WO2013075680A1

WO2013075680A1 - A method for the preparation and isolation of salts of vardenafil with acids

Info

Publication number: WO2013075680A1
Application number: PCT/CZ2012/000120
Authority: WO
Inventors: Ales Halama; Ivo Strelec; Ondrej Dammer
Original assignee: Zentiva, K.S.
Priority date: 2011-11-24
Filing date: 2012-11-26
Publication date: 2013-05-30
Also published as: IL232652A; CZ303877B6; CZ2011767A3; IL232652A0; BR112014012430A2; CN103946225A; CN103946225B; HUP1400334A2; HUP1400334A3; IN2014KN01308A

Abstract

The subject of this invention provides a method of preparation and isolation of water-insoluble or partially soluble salts of vardenafil of formula 1, in particular its salts with acids in the ratio of components 1 : 1 (of formula 2a, HA stands for any acid), and of crystalline hydrates of said salts. These solid forms, in particular crystalline vardenafil hydrochloride trihydrate of formula 4, can be directly, without additional purification, used in preparation of a medicine for the therapy of erectile dysfunction. The present solution is based on using water as a suitable medium both for obtaining of extracts of the water-soluble forms of vardenafil, and for isolation and subsequent crystallization of solid water-insoluble or partially soluble salts of vardenafil with acids (1 : 1). Crystallization of the isolated salts takes place after adjustment of pH of the aqueous solutions by means of aqueous solutions of bases or acids, wherein no organic solvent or a mixture thereof with water is needed for the crystallization. The method according to this invention reduces costs for organic solvents, increases efficiency of isolation of the vardenafil salts with acids, and facilitates preparation of poorly stable hydrates of these salts.

Description

A method for the preparation and isolation of salts of vardenafil with acids

Technical Field

The invention relates to a new, economically advantageous, and industrially applicable method of preparing vardenafil, a pharmaceutical substance used in preparation of various medicines (LEVITRA, VIVANZA, NUVIVA).

Background Art

Vardenafil of formula 1 is an orally active substance in the therapy of erectile dysfunction, wherein its therapeutic effect is based on selective inhibition of the enzyme phosphodiesterase 5 (PDE5). Vardenafil, chemically 2-[2-ethoxy-5-(4-ethylpiperazin-l-yl)sulfonylphenyl]-5- methyl-7-propyl-lH-imidazo[5,l-i][l,2,4]triazin-4-one, is described by chemical formula 1.

Two polymorphic structures have been known for the free base of vardenafil described by formula 1 (Form I described in patent WO 1999024433 and Form II described in patent US 2007197535). Vardenafil can further form salts, which are described by general chemical formula 2, wherein HA stands for any acid. Dominant position among solid forms of vardenafil is held by the respective hydrochlorides and their hydrates (WO 1999024433 and US 2007197535, Bioorg. Med. Chem. Lett. 12 (2002) 865-868), which are described by general formula 3. The hydrochloride trihydrate (WO1999024433, WO 2002050076) described by chemical formula 4, is a particularly important form of vardenafil, which is used for preparing dosage forms (WO 2010130393, WO 200815181 1 , WO 20051 10420, WO2004006894). An amorphous form of vardenafil hydrochloride trihydrate has been described (US2007197535), as well as a thermodynamically stable crystalline form used in preparing dosage forms, which was disclosed in patent application WO2004006894. The crystalline hydrate according to formula 4 is instable due to possible loss of crystal water in using this salt for preparation of a dosage form (WO2004006894), but also in any inappropriate manipulation with this salt during its preparation.

In both patent and scientific literature there have so far been described four different processes of chemical synthesis leading to vardenafil of formula 1.

The first process developed by Bayer (WO 1999024433, Bioorg. Med. Chem. Lett. 2002, 12(6) 865) proceeds according to Scheme 1. An alternative process, also developed by Bayer (WO2002050076), proceeds according to Scheme 2, the final synthetic steps (shown inside the frame in the Schemes) being important for comparison with the former process. For both procedures, compound of formula 5, chemically 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H- imidazo[5,l-f][l ,2,4]triazin-4-one, is the key intermediate, which can be obtained from O-ethylsalicyl amide and alanine in several steps. The two processes differ in making the final steps starting from the identical advanced intermediate of formula 5.

The first process utilizes chlorosulfonic acid as a source of the sulfone functional group in the target molecule. First, the intermediate of formula 5 is chlorosulfonated with chlorosulfonic acid to produce sulfonyl chloride of formula 6. In the following step, the free base of vardenafil of formula 1 is prepared by treating with 1 -ethylpiperazine in a suitable organic solvent and subsequently isolated. Finally, the final salt of vardenafil of formula 4 is prepared by treating a solution of the free base of vardenafil of formula 1 in a suitable organic solvent with an aqueous solution of hydrochloric acid.

Scheme 1

O-ethyl salicylamide alanine

(a) HOS0₂Cl, (b) 1-ethylpiperazine, CH₂C1₂, (c) organic solvent, HQ (aq)

The second process differs in the method of introducing the sulfone functional group. In this case this is a two-step process wherein sulfonation with sulphuric acid is first carried out and followed by chlorination with thionyl chloride. This two-step process makes it possible to avoid a risky work with chlorosulfonic acid, which can be a more preferable variant on the industrial scale. Preparation and isolation of vardenafil free base of formula 1, as well as preparation of the final salt of formula 4 is then carried out under conditions similar to the previous solution. In this case, vardenafil hydrochloride trihydrate of formula 4 was prepared by treatment of a solution of the free base in a mixture of acetone and water with an aqueous solution of hydrochloric acid.

Scheme 2

(5) (7) (6) (1 ) (4)

(a) H₂S0₄, (b) SOCl₂, xylene, (c) 1 -ethylpiperazine, NaOH, (d) acetone-water (12: 1), HC1 (aq)

The third synthesis of vardenafil of formula 1, developed by Topharma (WO 2009030095), proceeds according to Scheme 3. The synthesis does not use the compound of formula 5 as it is based on different intermediates than in the two Bayer processes.

Scheme 3

The fourth synthetic procedure, which was also developed by Topharma (WO 2009082845, Org. Process Res. Dev. 2009, 13, 1206-1208), proceeds according to Scheme 4. In principle it is very similar to the Bayer processes. It is based on the same basic raw materials (O-ethyl salicylamide and alanine) and on the same reactions. However, it differs in the order of the individual steps. The key chlorosulfonation reaction was performed in the initial phase of the synthesis according to this procedure; in this way, a reverse sequence of the reaction steps was achieved in comparison with the original process.

The methods of preparation of the pharmaceutically applicable vardenafil hydrochloride trihydrate of formula 4, described in the literature (WO 1999024433, WO2002050076, US2007197535), start from the vardenafil free base of formula 1, which is isolated in the solid form from the reaction medium following its previous synthetic preparation. The free base is then converted to the desired salt by treating a solution of the free base in a suitable solvent with an aqueous solution of hydrochloric acid. A suitable organic solvent or a mixture of an organic solvent with water can serve as the solvent. For this purpose, use of an acetone/water mixture in the ratio of components 12 : 1 was described in the literature (WO2002050076, US2007197535).

Vardenafil free base (WO1999024433, WO2002050076, US2007197535) has usually been isolated from the reaction mixture obtained by the reaction of chlorosulfonyl chloride of formula 6 with 1-ethylpiperazine in a suitable organic solvent (dichloromethane or xylene). After completing the reaction, evaporation of the solvent used was carried out and the residue was crystallized from another solvent, for instance from anhydrous ether or acetone with admixture of 4% water. According to WO 1999024433, this procedure afforded the vardenafil free base of formula 1 with the yield of 66%; according to US2007197535, the yield of an analogical procedure was 54%. A procedure was also described that did not require evaporation of the solvent used for the chemical reaction (WO2002050076). In this case, the reaction was carried out in xylene, followed by extraction of the product into an aqueous solution of hydrochloric acid, separation of the aqueous phase, mixing with acetone, and followed by neutralization of the obtained solution with a solution of sodium hydroxide. After cooling this mixture down, the free base was obtained in the solid state. In this case, the solid form of the vardenafil free base of formula 1 was obtained by crystallization from a solution of acetone and water solution after cooling it down.

The present solution represents a new, technologically simple, highly efficient, and industrially applicable method of obtaining chemically pure salts of vardenafil of formula 2 with acids in the ratio of components 1 : 1, and crystalline hydrates of these salts, in particular vardenafil hydrochloride trihydrate of formula 4.

Disclosure of Invention

The present invention provides a method of preparation, isolation, and purification of vardenafil of formula 1 in the form of its salts with suitable acids in the ratio of components 1 : 1, which makes use of different solubilities of the acidobasic forms of vardenafil in an aqueous media in dependence on the pH value of these media.

Detailed Description of Invention

The present invention relates to a method of preparation and isolation of salts of vardenafil with acids in the ratio of both components 1 : 1 described by formula (2a), where HA stands for an acid, and of crystalline hydrates of these salts, characterized by a procedure consisting of the following steps:

(2a)

(a) preparation of a solution of vardenafil in an organic solvent, preferably in a solvent that is immiscible or partially miscible with water;

(b) extraction of vardenafil from said solution in an organic solvent by means of an aqueous solution of an acid or, on contrary, an aqueous solution of a base, to obtain an aqueous solution of the water-soluble acidobasic form of vardenafil, which can be a salt of vardenafil with an acid (1 : 2) or a salt of vardenafil with a metal;

(c) adjustment of pH of the aqueous extracts obtained according to steps (a) and (b) to a value of 3.2 to 4.2, preferably to a value of 3.7 to 3.8, at temperature of 20 to 30 °C by means of addition of a base to the solution containing the salts of vardenafil with acids in the ratio (1 :2), or by means of addition of an acid to the solution containing the salt of vardenafil with a metal;

(d) isolation of the crystalline salt of vardenafil with an acid (1 : 1) described by formula (2a), wherein HA stands for an acid.

For the purposes ofthis invention, the acid HA is hydrochloric acid, hydrobromic acid, nitric acid, or trifluoroacetic acid.

The salt of vardenafil with a metal is represented by salts with alkali metals, in particular salts with Na, K and Li.

Said organic solvent, preferably a solvent that is immiscible or partially miscible with water, for preparation of the solution of vardenafil, can include, for example, a Cj-C₆ chlorinated solvent with 1 to 4 atoms of chlorine, preferably dichloromethane. A further subject of the present invention provides a method of preparing crude vardenafil, in which the substance 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,l-fJ[l ,2,4]triazin-4- one of formula 5

(5)

is chlorosulfonated with chlorosulfonic acid in a Ci-C₆ organic chlorinated solvent with one to four chlorine atoms, preferably in dichloromethane, wherein 4-ethoxy-3-(5-methyl-4-oxo-7- propyl-3,4-dihydroimidazo-[5, l-f][l,2,4]triazin-2-yl)-benzenesulfonyl chloride of formula 6 is isolated in the solid state,

and is finally reacted with 1-ethylpiperazine, thus giving a solution of vardenafil in an organic solvent, which solution, prepared in this manner, can preferably be used for preparation of salts of vardenafil with acids (1 : 1).

The method according to this invention also includes preparation of vardenafil in the form of a crystalline hydrochloride trihydrate, which consists of the following steps:

(a) chemical synthesis consisting, in the first step, of reaction of 2-(2-ethoxyphenyl)-5- methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one with chlorosulfonic acid, carried out in dichloromethane, followed by reaction of the product of the first step with 1-ethylpiperazine, resulting in a solution of vardenafil in dichloromethane;

(b) extraction of the water-soluble form of vardenafil from the solution of vardenafil in dichloromethane by means of an aqueous solution of hydrochloric acid; (c) adjustment of pH of the aqueous solution obtained according to step (b) at a temperature of 20 to 30 °C by means of addition of a solution of sodium hydroxide to a pH value of 3.2 to 4.2, preferably to a pH value of 3.7 to 3.8;

(d) crystallization and isolation of the separated crystalline vardenafil hydrochloride trihydrate.

The present invention is based on the use of two basic principles. The first one is capability of vardenafil to form four acidobasic forms. The second principle is different solubilities of these four acidobasic forms in water. By synergetic application of both principles, it is possible to selectively obtain the desired form of vardenafil high quality and without addition of organic solvents in crystallization of these forms.

The present invention relates to a new method of preparing crystalline forms of vardenafil, in particular its salts with acids (1 : 1), and crystalline hydrates of these salts. Preparation of the crystalline salts of vardenafil with acids by change of pH of the aqueous solution of another, more soluble, form of vardenafil is a substantial and preferable feature of the method according to this invention, which is distinctive from prior methods. An aqueous solution is to be understood to means a solution which uses water as the solvent and does not contain an intentional addition of another non-aqueous solvent. Such aqueous solutions of soluble forms of vardenafil can be obtained by extracting reaction mixtures containing vardenafil dissolved in the organic solvent used by means of aqueous solutions of acids or, on contrary, of bases. Appropriate adjustment of the pH of thus obtained acidic or, on contrary, alkaline aqueous solutions containing a soluble form of vardenafil can preferably result in obtaining corresponding crystalline salts of vardenafil, characterized by low solubility in water. Direct isolation of salts of vardenafil without necessity of previous isolation of the free base in the solid state is a preferred feature of the method according to this invention.

Thus, the method according to this invention utilizes water as a preferable medium both for obtaining aqueous solutions of the water-soluble forms of vardenafil that enable an easy separation of by-products and impurities, and for preparing poorly water-soluble final solid forms of vardenafil. This method, used in a specific embodiment for preparation of the vardenafil free base or of vardenafil hydrochloride trihydrate, is illustrated in Scheme 5. Scheme 5

The embodiments of isolation of the vardenafil salts with acids (1 : 1) according to Scheme 5 make it possible to select from two possibilities. The first possibility is isolation o'f the free base of vardenafil of formula 1 and its subsequent conversion to a salt with an acid (1 : 1) in the second step. The second possibility is more preferable direct isolation of the vardenafil salts with acids from the aqueous medium, i.e. without previous isolation of the free base in the solid state. In case of the embodiment according to Scheme 5, hydrochloride trihydrate of formula 4 is obtained as a product but analogical solutions can generally be applied to other salts as well. In preferable embodiments of the invention, wherein the reaction mixture from the synthesis of vardenafil is directly processed, the isolation of vardenafil from the reaction medium is started by extraction using an aqueous solution of a suitable acid, for example hydrochloric acid. The obtained aqueous solution, which in this case contains the well soluble twice protonated form, i.e. vardenafil dihydrochloride, is then partially neutralized by means of a suitable base, for instance an aqueous solution of sodium hydroxide. The composition of the solid form of vardenafil, which is isolated in the end of the process, is determined by the resulting pH value of the aqueous solution, or of the formed aqueous suspension. The procedure can also be reverse, wherein vardenafil is extracted from the reaction mixture by means of a solution of a base and the pH of the obtained aqueous solution is adjusted to the desired value by means of addition of a suitable acid. An optimum pH found for the isolation of vardenafil as the free base falls within the interval from 7 to 10, an optimum pH value for the isolation of the vardenafil salts with acids in the ratio of components 1 : 1 was found in the interval from 3.2 to 4.2. The said pH values are rather reference ones as they depend on several factors, for instance temperature and concentrations of various components. For example, at a temperature of 20 to 30 °C, the interval of 8.8 to 9.4 appears to be the optimum pH for crystallization of the vardenafil free base and that of 3.7 to 3.8 appears to be optimum for crystallization of vardenafil hydrochloride trihydrate. Thus, for each specific case, an optimum pH value should be specified experimentally by means of acidobasic titration (see Fig. 1). Finding of an optimum pH value increases efficiency of the whole process as, at an optimum pH value, the desired form selectively precipitates in a maximum yield from the aqueous solution, the other undesired components remaining dissolved in the aqueous solution.

The vardenafil free base of formula 1 contains two basic centres. It can thus bind one, or possibly two protons provided by a suitable acid, see Scheme 6. For this reason, vardenafil can form salts with monobasic acids in the ratio of components 1 : 1 or 1 : 2. Examples of such salts with a strong monobasic acid include mono- and di- hydrochloride of vardenafil of formula 3. The free base of vardenafil of formula 1 further also contains one weak acidic centre, which is able to release a proton in the reaction with a strong base. For this reason, vardenafil can, for example, form salts with suitable metals in the ratio of components 1 : 1. Examples of such salts include the sodium salt of formula 8 formed by treatment of the vardenafil free base with sodium hydroxide. An example of acidobasic reactions in the reactions of various forms of vardenafil with hydrochloric acid or, on contrary, with sodium hydroxide is described in Scheme 6. The dependence of these reactions on pH of the medium can be expressed by means of equilibrium constants pKi, pK₂ and pK₃.

Scheme 6

Different solubilities of the said acidobasic forms in water is the second important feature that enables selective preparation and isolation of the desired solid forms. The vardenafil forms well soluble in water can be isolated from the reaction mixtures in the form of aqueous solutions, which can be both acidic and alkaline. The undesired chemical impurities, for instance unreacted raw materials, then remain dissolved in the separated organic phase. An adjustment of pH of the aqueous solutions of the soluble forms of vardenafil leads to conversion of the soluble forms to the forms insoluble in water, or to partially soluble forms. The insoluble or partially soluble forms of vardenafil can form crystalline structures in an aqueous medium, preferably crystalline hydrates of the salts of vardenafil with acids (1 : 1); this is crystalline trihydrate in case of the salts of vardenafil with hydrochloric acid.

Of the four acidobasic forms, the vardenafil base itself in particular is poorly soluble in water. The sodium salt and dihydrochloride are well soluble, whereas the monohydrochloride can be easily crystallized from water in the form of the less soluble trihydrate. The adjustment of pH leading to the desired conversion of the more soluble acidobasic form of vardenafil into the less soluble form can most simply be carried out by addition of an aqueous solution of an acid or base to a solution of the more soluble form of vardenafil, usually under stirring. The less soluble solid form of vardenafil which has crystallized from the aqueous solution after the pH adjustment is isolated by a suitable method, for example, by means of filtration or centrifugation; the residual chemical impurities, for example undesired inorganic salts that are formed during the pH adjustment, remaining dissolved in the separated aqueous phase. The obtained crystalline substance can finally be freed from the residual mother liquors by washing with water and recovered in a quality corresponding to the desired specification by a suitable drying method under defined conditions (in particular pressure, temperature, time of drying, or flow rate of the gas) in a suitable technological apparatus. It has been demonstrated by means of X-ray powder diffraction in case of vardenafil hydrochloride trihydrate that the crystalline form of the product obtained by the procedure according to this invention is identical with that used in manufacturing the dosage form of the medicine which is used in the therapy of erectile dysfunction (this crystalline form was described in patent application WO2004006894). An advantageous feature of the procedure according to this invention also includes the surprising purification effect of the process, wherein, after the change of pH of aqueous solutions containing the soluble forms of vardenafil, an insoluble form of vardenafil precipitates that is characterized by high quality which meets the requirements posed on pharmaceutical ingredients. Thus, in carrying out the isolation of the salts of vardenafil with acids (1 : 1) according to this invention, an advantageous state has unexpectedly been attained wherein no additional manipulation for modifying both the crystalline morphology of the separated form of vardenafil and its chemical purity is required.

In crystallizing the solid forms of vardenafil by the method of the invention no presence of an organic solvent in a mixture with water is required. As for obtaining the vardenafil salts, these can be obtained by direct processing of the reaction mixture after the synthesis of vardenafil, isolation of the free base in the solid state not being necessary. This solution brings numerous advantages. It reduces loses of the product due to a lower number of manipulations and provides higher yield in comparison with the processes in which the free base of vardenafil is first isolated. In preparing hydrates of the salts, the method of the invention makes it possible to more easily reach a defined content of crystal water even in case of such instable hydrate as the vardenafil hydrochloride trihydrate of formula 4. Using water as a crystallization medium eliminates costs for organic solvents necessary in other methods of carrying out crystallization of the final solid form. Moreover, the vardenafil salts obtained by the procedure according to the present invention do not contain residues of organic solvents that would otherwise have to be removed from the pharmaceutical substance before it is used in dosage forms. In fact, especially in the hydrates of vardenafil salts prepared by other methods, reduction of the content of crystal water may occur during removing residual solvents by various methods of drying, which is undesirable for marketing authorisation of the pharmaceutical substance, for which the pertinent authorities require high reproducibility and defined composition. The method of the invention has a further advantage in enabling to directly and in a reproducible manner obtain, by single crystallization, the desired crystalline form of vardenafil, such as monohydrochloride trihydrate characterized by a profile of impurities corresponding to requirements for the pharmaceutical substance, without necessity of additional purification; thus allowing direct use of thus obtained crystalline form of vardenafil for producing pharmaceutical compositions.

In a particularly preferred embodiment the method of the invention makes it possible to obtain the solid form of vardenafil in a high yield and purity in two steps from the starting compound of formula 5 by carrying out chlorosulfonation reaction of the starting compound of formula 5 with a solution of chlorosulfonic acid in dichloromethane, wherein, after mixing the reaction mixture with ice, sulfonylchloride of formula 6 is obtained as a solid substance. The yield of the first step, calculated on the expected free base of sulfonylchloride of formula 6, would be within the range of 1 10 to 1 15 %, which is theoretically impossible. The reason lies in the capability of sulfonylchloride of formula 6 to form salts with acids; consequently, the product of the first step is in fact a mixture of the free base of formula 6 and its salts with acids, namely with sulphuric and hydrochloric acids, see Scheme 7. This solid mixture can preferably be used without any treatment in the next synthetic step; the yield of the process should be then calculated for the two synthetic steps together.

Scheme 7

(6 )* HC I (6 ) (6)* H₂S 0₄

Already the finding of an appropriate solvent enabling a technologically controllable reaction of chlorosulfonic acid with the starting compound of formula 5 and the subsequent easy decomposition of excess chlorosulfonic acid by water (ideally in the form of ice whose latent heat of liquefaction absorbs the released heat of reaction), and washing the formed acids in the separated aqueous phase is a substantial improvement of the method known from application WOl 999024433. Chlorinated Q - C₆ hydrocarbons with one to four CI atoms, such as dichloromethane or chloroform, have proved to be suitable solvents for this reaction. Recovery of the crystalline intermediate of formula 6 in the form poorly soluble in dichloromethane (contrary to the state of the art wherein this intermediate was extracted with dichloromethane after having been prepared by reaction in chlorosulfonic acid itself and its decomposition in water), which has proved to result from the synergetic effect of careful performance of the chlorosulfonation reaction in the solvent and using of a sufficiently pure starting compound of formula 5, provides further possibilities. The reaction of the product of the first step, i.e. a mixture of acidobasic forms of the substance of formula 6, with 1 -ethylpiperazine gives the target structure of vardenafil. The reaction can also be performed in water or in numerous polar or non-polar solvents, preferably in water- immiscible solvents. It is possible to use the separated solid mixture of salts of formula 6 or to work directly with the reaction mixture from the previous step freed of most of acidic components by washing. In the second case, it is most preferable to perform both reaction steps in the same solvent, i.e. the embodiment that does not require addition of a second solvent (co-solvent) for performing the second step or removal of the solvent used in the first step. Dichloromethane has proved to be a preferable solvent for such direct processing of the reaction mixture from the first step. Prior solutions have contemplated evaporation of the solvent used in the synthesis and crystallization of the vardenafil free base from another organic solvent (WO1999024433, WO2002050076 and US2007197535). The procedure according to this invention advantageously isolates vardenafil by means of extraction with an aqueous medium and thus does not involve such energy-demanding processes as evaporation of the solvent and subsequent crystallization of the free base.

The advantage of the solution according to this invention is also documented by comparing the direct isolation of the vardenafil salt with the procedure that additionally involves isolation of the free base in the solid state, see Scheme 5. While the direct method provided vardenafil hydrochloride trihydrate with total yields of 69 - 86% (calculated on the starting material of formula 5) in two partial steps, the process which is longer by one step, characterized by isolation of the free base, provided a lower total yield of 58%, see Scheme 5. Moreover, no organic solvent was required in the direct process for crystallization of the isolated salt. The advantage of the solution according to this invention is also documented by yields of isolations of the free base found in the literature. For this isolation, yields of 54 or 66% were published (US2007197535 and WOl 999024433), i.e. substantially lower values than those obtained for the salts of vardenafil with acids (1 : 1) using the method of the present invention, which is more simple in terms of technology.

The conditions and results of the experiments performed by us are described in more detail in the experimental part. This concerns, in particular, description of the vardenafil synthesis until the stage of a solution in an organic solvent, and description of the preparation of aqueous solutions of soluble forms of vardenafil, adjustment of their pH, and subsequent crystallization of the less water-soluble forms, such as the vardenafil free base and the crystalline hydrate of a salt of vardenafil with hydrochloric acid (1 : 1). Described is also an experiment documenting solubility of vardenafil hydrochloride in water, acetone, and mixtures of both solvents at the temperature 25 °C. Finally, an experiment is described that represents acidobasic titration of a solution of dihydrochloride dihydrate in water using a solution of sodium hydroxide, i.e. an example of determination of the optimum pH value for isolating the water-insoluble or partially soluble forms of vardenafil. Both the later experiments simulate conditions usually existing in the process of producing the solid forms of vardenafil by the procedure which is characteristic for the present invention. Brief Description of Drawings

Fig. 1 depicts a titration curve obtained in titrating an aqueous solution of vardenafil dihydrochloride dihydrate with a 10% solution of sodium hydroxide in water; the titration was carried out at the temperature 26 °C.

Fig. 2 depicts a solubility curve of vardenafil hydrochloride trihydrate in acetone/water mixtures at the temperature 25 °C.

Fig. 3 depicts comparison of X-ray powder diffraction patterns measured for vardenafil hydrochloride trihydrate of formula 4, prepared under various conditions: (a) from a mixture of acetone and hydrochloric acid (according to Example 7);

(b) from aqueous extracts after pH change (according to Example 3);

(c) by recrystallization of the crude product from water (according to Example 4).

Examples The subject of the invention is explained in more detail by the following Examples that, nevertheless, have no influence on the scope of protection defined in the Claims.

EXAMPLE 1 (procedure for the preparation of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4- dihydroimidazo-[5,l-fJ[l,2,4]triazin-2-yl)benzenesulfonylchloride)

A solution of 50 g of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5, l-f][l,2,4]triazin- 4-one, dissolved in 500 ml of dichloromethane was added dropwise to a solution of 100 ml of chlorosulfonic acid and 50 ml of dichloromethane during ca. 90 minutes. The mixture was further stirred at laboratory temperature (23 °C) overnight, 24 hours in total. On the following day, the reaction mixture was poured into 800 g of ice. After the ice has thawed, the mixture was thoroughly mixed. The precipitated solid substance was filtered off, the filtration cake was washed with dichloromethane (2 x 100 ml) and the isolated solid product was vacuum dried (20 °C, 1 to 2 kPa (10 to 20 mbar)). The product was obtained in the form of an off-white powder in the yields of from 1 10 to 1 15% (calculated on the non-protonated form of the product).

EXAMPLE 2 (procedure of preparing a solution of vardenafil in an organic solvent)

25 g of the product from the preceding step (Example 1) was suspended in 200 ml of dichloromethane; the suspension was thoroughly mixed. Then, 23 ml of 1 -ethylpiperazine was slowly added dropwise. The turbid solution was further stirred for ca. 30 min; then this solution was washed with water (5 x 100 ml). A solution of the vardenafil free base in dichloromethane was obtained.

EXAMPLE 3 (procedure of isolating vardenafil hydrochloride trihydrate from a solution of the free base in an organic solvent)

The dichloromethane solution of the vardenafil free base, obtained according to Example 2, was extracted with 50 ml of 2M hydrochloric acid. The separated aqueous layer (pH 1.8 to 2.0), containing the solution of vardenafil dihydrochloride, was partially neutralized with a 2M solution of sodium hydroxide to the pH value of 3.75 ± 0.05 at a temperature of 24 to 28 °C. The precipitated suspension was stirred for 30 minutes, then filtration and washing of the cake with distilled water was performed. A crystalline product (m. p. 195 to 197 °C) was obtained. Repeated procedures produced yields of 63 to 75%; chemical purity 99.75% to 99.85%) according to HPLC; water content 9.20 to 9.30% (w/w); content of chloride ions 5.9 to 6.2% (w/w); sulphate ashes always below 0.10 %. The crystal morphology of the product was checked by means of the X-ray powder diffraction; see Fig. 3 (b). The crystalline modification found was always identical with the crystalline form of vardenafil hydrochloride trihydrate described in patent application WO2004/006894A1 (see Fig. 8 and Tab. 8 of the cited application).

EXAMPLE 4 (crystallization of vardenafil hydrochloride trihydrate from water)

150 ml of distilled water was added to 20 g of vardenafil hydrochloride trihydrate obtained by the procedure according to Example 3. The mixture was stirred and heated to ca. 90 °C. The still hot solution was filtered. The filtrate was stirred under slow cooling to reach laboratory temperature for ca. 2 to 3 hours. The precipitated product was filtered; the cake was washed with distilled water and free dried. Repeated procedures produced yields of 72 to 75%, m. p. 193 to 196 °C; water content 9.2 to 9:3%. The crystalline modification was identical with the product prepared according to Example 3 ; see Fig. 3 (c).

EXAMPLE 5 (crystallization of vardenafil hydrochloride trihydrate from acetone/water mixture)

10 g of vardenafil hydrochloride trihydrate, obtained by the procedure according to Example 3, was dissolved in a mixture of acetone (100 ml) and water (10 ml) at ca. 55 °C. The still warm solution was filtered, 20 ml of acetone was added to the filtrate, and the stirred mixture was slowly cooled down to laboratory temperature. The precipitated product was filtered and the cake washed with 5 ml of acetone. The yield of crystallization was 55%. The crystalline modification was identical with that of the products prepared according to Examples 3 and 4. EXAMPLE 6 (procedure of isolating the vardenafil free base from a solution in an organic solvent)

(1) (1)

The dichloromethane solution of the vardenafil free base, obtained according to Example 2, was extracted with 50 ml of 2M hydrochloric acid. The separated aqueous layer (pH 1.7), containing a solution of vardenafil dihydrochloride, was alkalized with a 2M solution of sodium hydroxide to the target pH value 9.0 ± 0.2 at a temperature of 24 to 28 °C. The precipitated suspension was stirred for ca. 30 minutes, filtered, the cake was washed with distilled water and vacuum dried. An off-white, crystalline product was obtained in the yield of 69% and m. p. 183 to 185 °C.

EXAMPLE 7 (preparation of vardenafil hydrochloride trihydrate from the free base)

(1 ) (4)

The free base of vardenafil (6.0 g) was suspended in a mixture of 30 ml of acetone and 2 ml of water. This suspension was heated to 50 °C. 1.1 ml of concentrated hydrochloric acid was added dropwise. The suspension was heated to obtain a solution, filtered, and the stirred filtrate was slowly cooled down to laboratory temperature. The precipitated product was filtered and free-dried. A crystalline product was obtained with the yield of 77%, m. p. 196 to 198 °C, and water content 9.1 % (w/w). The crystalline modification was identical with that of the products prepared according to Examples 3, 4 and 5; see Fig. 3 (a). EXAMPLE 8 (preparation of vardenafil hydrochloride trihydrate from alkaline aqueous solutions)

(1 ) (4)

The dichloromethane solution of the vardenafil free base, obtained according to Example 2, was washed with 50 ml of 2M sodium hydroxide. The separated aqueous layer (pH ca. 14), containing a solution of the sodium salts of vardenafil, was acidified with 2M hydrochloric acid to the target pH value 3.75 ± 0.05 at a temperature of 24 to 28 °C. The precipitated suspension was stirred for 60 minutes, filtered, and the cake was washed with distilled water. An off- white crystalline product was obtained with the yield of 66% and m. p. 194 to 196 °C.

EXAMPLE 9 (solubilities of vardenafil hydrochloride dihydrate in water, acetone and mixtures thereof)

Vardenafil hydrochloride trihydrate (1 to 2 g) was stirred in a series of acetone/water mixtures (100%, 95%, 90%, 75%, 50%, 25%, 10%, 5%, and 0% of acetone) having the volume 10.0 ml at 25 °C for 1 h; the undissolved component was filtered, and, after drying, weighed. Subsequently, subtraction of the weights of the undissolved portions from the initial weight was carried out, and the obtained weight (mg) was divided by the volume of the solvent used (ml). The result gives a curve of solubility of vardenafil hydrochloride trihydrate in a mixture acetone/water at 25 °C (see Fig. 2). Minimum solubilities were found for pure water and a mixture of acetone with about 7% of water (v/v). Maximum solubility was found in a mixture of acetone with water containing 40 to 50% of water (v/v).

EXAMPLE 10 (alkalimetric titration of a solution of vardenafil dihydrochloride dihydrate)

8.0 g of vardenafil dihydrochloride dihydrate (prepared by the procedure according to Example 5 in US2007197535A1) was dissolved in water at 25 °C and this solution was diluted with water to the resulting volume of 25 ml. The obtained solution was titrated with a 10% solution of sodium hydroxide, during which the dependence of pH of the mixture containing various forms of vardenafil on the volume of added sodium hydroxide was monitored. In the obtained titration curve (Fig. 1) it was possible to read experimental values of the equilibrium constants pKl (ca. 2.1), pK2 (ca. 5.3), pK3 (ca. 13.5), and three points of equivalence corresponding to the consumption of the agent necessary to convert one acidobasic form to the other. In the given embodiment, pH of ca. 3.7 to 3.8 was found which corresponds to the point of equivalence for the salt of vardenafil with a strong acid in the ratio of components 1 : 1, and pH of ca. 9.3 to 9.4 corresponding to the point of equivalence for the vardenafil free base.

Claims

1. A method for the preparation and isolation of salts of vardenafil with an acid in the ratio of the two components 1 : 1, described by formula (2a), wherein HA stands for an acid, and of crystalline hydrates of said salts, characterized in that it^' consists of the following steps:

(2a)

a) preparation of a solution of vardenafil in an organic solvent, preferably in a solvent that is immiscible or partially miscible with water; b) extraction of vardenafil from said solution in an organic solvent by means of an aqueous solution of an acid or, on contrary, an aqueous solution of a base, to obtain an aqueous solution of the water-soluble acidobasic form of vardenafil, which can be a salt of vardenafil with the acid HA (1 : 2) or a salt of vardenafil with a metal; c) adjustment of pH of aqueous extracts obtained according to steps (a) and (b) to a value of 3.2 to 4.2, preferably to a value of 3.7 to 3.8, at temperature of 20 to 30 °C by means of addition of a base to the solution containing salts of vardenafil with acids in the ratio (1 : 2), or by means of addition of an acid to the solution containing a salt of vardenafil with a metal;

d) isolation of the crystalline salt of vardenafil with an acid (1 : 1) described by formula (2a), wherein HA stands for an acid.

2. The method according to claim 1 , characterized in that HA stands for an acid selected from the group including hydrochloric acid, hydrobromic acid, nitric acid, and trifluoroacetic acid.

3. The method according to claim 1 , characterized in that a solution of vardenafil in a Ci-C₆ chlorinated solvent 1 with one to four atoms of chlorine is prepared in step (a).

4. The method according to claim 3, characterized in that the chlorinated solvent is dichloromethane.

5. The method according to claim 1 , characterized in that the aqueous solution of a base used for extraction of the soluble form of vardenafil in step (b) is a solution of an alkali metal hydroxide selected from the group including lithium hydroxide, sodium hydroxide, and potassium hydroxide.

6. The method according to claim 1 , characterized in that an aqueous solution of an acidobasic form of vardenafil is obtained in step (b), which is the salt of vardenafil with an acid (1 :2) described by chemical formula 2b, wherein HA stands for a acid selected from the group including hydrochloric acid, hydrobromic acid, nitric acid, and trifluoroacetic acid, or the salt of vardenafil with a metal described by chemical of formula 8, wherein M stands for an alkali metal selected from the group of Na, Li, and K.

7. The method according to claim 1, characterized in that an aqueous solution of a base selected from the group including lithium hydroxide, sodium hydroxide, and potassium hydroxide is used for adjustment of pH in step (c).

8. The method according to claim 1 , characterized in that an aqueous solution of an acid selected from the group including hydrochloric acid, hydrobromic acid, nitric acid, and trifluoroacetic acid is used for adjustment of pH in step (c).

9. The method according to any one of claims 1 to 8, characterized in that a salt of vardenafil with hydrochloric acid is isolated in step (d).

10. The method according to any one of claims 1 to 9, characterized in that crystalline vardenafil hydrochloride trihydrate of formula 4 is isolated.

(4)

1 1. The method according to claim 3, characterized in that said solution of vardenafil is prepared from crude vardenafil, which is prepared by chlorosulfonating 2-(2- ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5, l -f][l ,2,4]triazin-4-one of formula 5

(5)

with chlorosulfonic acid in a Ci-C₆ organic chlorinated solvent with one to four chlorine atoms, preferably in dichloromethane, isolating 4-ethoxy-3-(5-methyl-4-oxo-7-propyl- 3,4-dihydroimidazo-[5, l -fJ[l ,2,4]triazin-2-yl)-benzenesulfonylchloride of formula 6 in the solid state,

and reacting the same with 1-ethylpiperazine.

12. The method for the preparation of vardenafil in the form of crystalline hydrochloride trihydrate according to any of claims 1 to 1 1 , characterized in that it consists of the following steps:

(a) chemical synthesis consisting, in the first step, of reaction of 2-(2-ethoxyphenyl)-5- methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one with chlorosulfonic acid carried out in dichloromethane, followed by reaction of the product of the first step with 1 -ethylpiperazine to obtain a solution of vardenafil in dichloromethane;

(b) extraction of the water-soluble form of vardenafil from the solution of vardenafil in dichloromethane by means of an aqueous solution of hydrochloric acid;

(c) adjustment of pH of the aqueous solution obtained according to step (b) at a temperature of 20 to 30 °C by means of addition of a solution of sodium hydroxide to a value of 3.2 to 4.2, preferably to a value of 3.7 to 3.8;

13. Use of salts of vardenafil with acids (1 : 1), prepared by the method according to claims 1 to 12, in preparing pharmaceutical compositions for therapy of erectile dysfunction.