Europäisches Patentamt *EP000812320B1* (19) European Patent Office

Office européen des brevets (11) EP 0 812 320 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: C07D 295/14, A61K 31/40 of the grant of the patent: 12.07.2000 Bulletin 2000/28 (86) International application number: PCT/IB96/00254 (21) Application number: 96904993.1 (87) International publication number: (22) Date of filing: 12.02.1996 WO 96/26197 (29.08.1996 Gazette 1996/39)

(54) AMORPHOUS PIRETANIDE, PIRETANIDE POLYMORPHS, PROCESS FOR THEIR PREPARATION AND THEIR USE AMORPH PIRETANIDE, POLYMORPHE DAVON, VERFAHREN ZUR DESSEN HERSTELLUNG UND IHRE VERWENDUNG PIRETANIDE AMORPHE, POLYMORPHES DE PIRETANIDE, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION

(84) Designated Contracting States: (74) Representative: Fischer, Hans-Jürgen, Dr. AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT Aventis Pharma Deutschland GmbH, SE Patent- und Lizenzabteilung 65926 Frankfurt am Main (DE) (30) Priority: 22.02.1995 JP 3321595 22.02.1995 JP 3321695 (56) References cited: EP-A- 0 243 891 EP-A- 0 465 841 (43) Date of publication of application: DE-A- 2 419 970 FR-A- 2 373 280 17.12.1997 Bulletin 1997/51 • PATENT ABSTRACTS OF JAPAN vol. 17, no. 689 (73) Proprietor: Hoechst Pharmaceuticals & (C-1143), 16 December 1993 & JP,A,05 230044 Chemicals K.K. (HOECHST JAPAN), 7 September 1993, cited in Tokyo 107 (JP) the application

(72) Inventors: Remarks: • CHIKARAISHI, Yuji The file contains technical information submitted Sakado-shi, Saitama 350-02 (JP) after the application was filed and not included in this • MATSUDA, Yoshihisa specification Kata-ku, Kyoto 603 (JP) • OTSUKA, Makoto Neyagawa-shi, Osaka 572 (JP)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 812 320 B1

Printed by Jouve, 75001 PARIS (FR) EP 0 812 320 B1

Description

[0001] This invention relates to a novel amorphous piretanide, a novel class of piretanide polymorphs, a process for their preparation and their use. 5 [0002] Piretanide [chemical name: 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid] is known to be a pharma- ceutical agent as a drug. The amorphous piretanide and the piretanide polymorph of this invention have a high solubility in an aqueous solution at various pH values and consequently can show a higher . [0003] A substance having the same chemical composition, but a different crystalline structure and a crystalline form, has been referred to as "polymorph". In general, it is known that many organic compounds have their polymorphs, 10 depending upon differences in the sort of recrystallization solvents, pH values, temperatures and pressures in recrys- tallization. [0004] Piretanide is usually recrystallized from a mixed solvent of methanol and water (hereinafter referred to as piretanide form A: See, Japanese Patent Kokai No.: 83547/1977). However, it has a water solubility as low as 7.9 mg/ 100 ml (at 20°C) and, particularly, it is further slightly soluble in an acidic environment. For instance, piretanide form 15 A has a solubility (at 37°C) of 7.5 mg/100 ml and 4.2 mg/100 ml in a buffer at a pH value of 1 and 3, respectively. [0005] For improving the slight solubility of piretanide form A in an acidic environment, there has been suggested a piretanide polymorph obtained by crystallizing piretanide from a lower aliphatic or a cyclic ether to form a crystalline solvate and then heating the resultant solvate (hereinafter referred to as piretanide form B: See, Japanese Patent Kokai No.: 230044/1993 and Chem. Pharm. Bull., (1994), Vol. 42, pp. 1123 - 1128). Piretanide form B has a 20 solubility (at 37°C) of 12.4 mg/ml and 6.4 mg/100 ml in a buffer at a pH value of 1 and 3, respectively, and its solubility in an acidic environment increased by a factor of 1.5 - 1.7 than that of piretanide form A. In view of a pH value of about 1 in gastric juice, piretanide form B has a crystalline form more suitable for oral administration. [0006] Piretanide has been applied not only as a pharmaceutical preparation for oral administration but also an injection and, in the latter case, its higher solubility at a pH value around neutrality is desirable. As piretanide forms A 25 and B have a solubility of 193.8 mg/100 ml and 195.4 mg/100 ml at a pH value of 6.8 (at 37°C), respectively, they have a higher solubility than that in an acidic environment. Nevertheless, there has been desired a crystalline piretanide having a far higher solubility at a pH value around neutrality. [0007] It is therefore a primary object of this invention to provide a crystalline piretanide having an excellent solubility at a pH value around neutrality. 30 [0008] According to this invention, there is provided

1) an amorphous piretanide having the following characteristics:

(a) exothermic peaks at about 136°C and about 209°C, 35 (b) an endothermic peak at about 207°C, and (c) a melting peak at about 225°C in differential thermal curves; (d) a halopattern without diffraction peak (2θ) in X-ray powder diffraction analysis; and (e) characteristic absorptions at around 1700 cm-1 and 3200 - 3500 cm-1 in an infra-red absorption spectrum; and 40 2) a piretanide polymorph having the following characteristics:

(a) an endohermic peak at about 132°C, (b) an exothermic peak at about 143°C, and 45 (c) a melting peak at about 224°C, in differential thermal curves; (d) diffraction peaks (2θ) at 10.5, 12.2, 15.6, 19.1, 19.9, 22.0, 22.8, 25.6 and 30.6° in X-ray powder diffraction analysis, and (e) characteristic absorptions at around 1700 cm-1 and 3200 - 3500 cm-1 in an infra-red absorption spectrum.

50 [0009] According to this invention, there is also provided a process for preparing

1) the above-defined amorphous piretanide which comprises dissolving piretanide in an aqueous solution of a base, adjusting a pH value of the solution by an acid to a pH range from not less than 3.87 to not more than 4.37 and recovering the precipitate thus separated; 55 2) the above-defined piretanide polymorph which comprises dissolving piretanide in an aqueous solution of a base, adjusting a pH value of the solution to a pH range of less than 3.50 by an acid and recovering the precipitate thus separated.

2 EP 0 812 320 B1

[0010] Moreover, there is also provided a method for the treatment and prevention of edema having administering an effective amount of the above-mentioned amorphous piretanide or piretanide polymorph and a pharmaceutically acceptable carrier.

5 BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Fig. 1 shows a differential thermal curve of the present amorphous piretanide. [0012] Fig. 2 shows a differential thermal curve of the present piretanide polymorph. [0013] Fig. 3 shows a differential thermal curve of piretanide form A. 10 [0014] Fig. 4 shows an X-ray powder diffraction pattern of the present amorphous piretanide. [0015] Fig. 5 shows an X-ray powder diffraction pattern of the present piretanide polymorph. [0016] Fig. 6 shows an X-ray powder diffraction pattern of piretanide form A. [0017] Fig. 7 shows an infra-red absorption spectrum of the present amorphous piretanide. [0018] Fig. 8 shows an infra-red absorption spectrum of the present piretanide polymorph. 15 [0019] Fig. 9 shows an infra-red absorption spectrum of piretanide form A. [0020] It is apparent that the present piretanide crystals (according to Fig. 4) are amorphous, since no diffraction peak which indicates to be crystalline appears in X-ray powder diffraction analysis. The present amorphous piretanide shows, as stated above, characteristic peaks different from those of the piretanide crystals previously known in the differential thermal curves, X-ray powder diffraction analysis and infra-red absorption spectrum. 20 [0021] According to the present process for preparing an amorphous piretanide, piretanide is first dissolved in an aqueous solution of a base at room temperature with stirring. The solvent which is employed in this invention includes water and an aqueous organic solvent such as aqueous alcohol, e.g. aqueous methanol, aqueous , aqueous propanol and the like. The aqueous solution of a base includes, for example, those aqueous solutions of bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like. A basic aqueous solution of piretanide has 25 a pH value of 11 - 13, preferably a pH value of 12. To the basic aqueous solution of piretanide is then added an aqueous solution of an acid to adjust a pH value of the resulting solution to a range from not less than 3.87 to not more than 4.37, preferably a pH value of 4.0 - 4.3. [0022] The pH value to be adjusted herein is significant and a pure amorphous piretanide can be obtained within the pH range as defined above. In a pH range of less than 3.87 and more than 3.50, there is obtained a mixture of amorphous 30 piretanide and piretanide polymorph having a different crystalline form from said piretanide and then it is undesirably required to carry out an additional separating procedure of the crystals of two forms. At a pH range of less than 3.50, there is obtained the pure piretanide polymorph as stated above, while the precipitates cannot be satisfactorily sepa- rated out at a pH range of more than 4.37. [0023] The aqueous solution of an acid which is employed in this invention includes a aqueous solution of inorganic 35 or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, and an aqueous solution of hydrochloric acid is particularly preferable. [0024] The precipitates thus separated out (the present amorphous piretanide) are then recovered by filtration and dried in the presence of a drying agent such as phosphorus pentoxide and the like under reduced pressure, preferably 2 kPa (15 mmHg) or lower, at room temperature for a period of 10 or more hours, preferably for a period of 12 - 15 hours. 40 [0025] The present amorphous piretanide is confirmed to be one of the piretanide polymorphs according to HPLC and TLC and then the physico-chemical properties thereof, as well as solubility in an aqueous solution of various pH values are investigated. [0026] Differences in properties between the present amorphous piretanide and piretanide form A will be discussed hereinbelow from the standpoint of physico-chemical properties, using thermal analysis (differential thermal curve), X- 45 ray powder diffraction analysis and infra-red absorption spectrum. [0027] The present amorphous piretanide shows a melting peak at about 225°C after showing an exothermic peak at about 136°C due to a change in crystalline forms and continuous peaks of endothermic at about 207°C and exo- thermic at about 209°C due to a melting re-crystallization in the differential thermal curves as seen in Fig. 1, which is clearly different from piretanide form A as seen in Fig. 3. In the X-ray powder diffraction, all the peaks including char- 50 acteristic peaks of piretanide form A (2θ=8.3, 10.3, 13.2, 20.7 and 21.7°) disappear and a halo-pattern (See, J. Pharm. Pharmacol., 1992, Vol. 44, pp. 627 - 633) is seen. The results of the X-ray powder diffraction analysis of the present amorphous piretanide and piretanide form A are shown in Figs. 4 and 6, respectively. The infra-red absorption spectrum exhibits that two peaks around 1700cm-1 attributable to a stretching vibration in carboxylic acid of piretanide form A were shifted to a somewhat higher wave number side to form one peak, while the two peaks of piretanide form A at 55 3359cm-1 attributable to a stretching vibration in and 3411cm-1 attributable to a stretching vibration in carboxylic acid have an absorption spectrum which forms one peak with a shoulder curve at 3386cm-1. The infra-red absorption spectra of the present amorphous piretanide and piretanide form A are shown in Figs. 7 and 9, respectively. [0028] The present amorphous piretanide has been confirmed to contain one molecule of water per two molecules

3 EP 0 812 320 B1

of piretanide according to moisture determination, whereas piretanide form A does hardly contain water. In regard to solubility in an aqueous solution at various pH values, the present piretanide in an acidic environment showed a sol- ubility of 15.2 mg/100 ml and 6.5 mg/100 ml in a buffer at a pH value of 1 and 3, which increased by a factor of 2.0 and 1.5 than those of piretanide form A, respectively. In addition, the amorphous piretanide in a neutral environment 5 showed a solubility of 901.3 mg/100 ml in a buffer at a pH value of 6.8, which increased by a factor of 4.5 than that of piretanide form A. [0029] The present piretanide polymorph shows, as stated above, characteristic peaks different from those of the piretanide crystals previously known in the differential thermal curves, X-ray powder diffraction analysis and infra-red absorption spectrum (see Fig. 2, 3, 5, 6, 8, 9). 10 [0030] According to the present process for preparing a piretanide polymorph, piretanide is first dissolved in an aqueous solution of a base at room temperature with stirring. The solvent which is employed in this invention includes water and an aqueous organic solvent such as aqueous alcohol, e.g. aqueous methanol, aqueous ethanol, aqueous propanol and the like. The aqueous solution of a base includes, for example, those aqueous solutions of bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like. A basic aqueous solution of piretanide has 15 a pH value of 11 - 13, preferably a pH value of 12. To the basic aqueous solution of piretanide is then added an aqueous solution of an acid to adjust a pH value of the resulting solution to a range of less than 3.50, preferably a pH value of 2.0 - 3.4. The pH value to be adjusted herein is significant and a pure piretanide polymorph can be obtained within the pH range as defined above. In a pH range of not less than 3.50 to not more than 3.87, there is obtained a mixture of the present piretanide polymorph and another 20 different amorphous piretanide and then it is undesirably required to perform an additional separating procedure of the crystals of two forms. At a pH range of not less than 3.87, there is obtained the pure amorphous piretanide as stated above. [0031] The aqueous solution of an acid which is employed in this invention includes an aqueous solution of inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, and an aqueous solution of 25 hydrochloric acid is particularly preferable. The precipitates thus separated out (the present piretanide polymorph) are then recovered by filtration and dried in the presence of a drying agent such as phosphorus pentoxide and the like under reduced pressure, preferably 2 kPa (15 mmHg) or lower, at room temperature for a period of 10 or more hours, preferably for a period of 12 - 15 hours. [0032] The present piretanide polymorph is confirmed to be one of the piretanide polymorphs according to HPLC 30 and TLC and then the physico-chemical properties thereof, as well as solubility in an aqueous solution of various pH values are investigated. [0033] Differences in properties between the present piretanide polymorph and piretanide form A will be discussed hereinbelow from the standpoint of physico-chemical properties, using thermal analysis (differential thermal curve), X- ray powder diffraction analysis and infra-red absorption spectrum. The present piretanide polymorph shows, in the 35 differential thermal curves, continuous peaks of endothermic at about 132°C and exothermic at about 143°C and a melting peak at about 224°C as seen in Fig. 2, which is clearly different from piretanide form A as seen in Fig. 3. In the X-ray powder diffraction, a part of characteristic peaks of piretanide form A (2θ=8.3, 10.3, 13.2, 20.7 and 21.7°) disappears and newly appear peaks (2θ = 10.5, 12.2, 15.6, 19.1, 19.9, 22.0, 22.8, 25.6 and 30.6°). The results of the X-ray powder diffraction analysis of the present piretanide polymorph and piretanide form A are shown in Figs. 5 and 40 6, respectively. The infra-red absorption spectrum exhibits that two peaks around 1700cm-1 attributable to a stretching vibration in carboxylic acid of piretanide form A were shifted to a higher wave number side, while the two peaks of piretanide form A at 3359cm-1 attributable to a stretching vibration in sulfonamide and 3411cm-1 attributable to a stretch- ing vibration in carboxylic acid have an absorption spectrum which forms one peak with a shoulder curve at 3386cm-1. The infra-red absorption spectra of the present piretanide polymorph and piretanide form A are shown in Figs. 8 and 45 9, respectively. [0034] The present piretanide polymorph as obtained by the process described above is confirmed to contain one molecule of water per two molecules of piretanide according to moisture determination, whereas piretanide form A does hardly contain water. [0035] In regard to solubility in an aqueous solution at various pH values, the present piretanide polymorph in an 50 acidic environment showed solubilities of 12.2 mg/100 ml and 6.7 mg/100 ml in a buffer at a pH value of 1 and 3, respectively, all of which increased by a factor of 1.6 than those of piretanide form A. In addition, the present piretanide polymorph in a neutral environment showed a solubility of 927.3 mg/100 ml in a buffer at a pH value of 6.8, which increased by a factor of 4.8 than that of piretanide form A. [0036] The invention also relates to pharmaceutical preparations comprising a compound of amorphous piretanide 55 or piretanide polymorph. [0037] Pharmaceutical preparations contain an effective amount of the active amorphous piretanide or piretanide polymorph and if necessary other active compounds together with an inorganic or organic pharmaceutically utilizable excipient. Administration can be carried out intranasally, intravenously, subcutaneously or orally. The dosage of the

4 EP 0 812 320 B1

active compound depends on the mammalian species, the body weight, the age and the manner of administration. [0038] The pharmaceutical preparations of the present invention are prepared in a dissolving, mixing, granulating or coating process known per se. [0039] For a form for oral administration, the active compounds are mixed with the additives customary therefor such 5 as excipients, stabilizers or inert diluents and brought by means of customary methods into suitable administration forms such as tablets, coated tablets, hard gelatin capsules, aqueous alcoholic or oily suspensions or aqueous, alco- holic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, car- bonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular maize starch. The preparation in this case can be dry and moist granules. Suitable oily excipients or solvents are, for example, vegetable 10 or animal oils, such as sunflower oil and cod liver oil. [0040] For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are brought into solutions, suspensions or emulsions, if appropriate with the substances customary therefor such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, water, physiological saline solution or alcohols, such as ethanol, propanediol or , and sugar solutions such as glucose or solutions or mixtures 15 of said solvents.

Example 1

Preparation of Amorphous Piretanide 20 [0041] To 10 g of piretanide form A was added 1000 ml of 0.1 N sodium hydroxide and dissolved at room temperature. To the resulting solution was added 160 ml of 0.5 N hydrochloric acid with stirring at 700 rpm. After an precipitates once separated out was redissolved, 35 ml of 0.5 N hydrochloric acid was further added to adjust a pH value to 4.0, and the amorphous form thus separated out was recovered by filtration and then dried over phosphorus pentoxide 25 under reduced pressure at room temperature for a period of 12 hours to obtain 9.2 g of the desired product.

Example 2

Confirmation of Piretanide Polymorph 30 1) Confirmation of piretanide by HPLC

[0042] The amorphous form obtained as described in Example 1 was analyzed by HPLC in order to confirm that it is piretanide, as set forth below. 35 About 15 mg of the amorphous form was weighed and dissolved in 0.5 ml of a 0.1 N aqueous solution of sodium hydroxide and then water was added to make up to an exact volume of 10 ml. An aliquot of 2 ml of this solution was taken and made up to an exact volume of 25 ml with methanol, and used this solution as a sample solution. Performed was the test with 15 µl of a sample under the following conditions:

40 [Operation conditions]

[0043]

Detector: an ultraviolet absorption photometer (wavelength: 254 nm) 45 Column: a stainless steel column 4 mm in inside diameter and 30 cm in length, packed with octadecylsilylated silica gel (10µm in particle diameter) (µBondapak C18) Mobile phase: a mixture of methanol, water and glacial acetic acid (60:40:0.2) Consequently, the amorphous form obtained as described in Example 1 showed peaks at the same retention time as piretanide did.

50 2) Confirmation of piretanide by TLC

[0044] The amorphous form obtained as described in Example 1 was analyzed by TLC in order to confirm that it is piretanide. About 10 mg of the amorphous form was weighed and dissolved in 1 ml of methanol, and used this solution as a sample 55 solution. 10 µl of the test solution was spotted on a thin layer plate and developed with a developing solvent to a distance of about 10 cm and then the thin layer plate was air dried. The plate was irradiated with ultraviolet light (254 nm) and then observed.

5 EP 0 812 320 B1

[Operation conditions]

[0045] Thin layer plate: Silica gel 60F254 precoated plate with a thickness of 0.25 mm (available from E. Merck AG)

5 Developing solvent: a mixture of isopropanol, and glacial acetic acid (14:6:1), a mixture of , methyl ethyl ketone and glacial acetic acid (50:50:1), a mixture of isopropanol, methyl ethyl ketone and glacial acetic acid (50:50:1.) Consequently, the amorphous form obtained as described in Example 1 showed the same Rf value as piretanide did in the three developing solvents as defined above.

10 Example 3

Instrumental Analysis of Piretanide (Differential thermal curve, X-ray powder diffraction and infra-red absorptrion spectrum)

15 [0046] The amorphous form obtained as described in Example 1 was analyzed with differential thermal curve (Rigaku Denki K.K., Type: 8085E2), X-ray powder difffraction (Mac Science K.K., Type: MXP3) and infra-red absorption spec- trum (JEOL Co., Type: JIR5500), using piretanide form A as a control. The results are shown in Figs. 1, 3, 4, 6, 7, 9.

Example 4 20 Moisture Determination of Amorphous Piretanide

[0047] The moisture content of about 10 mg of the amorphous piretanide obtained as described in Example 1 was determined by means of a moisture determination apparatus (Hiranuma Sangyo K.K., Type: AQ 5). 25 [0048] Consequently, the moisture content as determined by the apparatus was about 0.22 mg. On the basis of the molecular weight of piretanide (367.40) and the molecular weight of water (18.0), it has been found that one molecule of water is included per two molecules of piretanide.

Example 5 30 Solubility of Amorphous Piretanide

[0049] The amorphous piretanide obtained as described in Example 1 was analyzed for solubility in a buffer at various pH values by means of a dissolution tester, using piretanide form A as a control. 35 [0050] A sufficient amount of the amorphous piretanide to ensure supersaturation was added to 500 ml each of the buffers at various pH values as indicated below, and about 10 ml of a solution was sampled at appropriate intervals and filtered using a 0.45 µm filter. About 5 ml of the initial solution was discarded and the remainder was used as a sample solution and, if required, diluted with the same buffer. Solubility was determined by absorbance at 275 nm.

40 [Operation conditions]

[0051]

Buffer: pH 1 Potassium chloride-hydrochloric acid system 45 pH 3 Sodium chloride--hydrochloric acid system pH 6.8 JP XII, second fluid Solution temperature 37°C Solvent volume 500 ml 50 Rotating speed 200 rpm

[0052] Consequently, the amorphous piretanide showed a solubility of 15.2 mg and 6.5 mg in 100 ml each of the buffers at a pH value of 1 and 3, respectively, and the respective solubility increased by a factor of 2.0 and 1.5 than 55 that of piretanide form A (7.5 mg/100 ml at a pH value of 1 and 4.2 mg/100 ml at a pH value of 3). The amorphous piretanide in a neutral environment showed a solubility of 901.3 mg in 100 ml of a buffer at a pH value of 6.8 and its solubility increased by a factor of 4.7 than that of piretanide form A (193.8 mg/100 mg). [0053] As apparent from the above results, the present amorphous piretanide can show a superior solubility in an

6 EP 0 812 320 B1

aqueous solution in acidic and neutral environments, especially in a neutral envinronment. For instance, the solubility at 37°C in a buffer at a pH value of 1 of the present amorphous piretanide increased by a factor of 2 and 1.2 than that of piretanide forms A and B, respectively, while its solubility increased by a factor of 4.7 and 4.6 at 37°C in a buffer at a pH value of 6.8 than those of piretanide forms A and B, respectively. As gastric juice has a pH value of about 1 and 5 an injection has been usually adjusted to a neutral state, the present amorphous piretanide has a higher bioavailability and can be preferably used for a pharmaceutical preparation for oral administration and an injection.

Example 6

10 Preparation of Piretanide Polymorph

[0054] To 10 g of piretanide form A was added 1000 ml of 0.1 N sodium hydroxide and dissolved at room temperature. To the resulting solution was added 160 ml of 0.5 N hydrochloric acid with stirring at 700 rpm. After an precipitates once separated out was redissolved, 35 ml of 0.5 N hydrochloric acid was further added to adjust a pH value to 4.0, 15 and the amorphous form thus separated out was recovered by filtration and then dried over phosphorus pentoxide under reduced pressure at room temperature for a period of 12 hours to obtain 9.5 g of the desired polymorph.

Example 7

20 Confirmation of Piretanide Polymorph

1) Confirmation of piretanide by HPLC

[0055] The amorphous form obtained as described in Example 6 was analyzed by HPLC in order to confirm that it 25 is piretanide, as set forth below. About 15 mg of the amorphous form was weighed and dissolved in 0.5 ml of a 0.1 N aqueous solution of sodium hydroxide and then water was added to make up to an exact volume of 10 ml. An aliquot of 2 ml of this solution was taken and made up to an exact volume of 25 ml with methanol, and used this solution as a sample solution. Performed was the test with 15 µl of a sample under the following conditions: 30 [Operation conditions]

[0056]

35 Detector: an ultraviolet absorption photometer (wavelength: 254 nm) Column: a stainless steel column 4 mm in inside diameter and 30 cm in length, packed with octadecylsilylated silica gel (10 µm in particle diameter) (µBon- dapak C18) Mobile phase: a mixture of methanol, water and glacial acetic acid (60:40:0.2) Consequently, the amorphous form obtained as described in Example 6 showed peaks at the same retention time as piretanide did. 40 2) Confirmation of piretanide by TLC

[0057] The amorphous form obtained as described in Example 6 was analyzed by TLC in order to confirm that it is piretanide. 45 [0058] About 10 mg of the amorphous form was weighed and dissolved in 1 ml of methanol, and used this solution as a sample solution. 10 I of the test solution was spotted on a thin layer plate and developed with a developing solvent to a distance of about 10 cm and then the thin layer plate was air dried. The plate was irradiated with ultraviolet light (254 nm) and then observed.

50 [Operation conditions]

[0059] Thin layer plate: Silica gel 60F254 precoated plate with a thickness of 0.25 mm (available from E. Merck AG)

Developing solvent: a mixture of isopropanol, benzene and glacial acetic acid (14:6:1), 55 a mixture of chloroform, methyl ethyl ketone and glacial acetic acid (50:50:1), a mixture of isopropanol, methyl ethyl ketone and glacial acetic acid (50:50:1). Consequently, the amorphous form obtained as described in Example 6 showed the same Rf value as piretanide did in the three developing solvents as defined above.

7 EP 0 812 320 B1

Example 8

Instrumental Analysis of Piretanide (Differential thermal curve, X-ray powder diffraction and infrared absorptrion spectrum) 5 [0060] The piretamine polymorph obtained as described in Example 6 was analyzed with differential thermal curve (Rigaku Denki K.K., Type: 8085E2), X-ray powder difffraction (Mac Science K.K., Type: MXP3) and infra-red absorption spectrum (JEOL Co., Type: JIR5500), using piretanide form A as a control. The results are shown in Figs. 2, 3, 5, 6, 8, 9.

10 Example 9

Moisture Determination of Piretanide Polymorph

[0061] The moisture content of about 10 mg of the piretanide polymorph obtained as described in Example 6 was 15 determined by means of a moisture determination apparatus (Hiranuma Sangyo K.K., Type: AQ 5). Consequently, the moisture content as determined by the apparatus was about 0.25 mg. On the basis of the molecular weight of piretanide (367.40) and the molecular weight of water (18.0), it has been found that one molecule of water is included per two molecules of piretanide.

20 Example 10

Solubility of Piretanide Polymorph

[0062] The piretanide polymorph obtained as described in Example 6 was analyzed for solubility in a buffer at various 25 pH values by means of a dissolution tester, using piretanide form A as a control. [0063] A sufficient amount of the amorphous piretanide to ensure supersaturation was added to 500 ml each of the buffers at various pH values as indicated below, and about 10 ml of a solution was sampled at appropriate intervals and filtered using a 0.45 µm filter. About 5 ml of the initial solution was discarded and the remainder was used as a sample solution and, if required, diluted with the same buffer, if necessary, solubility was determined by absorbance 30 at 275 nm. [Operation conditions]

Buffer: pH 1 Potassium chloride-hydrochloric acid system pH 3 Sodium chloride-glycine-hydrochloric acid system pH 6.8 JP XII, second fluid 35 Solution temperature 37°C Solvent volume 500 ml Rotating speed 200 rpm

40 [0064] Consequently, the piretanide polymorph showed a solubility of 12.2 mg and 6.7 mg in 100 ml each of the buffers at a pH value of 1 and 3, respectively, and the respective solubility increased by a factor of 1.6 than that of piretanide form A (7.5 mg/100 ml at a pH value of 1 and 4.2 mg/100 ml at a pH value of 3). The piretanide polymorph in a neutral environment showed a solubility of 927.3 mg in 100 ml of a buffer at a pH value of 6.8 and its solubility 45 increased by a factor of 4.8 than that of piretanide form A (193.8 mg/100 mg). [0065] As apparent from the above results, the present piretanide polymorph can show a superior solubility in an aqueous solution in acidic and neutral environments, especially in a neutral envinronment. For instance, the solubility at 37°C in a buffer at a pH value of 1 of the present piretanide polymorph increased by a factor of 1.6 than that of piretanide forms A and an approximately similar solubility to that of piretanide form B, and it also increased by a factor 50 of 4.8 and 4.7 than those of piretanide forms A and B, respectively at 37°C in a buffer at a pH value of 6.8. As gastric juice has a pH value of about 1 and an injection has been usually adjusted to a neutral state, the present piretanide polymorph has a higher bioavailability and can be preferably used for a pharmaceutical preparation for oral adminis- tration and an injection.

55 Claims

1. An amorphous piretanide having the following characteristics:

8 EP 0 812 320 B1

(a) exothermic peaks at about 136°C and about 209°C, (b) an endothermic peak at about 207°C, and (c) a melting peak at about 225°C, in differential thermal curves; (d) a halo-pattern without diffraction peak (26) in X-ray powder diffraction analysis; and 5 (e) characteristic absorptions at around 1700 cm-1 and 3200 - 3500 cm-1 in an infra red absorption spectrum.

2. A process for preparing the amorphous piretanide as claimed in claim 1, which comprises dissolving piretanide in an aqueous solution of a base, adjusting a pH value of the solution to a pH range of from not less than 3.87 to not more than 4.37 by an acid and recovering the precipitate thus separated. 10 3. A piretanide polymorph having the following characteristics:

(a) an endothermic peak at about 132°C, (b) an exothermic peak at about 143°C, and 15 (c) a melting peak at about 224°C, in differential thermal curves; (d) diffraction peaks (26) at 10.5, 12.2, 15.6, 19.1, 19.9, 22.0, 22.8, 25.6 and 30.6° in X-ray powder diffraction analysis; and (e) characteristic absorptions at around 1700 cm-1 and 3200 - 3500 cm-1 in an infra-red absorption spectrum.

20 4. A process for preparing a piretanide polymorph as claimed in claim 3, which comprises dissolving piretanide in an aqueous solution of a base, adjusting a pH value of the solution by an acid to a pH range of less than 3.50 and recovering the precipitate thus separated.

5. A compound as claimed in one of claims 1 or 3 for use as a medicament. 25 6. A compound as claimed in one of claims 1 or 3 for use as a medicament for the treatment and prevention of edema.

7. A pharmaceutical preparation containing piretanide, wherein the piretanide is as claimed in one of claims 1 or 3.

30 8. A process for the production of a preparation as claimed in claim 7, which comprises bringing a compound as claimed in claim 1 or 3 into a suitable administration form together with a physiologically acceptable excipient and, if appropriate, other additives or auxiliaries.

9. The use of a compound as claimed in claim 1 or 3 for the preparation of a pharmaceutical preparation for the 35 treatment and prevention of edema.

Patentansprüche

40 1. Amorphes Piretanid, das die folgenden Eigenschaften aufweist:

(a) exotherme Peaks bei etwa 136°C und etwa 209°C, (b) einen endothermen Peak bei etwa 207°C, und (c) einen Schmelzpeak bei etwa 225°C in Differentialthermoanalyse-Kurven; 45 (d) ein Halo-Muster ohne Diffraktionspeak (2θ) bei der Röntgendiffraktionsanalyse an Pulver; und (e) charakteristische Absorptionen im Bereich von 1700 cm-1 und 3200-3500 cm-1 in einem infraroten Absorp- tionsspektrum.

2. Verfahren für die Herstellung des amorphen Piretanids gemäß Anspruch 1, wobei das Piretanid in einer wässerigen 50 Lösung einer Base gelöst wird, der pH-Wert der Lösung unter Verwendung einer Säure auf einen Wert im Bereich von nicht weniger als 3,87 bis nicht mehr als 4,37 eingestellt wird und das so getrennte Präzipitat gewonnen wird.

3. Polymorphe Form von Piretanid, die die folgenden Eigenschaften aufweist:

55 (a) einen endothermen Peak bei etwa 132°C, (b) einen exothermen Peak bei etwa 143°C, und (c) einen Schmelzpeak bei etwa 224°C in Differentialthermoanalyse-Kurven; (d) Diffraktionspeaks (2θ) bei 10,5, 12,2, 15,6, 19,1, 19,9, 22,0, 22,8, 25,6 und 30,6° in der Röntgendiffrakti-

9 EP 0 812 320 B1

onsanalyse an Pulver; und (e) charakteristische Absorptionen im Bereich von 1700 cm-1 und 3200-3500 cm-1 in einem infraroten Absorp- tionsspektrum.

5 4. Verfahren für die Herstellung einer polymorphen Form von Piretanid gemäß Anspruch 3, wobei das Piretanid in einer wässerigen Lösung einer Base gelöst wird, der pH-Wert der Lösung unter Verwendung einer Säure auf einen Wert im Bereich von weniger als 3,50 eingestellt wird, und das so getrennte Präzipitat gewonnen wird.

5. Verbindung gemäß einem der Ansprüche 1 oder 3 zur Verwendung als Arzneimittel. 10 6. Verbindung gemäß einem der Ansprüche 1 oder 3 zur Verwendung als Arzneimittel für die Behandlung und Prä- vention von Ödemen.

7. Piretanidhaltige Arzneimittelzubereitung, wobei das Piretanid ein Piretanid gemäß einem der Ansprüche 1 oder 3 15 ist.

8. Verfahren zur Herstellung einer Zubereitung gemäß Anspruch 7, wobei eine Verbindung gemäß Anspruch 1 oder 3 zusammen mit einem physiologisch verträglichen Exzipienten und, falls angemessen, anderen Additiven oder Hilfsmitteln in eine geeignete Darreichungsform gebracht wird. 20 9. Verwendung einer Verbindung gemäß Anspruch 1 oder 3 für die Herstellung einer pharmazeutischen Zubereitung für die Behandlung und Prävention von Ödemen.

25 Revendications

1. Pirétanide amorphe, ayant les caractéristiques suivantes:

(a) des pics exothermiques à environ 136°C et environ 209°C, 30 (b) un pic endothermique à environ 207°C et (c) un pic de fusion à environ 225°C dans des courbes d'analyse thermique différentielle, (d) un diagramme en halo sans pic de diffraction (29) dans l'analyse de poudre par diffraction des rayons X, et (e) des absorptions caractéristiques à environ 1 700 cm-1 et 3 200 - 3 500 cm-1 dans le spectre d'absorption infrarouge. 35 2. Procédé pour la préparation du pirétanide amorphe selon la revendication 1, comprenant la dissolution de piréta- nide dans une solution aqueuse d'une base, l'ajustement du pH de la solution dans un intervalle de pH allant d'une valeur non inférieure à 3,87 à une valeur non supérieure à 4,37, à l'aide d'un acide, et la récupération du précipité ainsi séparé. 40 3. Variété polymorphe de pirétanide, ayant les caractéristiques suivantes:

(a) un pic endothermique à environ 132°C, (b) un pic exothermique à environ 143°C et 45 (c) un pic de fusion à environ 224°C dans des courbes d'analyse thermique différentielle, (d) des pics de diffraction (2θ) à 10,5, 12,2, 15,6, 19,1, 19,9, 22,0, 22,8, 25,6 et 30,6° dans l'analyse de poudre par diffraction des rayons X, et (e) des absorptions caractéristiques à environ 1 700 cm-1 et 3 200 - 3 500 cm-1 dans le spectre d'absorption infrarouge. 50 4. Procédé pour la préparation d'une variété polymorphe de pirétanide selon la revendication 3, comprenant la dis- solution de pirétanide dans une solution aqueuse d'une base, l'ajustement du pH de la solution dans un intervalle de pH non inférieur à 3,50, à l'aide d'un acide, et la récupération du précipité ainsi séparé.

55 5. Composé selon l'une des revendications 1 à 3, pour utilisation en tant que médicament.

6. Composé selon l'une des revendications 1 à 3, pour utilisation en tant que médicament destiné au traitement et à la prévention de l'oedème.

10 EP 0 812 320 B1

7. Composition pharmaceutique contenant du pirétanide, dans laquelle le pirétanide est tel que revendiqué dans la revendication 1 ou 3.

8. Procédé pour la préparation d'une composition selon la revendication 7, comprenant la mise sous une forme 5 d'administration appropriée d'un composé selon la revendication 1 ou 3, conjointement avec un excipient physio- logiquement acceptable et, si cela est approprié, d'autres additifs ou adjuvants.

9. Utilisation d'un composé selon la revendication 1 ou 3, pour la préparation d'une composition pharmaceutique destinée au traitement et à la prévention de l'oedème. 10

15

20

25

30

35

40

45

50

55

11 EP 0 812 320 B1

12 EP 0 812 320 B1

13 EP 0 812 320 B1

14 EP 0 812 320 B1

15 EP 0 812 320 B1

16 EP 0 812 320 B1

17 EP 0 812 320 B1

18 EP 0 812 320 B1

19 EP 0 812 320 B1

20