and dried in oven under vacuum at 70 ^β C until constant weight. Melting point ^* = 149-150°C. The microscope analysis shows bladed shape crystals, well separated with a very narrow granulometry in the range of 10μ.

In the following Examples 8 and 9 a raw industrial product, formed by mixed polymorphs is used. Example 10 again uses an amorphous form. In these examples the same methods of the previous examples are used, but avoiding a complete dissolution of the starting material. This demonstrates that it is not necessary to obtain the desired polymorphic form and granulometry.

Example 8 35 g of moist raw terfenadine (-20 g dried terfenadine) coming from reduction of terfenadone, are added with a solution composed by 80 ml of propylene glicol and 65 ml of water (considering also the moisture in the product). The suspension is heated until 100°C under mechanical stirring, then the temperature is brought down between 85-95°C and the

mixture, that appears homogeneous and soft, is left under said conditions for 8 hours, then it is cooled until room temperature and filtered. The filtration is slow because of propylene glicol viscosity. The solid product is re-suspended 3 times in 120 ml of water, filtering every time to remove completely the propylene and dried under vacuum at 70°C until constant weight. Melting point - 149-150 ^β C. The microscope analysis shows bladed shape crystals, thin and well separated with granulometry in the range of 10-15μ.

Example 9 50 g of moist raw terfenadine (*-28 g dried terfenadine) coming from reduction of terfenadone, are added with 110 ml of tetraglyme under mechanical stirring. The suspension is heated until 80 ^β C but no dissolution is observed. 90 ml of water are added (considering also the moisture in the product), then the mixture is stirred for four hours at 80°C. Finally it is cooled until room temperature and filtered, suspended twice in 100 ml of H ₂ o, filtering every time and dried in oven under vacuum at 70°C until constant weight . At the microscope the crystals appear well separated and with a thin and lengthened form. The granulometry is in the range of 10-15μ. Melting point - 150-151 ^β C.

Example 10 50 g of amorphous terfenadine in 500 ml of 50/50 H ₂ o/ethylene glycol mixture are slowly heated until 80°C, under magnetic stirring in about two hours. The temperature should grow slowly to avoid the separation of melted product in water mixture. Doing so the

suspension is soft and it can be easily filtered, suspended twice in 250 ml H ₂ o, filtering every time, and dried in oven under vacuum at 100°C until constant weight. Melting point = ^** 149-150°C. At the microscope the crystals appear well separated and with a very narrow granulometry in the 2-5μ range.