RS20070008A - New pseudopolymorph of desloratidine formed with carbon dioxide - Google Patents

Abstract

The pseudopolymorph of desloratadine formed with carbon dioxide of the formula (I) has valuable anti-allergic effect and can be used as pharmaceutical active ingredient. The present invention also relates to the preparation of desloratadine of high purity. The present invention also relates to the use of the pseudopolymorph of desloratadine of the formula (I) for the preparation of salts of desloratadine of the formula (VI) (wherein X stands for an anion and n is 1 or 2).

Description

A NEW PSEUDOPOLYMORPH OF DESLORATADINE DERIVED FROM COAL

DIOXIDE

Field of invention

The present invention relates to a new pseudopolymorph of desloratadine. More specifically, the present invention relates to a new pseudopolymorphic form of desloratadine that is obtained with carbon dioxide and has the following formula:

The compound 8-chloro-6,11-dihydro-11-(4-piperylidene)-5H-benzo[5,6]cyclohepta[1,2-bipyridine (international name: desloratadine), whose formula is: is a known antihistamine drug, which is an active metabolite of the compound 8-chloro-6,11-dihydro-11-(1 -ethoxy-carbonyl-4-piperylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (international name: loratadine), whose formula is:

In the case of oral administration of desloratadine, the antiallergic effect is 3 to 4 times greater than the effect of loratadine, and the duration of the effect is almost 24 hours, which is an advantage in the case of using the drug once a day (Arzneim. Forch. Drug. Res 40(1), 4: 345 (2000)).

Two processes are known for obtaining desloratadine formula (IV), according to the description of Hungarian patent no. 194864.

According to one of these processes, the ethoxycarbonyl group of loratadine of formula V is eliminated by boiling in a mixture of ethanol, water and sodium hydroxide for 24 hours. The product is obtained in the form of an acetic acid salt, after extraction with chloroform. Desloratadine acetate is converted to the free base form by reaction with a base, after which the crude product is recrystallized from a mixture of benzene and hexane.

According to another process, 8-chloro-6,11-dihydro-11-(1-methyl-4-piperylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is demethylated by reaction with bromocyanide, after which the resulting 1-cyano compound is hydrolyzed by refluxing for 20 hours in a mixture of concentrated hydrochloric acid and acetic acid. After removal of the solvent, desloratadine in the base form is obtained from the residue by reaction with the base. The crude product is purified by recrystallization from hexane, until the melting point rises to 149 - 151 °C.

Desloratadine salts obtained with hydrochloric, methanesulfonic, sulfuric, acetic, maleic, fumaric and phosphoric acids are mentioned in the description of Hungarian patent no. 198964.

Hungarian published patent application no. P00/04701 refers to salts of desloratadine with one or two moles of acid, as well as their preparation. According to the published patent application, desloratadine of formula (IV) is obtained by eliminating the ethylcarbonyl group from position 1 of loratadine of formula (V), by boiling in concentrated mineral acids, preferably in a 60-80% sulfuric acid solution at 120 °C for 6-8 hours. Salts of desloratadine with two moles of acid, according to the general formula: can be isolated directly from the reaction mixture. Salts of desloratadine obtained with one mole of acid, according to the general formula:

they are obtained by reacting desloratadine in the form of a base of formula (IV) with the appropriate acid in a medium containing dichloromethane.

Two polymorphs of desloratadine hemifumarate are described in international PCT patent application no. 2004/012738. The difference between the melting points of these polymorphs is several degrees Celsius.

The process for obtaining desloratadine of formula (IV) described above has several undesirable characteristics.

According to the process described in Hungarian patent no. 194864, the hydrolysis of the ethoxycarbonyl group is carried out by boiling in an aqueous base solution for a very long time. Extreme degradation and formation of colored side products takes place during the twenty-four hour reaction. The color of the raw product is unacceptable for pharmaceutical use. The crude product must be recrystallized several times in order to obtain an acceptable product. Recrystallization is performed in a mixture of benzene and hexane, according to Hungarian patent no. 194864. The use of carcinogenic benzene and the large loss during recrystallization represent negative characteristics at the level of industrial production.

According to another process described in Hungarian patent no. 194864, the elimination of the methyl group from 8-chloro-6,11-dihydro-11-(1-methyl-4-piperylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is carried out during the reaction with bromocyanine, and the 1-cyano compound thus obtained is further hydrolyzed and decarboxylated in one step, by refluxing for 20 hours in a mixture of concentrated hydrogen chloride and acetic acid. Cyan bromo is an extremely toxic compound, which is undesirable in production on an industrial scale and requires the application of special safety measures.

Salts of desloratadine in which desloratadine is present in a ratio of 1:2 to acid are unstable according to data from Hungarian patent application no. P00/04701. In our experience, the stoichiometry of these salts changes during their storage, as the acid reaction compounds are partially eliminated.

The disadvantage of obtaining these compounds is that amine compounds are produced under extreme reaction conditions, which are used to obtain salts in excess of the corresponding acid, and the resulting salts crystallize together with the desired product.

Obtaining a salt of desloratadine in a molar ratio of 1:1 is preferable to obtaining a salt in a molar ratio of 1:2. The basic condition for obtaining these salts is the use of a desloratadine base of formula (IV) of sufficient degree of purity, which can only be obtained by appropriate purification procedures, after the reaction of elimination of the ethoxycarbonyl group.

The aim of the present invention is to obtain a new pseudopolymorph of desloratadine, which is suitable for use during the preparation of desloratadine base or desloratadine salt of a high degree of purity.

The above-mentioned goal is achieved by the process according to the present invention.

The essence of the invention

The present invention relates to a pseudopolymorph of desloratadine obtained with carbon dioxide, having the formula (I), and having a characteristic x-ray diffraction pattern shown in diagram 1, an IR spectrum shown in diagram 4 and the following data obtained by x-ray diffraction:

According to a further solution of the present invention, a procedure is provided for obtaining the above-mentioned pseudopolymorph of desloratadine obtained with carbon dioxide, which has formula (I), and which includes the steps: (a) reaction of a solution of desloratadine of formula (IV) in an organic solvent with carbon dioxide; or (b) decarboxyethylation of loratadine of formula (V) in a solution of 2-methoxyethanol or 2-ethoxyethanol with alkali metal hydroxide, after which desloratadine of formula (IV) is obtained with carbon dioxide, in an organic solvent.

Detailed description

The subject invention is based on the discovery that during the reaction of desloratadine of formula (IV) with carbon dioxide in an organic solvent, the adduct of 2 moles of desoratadine and 1 mole of carbon dioxide, which has formula (I), is precipitated. This represents a new pseudopolymorphic form of desloratadine. The new pseudopolymorphic form obtained with carbon dioxide has a very high degree of purity, which is confirmed by HPLC testing. Carbon dioxide gives an adduct only with desloratadine, while amine-type contaminants remain in the basic solution and can be easily separated from the desired adduct by filtration or centrifugation.

The formation of the compound of formula (I) is thus more surprising, since only a few adducts are known from previous studies, and even in those cases, the amines used have a much lower molecular weight.

X-ray diffractograms of polymorphs Pl and P2 are shown in diagrams 2 and 3.

The x-ray diffraction pattern shown in diagram 1 of the pseudopolymorph obtained with carbon dioxide is completely different from the x-ray diffraction pattern of polymorphs P1 and P2 (diagrams 2 and 3) of desloratadine.

X-ray powder diffractograms were obtained using a Bruker D8 Advanced x-ray diffractometer under the following conditions:

Equipment: Bruker D8 Advanced diffractometer

Radiation: CuKai(A. = 1.54060 A), CuKa2(?i = 1.54439 A)

Voltage: 40 kV

Zero signal current: 30 mA

Aids: Goedel mirror, Soller slit

Standard references used: SRM 640c

Silicone powder LOT no. H-375

Continuous measurement 0/0 scanning: 5 - 35.00° 2 8

Scale step: 0.04°

Sample: flat surface, unpowdered, stored and measured at room temp.

The infrared spectra of the known Pl and P2 polymorphs were obtained in the solid phase and are shown in diagrams 5 and 6. The infrared spectrum of the desloratadine pseudopolymorph obtained with carbon dioxide, according to diagram 4, has significant differences compared to the true infrared spectra of polymorphs Pl and P2.

According to thermo-gravimetric measurements (DTG, DSC), the subject pseudopolymorph does not release carbon dioxide until the temp. of 120 °C, and according to x-ray crystallographic experiments, its crystal structure remains unchanged. Decomposition begins close to the melting point, at 140 °C, when the compound of formula (I) releases a calculated amount of carbon dioxide.

According to process (a) for obtaining pseudopolymorphs of desloratadine with carbon dioxide, desloratadine of formula (IV) is reacted with carbon dioxide in an organic solvent. The reaction takes place in a solution formed with an ester, an ether or a mixture of an ester and a lower aliphatic alcohol, or with a mixture of an ether and a lower aliphatic alcohol. The reaction is carried out in ethyl acetate, tetrahydrofuran, diethyl ether, preferably in a mixture of ethyl acetate and methanol, a mixture of ethyl acetate and ethanol, a mixture of tetrahydofuran and methanol, or a mixture of diethyl ether and ethanol, or a mixture of diethyl ether and methanol. It is preferable to carry out the reaction in a medium containing ethyl acetate. The process can be carried out by introducing carbon dioxide gas or by adding dry ice to a solution of desloratadine obtained with an organic solvent.

The reaction of desloratadine of formula (IV) and carbon dioxide takes place at temp. from room to 40 °C, preferably at room temp.

The pseudopolymorph of formula (I) can be isolated by filtration and centrifugation. The product is very clean, no additional purification is required.

According to process (b), to obtain the pseudopolymorph of formula (I), loratadine of formula (V) is decarboxyethylated with alkali metal hydroxide in a solution of 2-methoxymethanol or 2-ethoxyethanol, and desloratadine of formula (IV) is obtained dissolved in an organic solvent and reacted with carbon dioxide. Sodium or potassium hydroxide can be used as the alkali metal hydroxide. The reaction can be carried out under heating, preferably at the boiling point of the solvent. After completion of the reaction, 2-methoxymethanol or 2-ethoxyethanol is evaporated, the residue is dissolved in an organic solvent.

As organic solvents, those listed in the process description (a) can also be used, and it is preferable that the solvent is ethyl acetate. The solution reacts with carbon dioxide similarly to process (a).

According to the preferred solution of process (b), after the elimination of the ester group, 2-methoxymethanol or 2-ethoxyethanol is evaporated, and the residue is dissolved in ethyl acetate, then carbon dioxide is introduced or dry ice is added to the resulting solution, and the pseudopolymorph of formula (I) is isolated by filtration or centrifugation.

According to a further solution, the subject invention provides a process for obtaining desloratadine of formula (IV) with a high degree of purity by means of decarboxyethylation of loratadine of formula (V) with alkali metal hydroxide, wherein the reaction takes place in 2-methoxymethanol or in 2-ethoxyethanol.

As the alkali metal hydroxide, sodium or potassium hydroxide can be used. The reaction can take place under heating conditions, preferably at the boiling point of the solvent. The reaction time is short and is 1 - 3 hours. After completion of the reaction, 2-methoxymethanol or 2-ethoxyethanol is removed, the obtained residue is dissolved in an organic solvent, preferably in ethyl acetate. After evaporation of the organic solvent, deloratadine is obtained in the form of a base.

According to a further solution, the subject invention provides a process for obtaining salts of desloratadine, which have the formula.

where X denotes an anion and n denotes 1 or 2,

wherein the process comprises the reaction of a salt solution of the desloratadine pseudopolymorph obtained with carbon dioxide, whose formula is (I), in an organic solvent, with a solution of the corresponding acid in a solution with some organic solvent.

Hydrochloric, hydrobromic, sulfuric, methanesulfonic, benzenesulfonic, maleic or fumaric acid can be used as acids.

According to the solution of the process described above for obtaining the compound of general formula (VI), where n = 1, the acid is used in an approximately equimolar amount with respect to the pseudopolymorph of formula (I).

According to another solution of the process described above for obtaining compounds of general formula (VI), where n = 2, the acid is used in a molar ratio of at least 2:1, preferably in a ratio of 2:1 to 3:1, relative to the pseudopolymorph of formula (I).

Solvents can be esters, eg, ethyl acetate or alcohols, eg, methanol or ethanol.

The reaction of the compound of formula (1) with acid takes place at temp. between room and 40 C°, preferably at room temp.

According to the process described above, the salts of formula (VI) have a high degree of purity.

A significant advantage of the present invention is that desloratadine of formula (IV) or salts of desloratadine of formula (VI) can be obtained in a form with a high degree of purity. This is due to the fact that the pseudopolymorph of desloratadine obtained with carbon dioxide, whose formula is (I), can be obtained in a form with a high degree of purity, which is suitable for further pharmaceutical use without further purification.

The procedure for obtaining the adduct of formula (I) is a more efficient purification step than the recrystallization step. This is due to the fact that during the elimination of the carboxyl group, in the course of obtaining desloratadine from loratadine, small amounts of side products are obtained that do not form adducts with carbon dioxide, and therefore remain in the basic solution after filtration of the adduct of formula (I).

In this way, desloratadine can be easily removed from the solution with amine-type impurities.

According to a further solution, the present invention provides pharmaceutical preparations which as an active ingredient contain the pseudopolymorph of desloratadine of formula (I) in a mixture with inert pharmaceutically acceptable carriers and/or auxiliaries.

Pharmaceutical preparations according to the present invention can be prepared in conventional forms intended for therapy.

Preparations according to the present invention can preferably be administered orally or parenterally.

Oral preparations can be. eg, tablets, capsules, coated tablets, solutions, syrups, suspensions or emulsions. Preparations for parenteral administration are preferably intravenous or intramuscular injections.

Pharmaceutical preparations may contain conventional pharmaceutically acceptable carriers and/or excipients. Examples of pharmaceutically acceptable carriers are, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrose, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, and the like.

In the case of capsules, the carrier usually serves as the capsule material, with no additional carrier required.

Other oral dosage forms are sachets and candies. Particularly useful dosage forms for solids are tablets, powders, capsules, granules, sachets and candies.

Waxes with a low melting point can be used as carriers for suppositories (for example, a mixture of glycerides of fatty acids or cocoa butter). The wax is melted, the active ingredient is mixed with the melt, and then everything is homogenized. The molten, homogenized mixture is then poured into molds and allowed to cool and harden.

Tablets can be obtained by mixing the active ingredient with appropriate carriers in the appropriate ratio and pressing the mixture into tablets of the desired shape and size.

Powders are obtained by mixing finely divided active ingredient with fine powder carriers.

Liquid dosage forms can be solutions, suspensions and emulsions, from which the active ingredient can be released with a sustained release, if necessary.

Solutions obtained with water or with a mixture of water and propylene glycol are preferred.

Liquid dosage forms suitable for parenteral administration are preferably prepared in a mixture of water and ethylene glycol.

Aqueous liquid dosage forms suitable for oral administration can be obtained by dissolving the active ingredient in water, after which suitable coloring agents, artificial flavors, stabilizers and thickeners are added, depending on the requirements of use.

Aqueous suspensions suitable for oral administration can be obtained by suspending the active ingredient in water in the presence of compounds with high viscosity, e.g., with natural or artificial gums, resins, methyl cellulose, sodium carboxymethyl cellulose or with some other known suspending agents.

One group of solid dosage forms is immediately before administration transformed into a liquid dosage form, which is administered as a liquid preparation for oral administration. These liquid forms can be solutions, emulsions or suspensions, which, in addition to the active ingredient, additionally contain artificial colors, aromas, stabilizers, buffers, natural or artificial sweeteners, dispersants, thickeners, etc.

Pharmaceutical preparations according to the present invention can be prepared in the form of a unit dose. Unit dosage forms contain the desired amount of active ingredient. They can be sold in the form of packages, which contain separate amounts of dosage forms (eg, a package of tablets, capsules, powders in ampoules or vials). The unit dosage form can be a capsule, tablet, sachet, candy and also a package containing the desired number of dosage units.

Pharmaceutical preparations according to the present invention can be obtained by mixing the pseudopolymorph of desloratadine formula (I) with inert pharmaceutically acceptable carriers and/or auxiliaries.

Pharmaceutical preparations according to the present invention can be obtained using conventional processes known in the pharmaceutical industry.

According to a further solution, the subject invention provides a pseudopolymorph of desloratadine of formula (I), for use as an active pharmaceutical ingredient.

According to yet another further solution, the present invention provides the use of a pseudopolymorph of desloratadine of formula (I) in a pharmacologically effective amount for the treatment of allergy.

According to a further solution, the present invention provides a method of treating allergy, which includes the administration of pseudopolymorph desloratadine of formula (I) in a patient who needs such treatment

Further details of the subject invention can be found in the following examples, without limiting the scope of protection of the subject invention.

Examples

Example 1. Desloratadine in base form

100 ml of 2-methoxymethanol (Methvlcellosolve), 10 ml of 40% aqueous sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 mol) of loratadine were added to a vessel equipped with intensive mixing equipment. The mixture was left to ferment for 3 hours. Completion of the reaction was monitored by TLC.

90 ml of 2-methoxymethanol was removed from the reaction mixture by distillation, and 100 ml of ice-cold water and 100 ml of ethyl acetate were added to the residue. After separation, the organic layer was dried, the solvent was evaporated, and the residue was crystallized from a 10:1 mixture of hexane and ethyl acetate.

Yield: 9.28 g (91.5%), off-white crystals.

M.p.: 149-151 °C.

Elemental analysis for C19H19CIN2(310.8):

Calculated: C (73.42), H (6.16), Cl (11.41), N (9.01).

Found: C (73.38), H (6.22), Cl (11.4), N (9.04).

Degree of purity determined by HPLC: 99.1%.

Example 2: Preparation of desloratadine pseudopolymorph with half a mole of carbon dioxide

The procedure is the same as in Example 1, with the exception that carbon dioxide gas is added to the solution of desloratadine formed with ethyl acetate during the preparation of the base until a saturated solution is obtained, instead of evaporating the solution. The crystals that are separated are filtered in the cold and washed with ethyl acetate.

Yield: 10.1 g (92.8%), white crystals.

M.p.: 144 - 148 °C (gradually decomposes above 100 °C)

Elemental analysis for Ci9H,9ClN2* 14 C02 (332.87):

Calculated: C (70.71), H (5.79), Cl (10.62), N (8.41).

Found: C (71.10), H (5.56), Cl (10.71), N (8.53).

Degree of purity determined by HPLC: 99.88%.

Example 3: Obtaining the pseudopolymorph of desloratadine from half a mole of carbon dioxide

100 ml of 2-methoxymethanol (Methvlcellosolve), 12 ml of a 50% aqueous solution of sodium hydroxide and 12.5 g of loratadine were added to a vessel equipped with intensive mixing equipment. The mixture was left to ferment for 2 hours. Completion of the reaction was monitored by TLC.

90 ml of 2-methoxymethanol was removed from the reaction mixture by distillation, and 100 ml of ice-cold water and 100 ml of ethyl acetate were added to the residue. After separating the layers, the organic layer was clarified, dried, and 5.0 g of dry ice was added to the bright yellow solution in small portions over half an hour. The crystals were precipitated, the cold solution was filtered, and the obtained crystals were washed with ethyl acetate.

Yield: 9.61 g (88.4%), off-white crystals.

M.p.: 144 - 148 °C (gradually decomposes above 100 °C)

Elemental analysis for Ci9Hi9ClN2xV2C02(332.87):

Calculated: C (70.71), H (5.79), Cl (10.62), N (8.41).

Found: C (71.01), H (5.86), Cl (10.51), N (8.38).

Degree of purity determined by HPLC: 99.7%.

Example 4: Obtaining the pseudopolymorph of desloratadine from half a mole of carbon dioxide from the base

A solution of 29.0 g (0.93 mol) of desloratadine in 120 ml of ethanol was added dropwise, over the course of one hour, to a vessel equipped with vigorous mixing equipment and into which 500 ml of ethyl acetate was placed. During the addition and crystallization step, 20.0 g of dry ice was gradually introduced into the suspension, from which carbon dioxide was evolved.

During the introduction of carbon dioxide, the white crystalline suspension was cooled to 5 °C, and the mixture was stirred for an additional hour, filtered, the crystals washed with ethyl acetate and dried at 60 °C.

Yield: 28.42 g (92.5%), white crystals.

M.p.: 144 - 148 °C (gradually decomposes above 100 °C)

Elemental analysis for C,9H|9C1N2xViC02(332.87):

Calculated: C (70.71), H (5.79), Cl (10.62), N (8.41).

Found: C (71.18), H (5.86), Cl (10.66), N (8.46).

Purity determined by HPLC: 99.84%, total contamination 0.16% (6 contaminant fractions).

Example 5: Obtaining desloratadine hydrobromide (1 : 1)

100 ml of 2-methoxymethanol (Methvlcellosolve), 10 ml of 40% aqueous sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 mol) of loratadine were added to a vessel equipped with intensive mixing equipment. The mixture was allowed to boil for 3 hours. Completion of the reaction was monitored by TLC.

90 ml of 2-methoxymethanol was removed from the reaction mixture by distillation, and 100 ml of ice-cold water and 100 ml of ethyl acetate were added to the residue. After separation of the layers, the product was extracted from the organic layer with a mixture of 5 ml of concentrated HCl and 100 ml of ice-cold water. The aqueous layer was clarified with activated carbon and then filtered. Desloratadine in base form was released using 5 ml of 40% sodium hydroxide solution, extracted with 120 ml of ethyl acetate and dried. The amount of base in the bright yellow solution was determined, and then a solution of hydrogen bromide in ethyl acetate was added in an equimolar amount. The white crystalline product was filtered at 0 °C and washed with ethanol.

Yield: 7.33 g (93.6%), white crystals.

T.t.: 268 - 272 °C (transforms at 198 - 200 °C)

Elemental analysis for C19H19CIN2*HBr (391.74):

Calculated: C (58.26), H (5.15), Br (20.04), Cl (9.05), N (7.15).

Found: C (58.08), H (5.17), Br (20.45), Cl (9.05), N (7.14).

Degree of purity determined by HPLC: >99.7%.

Example 6: Preparation of desloratadine hydrobromide (1 : 1) from desloratadine pseudopolymorph with carbon dioxide formed from half a mole of carbon dioxide

A solution of 1.61 g (20 mmol) of hydrogen bromide in ethyl acetate was added to the suspension of 7.1 g (20 mmol) of desloratadine adduct with carbon dioxide obtained according to example 2, in 100 ml of ethyl acetate, at temp. 20 - 25 °C, within 10 minutes. The suspension was stirred for 2-3 hours, until gas evolution was complete, and then it was cooled to 0 °C and filtered. The crystals were washed with ethanol.

Yield: 7.52 g (93.6%), white crystals.

T.t: 268 - 272 °C (transforms at 198 - 200 °C)

Elemental analysis for C,9H,9C1N2*HBr (391.74):

Calculated: C (58.26), H (5.15), Br (20.04), Cl (9.05), N (7.15).

Found: C (58.18), H (5.19), Br (20.55), Cl (9.15), N (7.19).

Degree of purity determined by HPLC: >99.7%.

Example 7: Preparation of desloratadine hydrochloride (1:1) from desloratadine pseudopolymorph with carbon dioxide formed from half a mole of carbon dioxide

A solution of 0.73 g (20 mmol) of hydrogen chloride in ethyl acetate was added to the suspension of 7.1 g (20 mmol) of desloratadine adduct with carbon dioxide obtained according to example 2, in 100 ml of ethyl acetate, at temp. 20 - 25 °C, within 10 minutes. The suspension was stirred for 3 hours, until the evolution of the gas was finished, and then it was cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 6.61 g (95.2%), white crystals.

M.p.: 261 -263 °C.

Elemental analysis for C19H19CIN2* HC1 (347.29):

Calculated: C (65.71), H (5.80, Cl (20.42), N (8.07).

Found: C (65.39), H (5.75), Cl (20.26), N (8.02).

Degree of purity determined by HPLC: >99.8%.

Example 8: Preparation of desloratadine dihydrochloride (1 : 2) from desloratadine pseudopolymorph with carbon dioxide formed from half a mole of carbon dioxide

The procedure described in Example 6 was repeated, with the fact that ethyl acetate was replaced by ethanol, and a solution of 1.8 g (50 mmol) of hydrogen chloride in ethanol was added, at temp. 20 - 25 °C. The suspension was stirred for 3 hours, then cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 7.40 g (96.4%), white crystals.

M.p.: 218 -220 °C.

Example 9: Preparation of desloratadine dihydrobromide (1:2) from desloratadine pseudopolymorph with carbon dioxide formed by half a mole of carbon dioxide

The procedure described in Example 7 was repeated, with the hydrogen chloride being replaced by a solution of 4.05 g (50 mmol) of hydrogen bromide in ethanol. The suspension was stirred for 3 hours, then cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 8.61 g (91.2%), white crystals.

M.p.: 247-250 °C.

Example 10: Preparation of desloratadine hemisulfate (1:1) from desloratadine pseudopolymorph with carbon dioxide formed by half a mole of carbon dioxide

The procedure described in Example 7 was repeated, with the fact that the salt was obtained using 1.96 g (20 mmol) of a solution of sulfuric acid in ethanol, at temp. 20 - 25 °C. The suspension was stirred for 3 hours, then cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 7.88 g (96.4%), white crystals.

M.p.: 281 -283 °C.

Example 11: Obtaining desloratadine methanesulfonate (1:1) from desloratadine pseudopolymorph with carbon dioxide formed by half a mole of carbon dioxide

The procedure described in Example 9 was repeated, with the fact that the salt was obtained using 2.02 g (21 mmol) of a solution of methanesulfonic acid in ethanol, at temp. 20 - 25 °C. The suspension was stirred for 3 hours, then cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 7.02 g (86.5%), white crystals.

M.p.: 255 -257 °C.

Example 12: Preparation of desloratadine besylate

The procedure described in Example 3 was repeated, with the fact that the salt was obtained using 3.34 g (21 mmol) of a solution of benzenesulfonic acid in ethanol, at temp. 20 - 25 °C. The suspension was stirred for 2 hours, then cooled to 0 °C and filtered, and the crystals were washed with ethanol.

Yield: 8.39 g (80.5%), white crystals.

M.p.: 223 - 225 °C.

Example 13: Preparation of desloratadine fumarate (1:1)

To a solution of 3.55 g (10 mmol) of the compound of formula (I) (Example 3) in 25 ml of ethanol, 1.16 g (10 mmol) of fumaric acid was added, and then the solution was heated at the boiling point for 5 minutes, i.e., until the fumaric acid dissolved.

The product is crystallized under conditions of cooling and supporting crystallization. The suspension was stirred for 2 hours at 0 °C, filtered and washed with ethanol.

Yield: 3.91 g (91.5%), white crystals.

M.p.: 185 - 187 °C.

Example 14: Preparation of desloratadine maleate (1:1)

To a solution of 3.55 g (10 mmol) of the compound of formula (I) (Example 3) in 25 ml of ethanol, 1.16 g (10 mmol) of maleic acid was added, and then the solution was heated at the boiling point for 5 minutes, i.e., until the maleic acid dissolved.

The product is crystallized under conditions of cooling and supporting crystallization. The suspension was stirred for 2 hours at 0 °C, filtered and washed with ethanol.

Yield: 3.74 g (87.6%), white crystals.

M.p.: 181-184 °C.

Example 15: Pharmaceutical preparation

To obtain tablets (100 mg), the following ingredients were used (required for 1

tablet):

Example 16: Pharmaceutical preparation

To obtain tablets (100 mg), the following ingredients were used (required for 1

tablet):

Example 17: Pharmaceutical preparation

To obtain tablets (100 mg), the following ingredients were used (required for 1

tablet):

Claims (23)

1. Desloratadine pseudopolymorph obtained with carbon dioxide, characterized by having the formula: which is characterized by its X-ray diffractogram shown in Diagram 1, infrared spectrum shown in Diagram 4 and the following X-ray diffraction data: X-ray diffraction peak values and their relative intensities (>5%) on the desloratadinexViCO2 x-ray diffractogram. 2. The process for obtaining the pseudopolymorph of desloratadine obtained with carbon dioxide, whose formula (I) is from claim 1, characterized by including the following steps: (a) reaction of the desloratadine solution of the formula: with carbon dioxide, in an organic solvent; or (b) decarbethoxylation of loratadine of the formula: with alkali metal hydroxide, in 2-methoxymethanol or in 2-ethoxyethanol, after which desloratadine of formula (IV) reacts with carbon dioxide, in a solution obtained with an organic solvent. 3. Process (a) according to claim 2, characterized in that the reaction takes place in an ester, an ether, or in a mixture of a lower aliphatic alcohol and an ester, or in a mixture of an ether and a lower aliphatic alcohol. 4. The process according to claim 3, characterized in that the reaction is carried out in ethyl acetate, tetrahydrofuran, diethyl ether, dioxane, or in a mixture of ethyl acetate and methanol, a mixture of ethyl acetate and ethanol, a mixture of tetrahydofuran and methanol, a mixture of tetrahydofuran and ethanol, a mixture of diethyl ether and ethanol, or a mixture of diethyl ether and methanol. 5. The process according to claim 4, characterized in that the reaction takes place in ethyl acetate. 6. Process (a) according to claim 2 or according to any of claims 3-5, characterized in that it comprises introducing carbon dioxide or adding dry ice to a solution of desloratadine of formula (IV) with some organic solvent. 7. Process (b) according to claim 2, characterized in that it includes removing 2-methoxymethanol or 2-ethoxyethanol by distillation, dissolving the residue in an organic solvent, and then introducing it into a carbon dioxide or dry ice solution. 8. The process according to claim 7, characterized in that it includes the use of ethyl acetate as an organic solvent. 9. The process according to any one of claims 2-8, characterized in that it comprises carrying out the reaction of desloratadine of formula (IV) with carbon dioxide, at temp. between room and 40 °C, preferably at room temperature. 10. A process for obtaining desloratadine formula (IV) with a high degree of purity by means of decarbethoxylation of loratadine formula (V), characterized by the fact that it includes carrying out the reaction in 2-methoxymethanol or 2-ethoxyethanol. 11. The process according to claim 10, characterized in that it includes removing 2-methoxymethanol or 2-ethoxyethanol from the reaction mixture, dissolving the residue in an organic solvent and evaporating the solution. 12. The process according to claim 11, characterized in that it includes the use of ethyl acetate as an organic solvent. 13. Process (b) according to claim 2 and any of claims 10 - 12, characterized in that it includes carrying out the reaction under heating conditions, preferably at the boiling point of the solvent used. 14. Process for obtaining desloratadine salt, whose general formula is: (where X represents an anion and n is 1 or 2), characterized by the reaction of a solution of pseudopolymorph desloratadine obtained with carbon dioxide, having the formula (I), in an organic solvent, with a solution of the corresponding acid in an organic solvent. 15. The process according to claim 14, characterized in that it includes the use of hydrochloric, hydrobromic, sulfuric, methanesulfonic, benzenesulfonic, maleic or fumaric acid. 16. A process for obtaining a salt of the general formula (VI) (in which n is 1), according to any one of claims 14 or 15, characterized in that it includes the use of an acid in an approximately equimolar amount, in relation to the pseudopolymorph of the formula (I). 17. A process for obtaining a salt of general formula (VI) (in which n is 2), according to any one of claims 14 or 15, characterized in that it includes the use of an acid in a molar ratio of at least 2:1, preferably in a molar ratio of 2:1 - 3:1, in relation to the pseudopolymorph of formula (I). 18. The process according to any one of claims 14 - 17, characterized in that it includes carrying out the reaction at temp. between room and 40 °C, preferably at room temperature. 19. Pharmaceutical preparation, characterized by the fact that it contains pseudopolymorph desloratadine of formula (I) as an active ingredient, in a mixture with pharmaceutically acceptable carriers and/or auxiliaries. 20. The process of obtaining a pharmaceutical preparation from claim 19, characterized in that it includes mixing pseudopolymorph desloratadine of formula (I) with pharmaceutically acceptable carriers and/or auxiliaries. 21. Pseudopolymorphic form of desloratadine of formula (I), characterized by the fact that it is used as a pharmaceutical active ingredient. 22. Use according to claim 21, characterized in that the pharmaceutical active ingredient is used as an anti-allergic agent. 23. A method of treating an allergy, characterized in that it includes the use of pseudopolymorph desloratadine of formula (I) in a patient who needs such treatment.