Salts

Abstract

The present invention relates to new crystalline salt forms of flibanserine which have valuable pharmacological properties, to a process for their manufacture, to pharmaceutical formulations containing them and to their use as medicament.

Claims

1. A salt of the compound 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one selected from the group consisting of: I. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2155 C. and characteristic peaks in the x-ray powder diffractogram of d=15.990.05 , 7.440.05 , 3.980.05 , and 3.440.05 ; II. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2175 C. and characteristic peaks in the x-ray powder diffractogram of d=16.430.05 , 5.080.05 , 4.350.05 , 3.470.05 , and 7.660.05 ; III. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of T.sub.fus (onset)=2525 C. and by the peaks in the X-ray powder diffractogram which occur at d=3.480.05 , d=3.330.05 , d=4.280.05 , d=3.430.05 and d=16.030.05 ; IV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of T.sub.fus (onset)=2525 C. and by the peaks in the X-ray powder diffractogram which occur at d=15.520.05 , d=5.150.05 , d=4.600.05 , d=4.360.05 and d=3.940.05 ; V. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one edisylate having a melting point of T.sub.fus (onset)=1445 C.; VI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate having a melting point of T.sub.fus (onset)=2385 C.; VII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mesylate having a melting point of T.sub.fus (onset)=2075 C.; VIII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one besylate having a melting point of T.sub.fus (onset)=2475 C.; IX. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of T.sub.fus (onset)=2095 C.; X. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of T.sub.fus (onset)=2545 C.; XI. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one sacharinate having a melting point of T.sub.fus (onset)=905 C.; XII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one phosphate having a melting point of T.sub.fus (onset)=1825 C.; XIII a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of T.sub.fus (onset)=985 C.; XIV. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of T.sub.fus (onset)=1725 C.; XV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one ethansulfonate having a melting point of T.sub.fus (onset)=2075 C.; XVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate having a melting point of T.sub.fus (onset)=2175 C.; XVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate having a melting point of T.sub.fus (onset)=1035 C.; XVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate the following data: TABLE-US-00060 Empirical formula C.sub.20H.sub.22F.sub.3N.sub.4O.sup.+C.sub.3H.sub.3O.sub.4.sup.22 C.sub.4H.sub.10O Fw 642.71 T [K] 120(2) [] 0.71073 Crystal system Monoclinic Space group P 2.sub.1/c Unit cell dimensions a [] 9.2650(3) b [] 24.2380(2) c [] 30.128(8) [] 90 [] 101.620(2) [] 90 V [.sup.3] 6627.0(4) Z 8 D.sub.m [g/cm.sup.3] 1.288 F(000) 2736 Crystal size [mm.sup.3] 0.25 0.1 0.08 range [] 1.5 .fwdarw. 24 Reflections collected 22364 Independent reflections 10286 [R.sub.int = 0.1143] S 1.093 R [I > 2(I)] R1 = 0.1070, wR2 = 0.1271 R indices (all data) R1 = 0.2167, wR2 = 0.1563 XIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate, having the following characteristics: TABLE-US-00061 Empirical formula C.sub.20H.sub.22F.sub.3N.sub.4O.sup.+C.sub.3H.sub.3O.sub.4.sup.2H.sub.2O Fw 530.50 T [K] 120(2) [] 0.71073 Crystal system Triclinic Space group P 1 Unit cell dimensions a [] 7.8050(2) b [] 8.0730(2) c [] 20.1470(4) [] 80.0090(8) [] 87.4660(8) [] 74.5320(9) V [.sup.3] 1204.92(3) Z 2 D.sub.m [g/cm.sup.3] 1.462 F(000) 556 Crystal size [mm.sup.3] 0.3 0.25 0.1 range [] 2 .fwdarw. 37 Reflections collected 14593 Independent reflections 12114 [R.sub.int = 0.0408] S 1.062 R [I > 2(I)] R1 = 0.0742, wR2 = 0.1389 R indices (all data) R1 = 0.1184, wR2 = 0.1594 XX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one salicylate the following data: TABLE-US-00062 Empirical formula C.sub.20H.sub.22F.sub.3N.sub.4O.sup.+C.sub.7H.sub.5O.sub.3.sup. Fw 528.53 T [K] 293(2) [] 0.71073 Crystal system Monoclinic Space group P 2.sub.1/c Unit cell dimensions a [] 16.3790(2) b [] 15.4410(4) c [] 10.1810(4) [] 90 [] 98.1820(12) [] 90 V [.sup.3] 2548.6(2) Z 4 D.sub.m [g/cm.sup.3] 1.377 F(000) 1104 Crystal size [mm.sup.3] 0.4 0.3 0.2 range [] 2.5 .fwdarw. 26 Reflections collected 12472 Independent reflections 4948 [R.sub.int = 0.0289] S 0.949 R [I > 2(I)] R1 = 0.0565, wR2 = 0.1471 R indices (all data) R1 = 0.0753, wR2 = 0.1647 XXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-tartrate having a melting point of T.sub.fus (onset)=1515 C.; XXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one hemifumarate having a melting point of T.sub.fus (onset)=1955 C.; XXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate having a melting point of T.sub.fus (onset)=1935 C.; XXIV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form I) (=hydrate form) having a melting point of T.sub.fus (onset)=1395 C.; XXV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one citrate having a melting point of T.sub.fus (onset)=1765 C.; XXVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mandelate having a melting point of T.sub.fus (onset)=1485 C.; XXVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-malate having a melting point of T.sub.fus (onset)=1765 C.; XXVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one succinate the following data: XXIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one naphthalenesulfonate peaks in the X-ray powder diffractogram which occur at d=4.920.05 , d=3.430.05 , d=4.000.05 and d=3.960.05 ; TABLE-US-00063 Empirical formula 2 C.sub.20H.sub.22F.sub.3N.sub.4O.sup.+C.sub.4H.sub.4O.sub.4.sup.22 H.sub.2O Fw 934.94 T [K] 293(2) [] 0.71073 Crystal system Triclinic Space group P 1 Unit cell dimensions a [] 9.5450(4) b [] 10.7120(5) c [] 11.7330(7) [] 97.597(2) [] 93.690(2) [] 110.663(3) V [.sup.3] 1104.6(1) Z 1 D.sub.m [g/cm.sup.3] 1.405 F(000) 490 Crystal size [mm.sup.3] 0.3 0.3 0.2 range [] 3.5 .fwdarw. 26 Reflections collected 6382 Independent reflections 4176 [R.sub.int = 0.0194] S 1.036 R [I > 2(I)] R1 = 0.0555, wR2 = 0.1386 R indices (all data) R1 = 0.0649, wR2 = 0.1484 XXX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate (form II) (=anhydrous form) having a melting point of T.sub.fus (onset)=2415 C.; XXXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate (form III) (=anhydrous form) having a melting point of T.sub.fus (onset)=2025 C.; XXXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate (form II) (=anhydrous form) having a melting point of T.sub.fus (onset)=2315 C.; XXXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form II) (=hydrate form) having a melting point of T.sub.fus (onset)=2315 C.

2. A pharmaceutical composition comprising the crystalline salt forms according to claim 1 and a pharmaceutically acceptable excipient.

3. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2155 C. and characteristic peaks in the x-ray powder diffractogram of d=15.990.05 , 7.440.05 , 3.980.05 , and 3.440.05 is an anhydrous form.

4. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2175 C. and characteristic peaks in the x-ray powder diffractogram of d=16.430.05 , 5.080.05 , 4.350.05 , 3.470.05 , and 7.660.05 is a solvate.

5. The salt of the compound of claim 3 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2155 C. and characteristic peaks in the x-ray powder diffractogram of d=15.990.05 , 7.440.05 , 3.980.05 , and 3.440.05 is crystallized from a mixture of water and ethanol.

6. The salt of the compound of claim 4 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2175 C. and characteristic peaks in the x-ray powder diffractogram of d=16.430.05 , 5.080.05 , 4.350.05 , 3.470.05 , and 7.660.05 is crystallized from a mixture of water and 1-methyl-2-pyrrolidinone.

7. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2155 C. and characteristic peaks in the x-ray powder diffractogram of d=15.990.05 , 7.440.05 , 3.980.05 , and 3.440.05 is further characterized by having weakly endothermic signals at approximately 122 C. and 186 C.

8. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T.sub.fus (onset)=2175 C. and characteristic peaks in the x-ray powder diffractogram of d=16.430.05 , 5.080.05 , 4.350.05 , 3.470.05 , and 7.660.05 is further characterized by having weakly endothermic signals at approximately 56 C. and 121 C.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1.1a: X-ray powder diffraction diagram of HCl 1=chloride, form I;

(2) FIG. 1.1b: X-ray powder diffraction diagram of HCl 3=chloride, form III;

(3) FIG. 1.2a: X-ray powder diffraction diagram of HBr 1=hydrobromid, form I;

(4) FIG. 1.2b: X-ray powder diffraction diagram of HBr 3=hydrobromid, form III;

(5) FIG. 1.3: X-ray powder diffraction diagram of Eds 1=edisylate, form I;

(6) FIG. 1.4: X-ray powder diffraction diagram of Tos 1=losylate, form I;

(7) FIG. 1.5: X-ray powder diffraction diagram of Mes 1=mesylate, form I;

(8) FIG. 1.6: X-ray powder diffraction diagram of Bes 1=besylate, form I;

(9) FIG. 1.7a: X-ray powder diffraction diagram of Oxa 1=oxalate, form I;

(10) FIG. 1.7b: X-ray powder diffraction diagram of Oxa 5=oxalate, form V;

(11) FIG. 1.8: X-ray powder diffraction diagram of Sac 1=sacchannate, form I;

(12) FIG. 1.9: X-ray powder diffraction diagram of Pho 1=phosphate, form I;

(13) FIG. 1.10a: X-ray powder diffraction diagram of Mae 1=maleate, form I;

(14) FIG. 1.10b: X-ray powder diffraction diagram of Mae 3=maleate, form III;

(15) FIG. 1.11: X-ray powder diffraction diagram of Ets 1=ethanesulfonate, form I;

(16) FIG. 1.12 X-ray powder diffraction diagram of Cas 1=camphorsulfonate, form I;

(17) FIG. 1.13. X-ray powder diffraction diagram of Mao 1=matonate, form I;

(18) FIG. 1.14: X-ray powder direction diagram of L-Tar 1=L-tartrate, form I;

(19) FIG. 1.15a: X-ray powder diffraction diagram of Fum 1=fumarate, form I;

(20) FIG. 1.15b: X-ray powder diffraction diagram of Fum 2=fumarate, form II;

(21) FIG. 1.16 X-ray powder diffraction diagram of Gly 1=glycolate, form I;

(22) FIG. 1.17: X-ray powder diffraction diagram of Cit 1=citrate, form I;

(23) FIG. 1.18: X-ray powder diffraction diagram of Man 1=mandelate, form I;

(24) FIG. 1.19: X-ray powder direction diagram of L-Mal 1=malate, form I;

(25) FIG. 1.20 X-ray powder diffraction diagram of Nas 1=naphtalene-sulfonate, form I;

(26) FIG. 1.21 X-ray powder diffraction diagram of TOS 2=tosylate, form II;

(27) FIG. 1.22 X-ray powder diffraction diagram of Fum 3=fumarate, form III;

(28) FIG. 1.23 X-ray powder diffraction diagram of Cas 2=camphorsulfonate, form II;

(29) FIG. 1.24 X-ray powder diffraction diagram of Gly 3=glycolate, form II.

EXAMPLES

Analytical Methods for the Characterization of the Salts

(30) The harvested crystals may be characterized by X-ray powder diffraction and thermal analysis (DSC). If suitable single crystals grow, single crystal X-ray structure analysis may be performed. The following equipment was used to characterize the crystalline salts forms.

(31) X-ray Powder Diffraction (=XRPD)

(32) XRPD patterns were obtained using a high throughput XRPD set-up. The plates were mounted on a Bruker GADDS dsffractometer equipped with a Hi-Star area detector. The diffractometer was calibrated using Silver Behenate for the long d-spacings and corundum for the short d-spacings.

(33) The data collection was carried out at room temperature using monochromatic CuK radiation in the region 2 between 1.5 and 41.5. The diffraction pattern of eacn well was collected wth an exposure time of 3-4 minutes.

(34) Single Crystal X-ray Structure Analysts

(35) Suitable single crystals were selected and glued to a glass fibre, which is mounted on a X-ray diffraction goniometer. X-ray diffraction data were collected for the mounted crystals at a temperature of 233 K using a KappaCCD system and MoK radiation generated by a FR590 X-ray generator (Bruker Nonius Delft, The Netherlands).

(36) Unit-cell parameters and crystal structure were determined and refined using the software package maXus (Mackay et al., 1997).

(37) Thermal Analysis (DSC)

(38) Melting properties were obtained from differential scanning calorimetry (=DSC) thermograms recorded on a DSC822e (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (T.sub.fus=156.6 C., H.sub.fus=28.45 J/g). Samples were sealed in standard 40 l aluminium pans and heated in the DSC from 25 to 300 C. with a heating rate of 20 C./min. Dry nitrogen gas was used to purge the DSC equipment during measurements at a flow rate of 50 ml/min. The melting temperature used was the T.sub.fus (onset) temperature of the corresponding melting peak tn the DSC diagram. The accuracy of the melting points specified is about 5 C.

(39) Hygroscopicity

(40) IGAsorp water sorption monitor from Hiden Isochema was used for the analysis of the hygroscopical behaviour at room temperature. humidity profile: from 10-90% r.h. in steps of 10%, sorption as well as desorption profiles were registered weight-in quantity: 10-20 mg

(41) Solubility

(42) Solubility of the different crystalline salt forms in water was determined by adding approx. 5 mg of compound into 5 ml of water at room temperature. The mixture was vigorously shaken for 2 hours at room temperature. Afterwards the undissolved solid was removed by filtering through a 0.45 m PTFE filter, in the filtrate the dissolved amount of compound was determined by UV-spectroscopy.

(43) Synthesis of the Salt Forms

(44) The process is illustrated by the following example of manufacturing process of the salts and crystalline salt forms, as can be done in parallel in 96 well assay plates (maximum volume of each well is about 200 l).

(45) Approximately 1 g of the free base of flibanserin were dissolved in 10 ml TFE/water 80:20. The acids used to prepare the salts were dissolved in different solvents such that the molar ratio of the flibanserin to the respective acid was set according to the information given in Table 3 under ratio base/acid. Fumaric acid was dissolved in THF/water 80:20. HCl in water and all other acids used were dissolved in TFE/water 80:20. However it is to mention that all other solvents which are able to dissolve the acid used could have been used. The 96 well plates were then placed in a vacuum chamber (1 kPa) at room temperature for 24 h in otder to evaporate the solvent. Afterwards, different solvents were added in each well according to the information given in Table 3 under crystallization solvent, and the well plates were sealed and heated up to 50 C. at a heating rate of approx. 5 C./min. The plate stayed then for an additional 30 minutes at 50 C. Afterwards, the plate was cooled at a cooling rate of 5 C./h to a final temperature of 3 or 20 C. according to the information given in Table 3 under T.sub.final[ C.]. At this temperature, the plates remained for a holding time of 24 h. The plates were then opened and the solids were collected by filtration. All salts specified in table 3 were synthesized according to the above specification.

(46) TABLE-US-00053 TABLE 3 Conditions for the preparation of the different salts of 1-[2-(4-(3-trifluoro- methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one salt salt form ratio crystallization T.sub.final form full name used acid base/a solvent [ C.] HCl chloride, form I hydrochloric acid 1:1 ethanol/water (80:20) 3 HCl3 chloride, form III hydrochloric acid 1:1 water/NMP* (80:20) 20 HBr 1 bromide from I hydrobromic acid 1:1 dichlormethane 20 HBr 3 bromide from III hydrobromic acid 1:1 methanol 20 Eds1 edisylate form I ethane-1,2 1:1 methanol 20 disulfonic acid Tos 1 tosylate form I p-toluenesulfonic 1:1 THF* 20 acid Mes 1 mesylate form I methanesulfonic 1:1 TBME* 20 acid Bes 1 besylate form I benzenesulfonic 1:1 TBME* 20 acid Oxa 1 oxalate form I oxalic acid 1:1 1,2 Dimethoxyethane 20 Oxa 5 oxalate form V oxalic acid 1:1 water/acetone (20:80) 3 Sac1 sacharinate form I sacharine 1:1 dichloromethane 3 Pho phosphate form I phsophoric acid 1:1 cyclohexanone 20 Mae1 maleate form I maleaic acid 1:1 THF* 3 Mae3 maleate form III maleaic acid 1:1 propyl acetate 20 Ets ethanesulfonate ethanesulfonic 1:1 1,2 Dimethoxyethane 20 acid Cas1 camphorsulfonate campher-10 1:1 cyclohexane 20 form I sulfonic acid Mao 1 malonate form I malonic acid 1:1 acetone/water (80:20) 3 Mao 2 malonate form II malonic acid 1:1 tert-Butanol 3 Mao 6 malonic form VI malonic acid 1:1 Nitromethane 3 Sal 1 salicylate form I salicylic acid 1:1 DMSO*/water (20:80) 3 L-Tart 1 L-tartate form L-tartaric acid 1:1 ethanol 20 Fum 1 fumerate form I fumaric acid 2:1 chloroform 20 Fum 2 fumerate form II fumaric acid 2:1 nitromethane 20 Gly 1 glycolate form I glycolic acid 1:1 TBME* 20 Cit1 citrate form I citric acid 2:1 ethanol/water (80:20) 20 Man 1 mandelate form I L-mandelic acid 1:1 ethanol 20 L-Mal 1 L-malate form I L-malic acid 1:1 ethanol 3 Suc 1 succinate form I succinic acid 1:1 H.sub.2O 20 Nas1 naphtalene- naphtalene-2- 1:1 2-butanone 3 sulfonate form I sulfonic acid Tos 2 tosylate form II p-toluenesulfonic 1:1 ethanol 20 (=anhydrous form) acid Fum 3 fumarate, form III fumaric acid 1:1 chloroform 20 (=anhydrous form) Cas 2 camphorsulfonate form II campher-10 1:1 ethanol 20 (=anhydrous form) sulfonic acid Gly 2 glycolate form II glycolic acid 1:1 TBME* 20 (=hydrate form) *THF = tetrahydrofurane *DMSO = dimethylsulfoxide *NMP = 1-methyl-2-pyrrolidinone *TBME = tert-butyl methyl ether *TFE = 2,2,2,-Trifuoroethanol

Examples of Formulations

(47) The Examples which follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

(48) TABLE-US-00054 A) Tablets per tablet active substance 100 mg lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg 740 mg

(49) The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

(50) TABLE-US-00055 B) Tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

(51) The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

(52) TABLE-US-00056 C) Coated tablets per coated tablet active substance 5 mg corn starch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 mg 80 mg

(53) The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45 C. and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.

(54) TABLE-US-00057 D) Capsules per capsule active substance 1 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg 420 mg

(55) The substance and corn starch are mixed ana moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

(56) TABLE-US-00058 E) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml

(57) The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterlised and sealed by fusion.

(58) TABLE-US-00059 F) Suppositories active substance 50 mg solid fat 1650 mg 1700 mg

(59) The hard fat is melted. At 40 C. the ground active substance is homogeneously dispersed. It is cooled to 38 C. and poured into slightly chillied suppository moulds.