Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
  • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids

Definitions

• the present invention relates to specific salts and salt forms of 4-(R)-(6,7-Dihydro-5H- pyrrolo[1 ,2-c]imidazol-5-yl)-3-fluoro-benzonitrile (also referred to as "Compound A" within this application) , these salts and salt forms for use in methods of treatment of diseases and conditions, the use of these salts and salt forms in the manufacture of medicaments for the treatment of diseases and conditions, methods of treatment comprising administering said salts or salt forms to a mammal in need thereof in therapeutically effective amounts for treating a disease of condition affecting said mammal,
• Compound A in the form of free base has a quite low melting point of about 111.5 °C which constitutes a certain risk regarding physical stability of the compound during manufacture, storage and processing to pharmaceutical formulations. Thus there was a need to find specific processing conditions or specific forms of this compound that allow for stable processing.
• the phosphate salt shows the most superior properties. It can be isolated and manufactured better and thus is advantageous over the free base compound, with additional properties such as a higher melting point over the free base and other salts, lower hygroscopicity and improved aqueous solubility.
• the nitrate salt also shows comparable advantages.
• the invention in a first aspect , relates to a phosphate salt of Compound A, especially in crystalline forms, particularly in crystalline Form A as described below.
• phosphate salt refers to the acid addition salt of compound A with phosphoric acid. More particularly, it refers to the dihydrogen- phosphate of compound A protonated once, that is, wherein compound A is protonated once and thus each molecule carries a single positive charge, while the counterion is H 2 P0 4 -).
• the second aspect of the invention relates to a nitrate salt of Compound A, especially in crystalline forms.
• the invention relates to the salts or salt forms mentioned herein in the manufacture of medicaments for the treatment of diseases and conditions, to said salts or salt forms (especially in the form of pharmaceutical compositions) for use in the treatment of diseases and conditions, to methods of treatment comprising administering said salts or salt forms to a mammal in need thereof in therapeutically effective amounts for treating a disease of condition affecting said mammal, pharmaceutical formulations comprising said salts or salt forms.
• the invention relates to a pharmaceutical composition that includes (an especially prophylactically or therapeutically effective amount of) a phosphate salt of Compound A and one or more pharmaceutically acceptable excipients, in particular for use in the treatment of conditions or diseases described herein, especially conditions or diseases mediated by aldosterone synthase or aromatase .
• the phar- maceutical compositions of this aspect of the invention may be formulated, e.g., for oral administration.
• the invention provides a process for making a nitrate salt or a phosphate salt, especially in crystalline form, respectively, of Compound A, the process comprising: (a) providing a solution of Compound A in either a protic or an aprotic polar solvent, especially in an aqueous- alcoholic or alcoholic solution (alcoholic especially referring to hydroxy-C 1-7 alkanes) (where said solution may have a temperature in the range e.g. from 0 °C to the boiling point of the solution, e.g. up to 90 °C, e.g. in the range from 10 to 50 °C); (b) adding nitric acid or phosphoric acid; and
• This process may also be a step (e.g. the final purification step) in the manufacture of the respective salt, e.g. at the end of the process described for the manufacture of the free base in WO 2007/024945 A1 , and the corresponding general method of manufacture is incorporated by reference herein and applied specifically to the preparation of the compound Compound A.
• Forms B, C, D, E, F, G and H of the phosphate salt may be obtained e.g. as described in the Examples, where the temperature is room temperature (23 °C ) ⁇ 10°C and the solvents may be replaced by corresponding solvents.
• the invention relates to a phosphate salt of Com- pound A, in particular with a molar ratio of Compound A to phosphate of about 1 : 1 , in particular in crystalline form.
• the invention relates to a crystalline phosphate salt of Compound A having a melting point that is at least 50 °C, at least 55°C or at least 85°C higher than that of the free base.
• the phosphate salt of Compound A has a melting temperature of at least 170°C or at least 197°C. In one embodiment, the phosphate salt of Compound A has a melting temperature between 205°C to 214°C, between 206°C to 213°C, between 208°C to 213°C, between 209°C to 212°C or between 209°C to 21 1 °C.
• TG/DTA thermogravimetry/differential thermal analysis
• the invention relates to "Form A" of the crystalline phosphate salt of Compound A, especially with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11 , 12, 13, 14, 15, 16 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6 , 10.0, 12.1 , 1 Z9, 14.0, 14.5, 15J5, 16 , 16J3, 17.5, 18.2, 18.4, 197, 20.4, 22.1 , 24.3, 29.2, with the underlined peaks defining a preferred embodiment and all peaks defining a more preferred embodiment.
• the "Form A" of the crystalline phosphate salt of Compound A has a melting temperature of 210 ⁇ 5°C, 210 ⁇ 2°C, 210 ⁇ 1 °C or 210 ⁇ 0.5°
• the invention relates to Form A with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.0, 12.9, 15.5, 16.0, 16.3, 19.7, 20.4, 22.1 , 24.3, 29.2.
• the two largest peaks of Form A in the XRPD diagram have a relative intensity of 1 to 0.5 to 0.7, especially of 1 to 0,55 to 0.65, more especially of 0.57 to 0.61 , e.g. of 1 to 0.59 (obtainable by integration of each of the peaks in the XRPD diagrams).
• the larger peak is at a 2-theta ( ⁇ ) value of 6.0 ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees and the smaller peak at a 2-theta ( ⁇ ) value of 19.7 ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees, respectively.
• Another embodiment relates to form A with an XRPD showing at least one or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 12.9 16.3 and 20.4 degrees.
• Preferred is the phosphate salt showing an XRPD as shown in Fig. 1-A.
• a specific embodiment of the invention relates to "Form A" of the crystalline phosphate salt of Compound A, having a melting point between 209 and 212 °C.
• the invention relates to a "Form B" of crystalline phosphate salt of Compound A with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 1 1 , 12, 13, 14, 15, 16, 17, 18 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.0, 9.8, 1 1.8, 12.7, 12.9, 14.0, 14.3, 15,2, 16.0, 16.3, 17.5, 18.0, 18.4, 103, 19.7, 20.1 , 22.1 , 24.3, 29.2, with the underlined peaks defining a preferred embodiment, all peaks defining a more preferred embodiment.
• crystalline phosphate salt Form B showing an XRPD as shown in Fig. 1-B.
• An embodiment of the invention relates to "Form B" of the crystalline phosphate salt of Compound A, having a melting point of 209 ⁇ 5 °C, for example between 207 and 21 1 °C, e.g. of 209.0 °C.
• the invention relates to a "Form C" of crystalline phosphate salt of Compound A with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 1 1 , 12, 13, 14, 15, 16, 17 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.0, 10.0, 11.9, 12.9, 14.0, 14.5, 15.5, 16.0, 16.3, 17J$, 18.2, 18.4, 103, 19.7, 20J, 22.1 , 24.3, 29.2, with the underlined peaks defining a preferred embodiment, all peaks defining a more preferred embodiment.. More preferred is the crystalline phosphate salt Form C showing an XRPD as shown in Fig. 1-C.
• An embodiment of the invention relates to "Form C" of the crystalline phosphate salt of Compound A, having a melting point of 191 ⁇ 5 °C, for example between 189 and 193 °C, e.g. of 190.7 °C
• the invention relates to a "Form D" of crystalline phosphate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 1 1 , 12, 13, 14, 15, 16, 17 or all of the following peaks/given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.2, 10.0, 12.4, 12.9, 3 , 14J5, 15.5, 16.0, 16J3, 17.5, 18.2, 18.4, 19J3, 19.7, 20.2, 22.1 , 24.3, 29.2, with the underlined peaks defining a preferred embodiment, all
• An embodiment of the invention relates to "Form D" of the crystalline phosphate salt of Compound A, having a melting point of 211 ⁇ 5 °C, for example between 208 and 213 °C, e.g. of 210.8 °C.
• the invention relates to a "Form E" of crystalline phosphate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6A, 10.3, 12.1 , 12.9, 13.3, 14.5, 15.2, 16.0, 16,8, 17.5, 18.2, 18.4, 19J3, 19.7, 20J, 22.1, 24.3, 29.2, with the underlined peaks defining a preferred embodiment, all peaks defining a more preferred embodiment..
• crystalline phosphate salt Form E showing an XRPD as shown in Fig. 1-E.
• An embodiment of the invention relates to "Form E" of the crystalline phosphate salt of Compound A, having a melting point of 214 ⁇ 5 °C, for example between 211 and 216 °C, e.g. of 213.6 °C
• the invention relates to a "Form F" of crystalline phosphate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.0, 10.0, 12.1 , 12.9, 13.8. 14.0, 15.5, 16.0, 16J3- 17.5, 18.2, 18.4, 19J.
• An embodiment of the invention relates to "Form F" of the crystalline phosphate salt of Compound A, having a melting point of 201 ⁇ 5 °C, for example between 199 and 203 °C, e.g. of 201.1 °C
• the invention relates to a "Form G" of crystalline phosphate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11 , 12, 13, 14, 15, 16, or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or +0.5, in particular ⁇ 0.2 degrees: 6.0, 12.1 , 13.1 , 14.0, 14.5, 15.5, 15.8, 16.3, 17.5, 18.2, 18.4, 19J3, 19.7, 20J, 22.1 , 24.3, 29.2, with the underlined peaks defining a preferred embodiment, all peaks defining a more
• crystalline phosphate salt Form G showing an XRPD as shown in Fig. 1-G.
• An embodiment of the invention relates to "Form G" of the crystalline phosphate salt of Compound A, having a melting point of 180 ⁇ 5 °C, for example between 177 and 183 °C, e.g. of 179.8 °C
• the invention relates to a "Form H" of crystalline phosphate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11 , 12, 13, 14, 15, 16, or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 6.0, 10.2, 12.1 , 13.1 , 14.0, 14.5, 15.5, 16.2, 16.5, 17.5, 18.2, 18.4, 19,3, 19.7, 20J., 22.2, 24.3, 29.5, with the underlined peaks defining a preferred embodiment, all peaks defining a more preferred embodiment. More preferred is the crystalline phosphate salt Form H showing an XRPD as shown in Fig. 1-H.
• An embodiment of the invention relates to "Form H" of the crystalline phosphate salt of Compound A, having a melting point of 208 ⁇ 5 °C, for example between 206 and 210 °C, e.g. of 208.0 °C
• the invention relates to a nitrate salt of Compound A, in particular with a molar ratio of Compound A to nitrate of about 1 :1 , in particular in crystalline form.
• the invention relates to a crystalline nitrate salt of Compound A having a melting point that is at least 40 °C higher than that of the free base , espe- daily (using TG/DTA as described above) between 160 and 163 °C.
• the invention relates to a crystalline nitrate salt of Compound A, with an XRPD showing at least one, more preferably two, three, four, five, six, seven, eight, nine, ten, 11 , 12, 13, 14, 15, 16, 17 or all of the following peaks, given as angle of refraction 2-theta ( ⁇ ) values, obtainable as described in the Examples, where each peak may vary by ⁇ 1 or ⁇ 0.5, in particular ⁇ 0.2 degrees: 1A_, 10.6, 12.5, 15.0, 15.7, 17.5, 18 , .
• nitrate salt showing an XRPD as shown in Fig. 2.
• a specific embodiment of the invention relates to a crystalline nitrate salt of Compound A showing the XRPD characteristics above and a melting point between 160 and 163 °C using TG/DTA .
• the compound 6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl-3-fluoro-benzonitrile as free base) and especially its enantiomers, especially 4-(R)-(6,7-dihydro-5H-pyrrolo[1 ,2-c]imi- dazol-5-yl)-3-fluoro-benzonitrile, can be manufactured as described in published inter- national patent application WO 2007/024945 which is incorporated by reference herein (see especially Table 2, and Chiral Resolution on page 87, F. 5).
• “About” where used means especially ⁇ 10%, ⁇ 5% or ⁇ 3% (referring to the given numeric value, respectively), if not indicated otherwise. In each of the invention embodiments, “about” can be deleted.
• “Prophylactically or therapeutically effective amount” means the amount of a compound that, when administered for treating or preventing a disease or disorder mentioned above or below, is sufficient to effect such treatment or prevention for the disease or disorder, prophylactic especially refers to the prevention of the onset or recurrence or ameliorating the onset or recurrence of such disease or disorder, therapeutic especially refers to the amelioration or complete suppression of one or more symptoms up to the cure of such disease or disorder.
• the “prophylactically or therapeutically effective amount” will vary depending on the salt(s) or salt form(s) used, the disease or disorder and its severity and the age, weight, etc., of the patient to be treated.
• composition is intended to encompass a product comprising the active ingredient(s), optionally at least one pharmaceutically acceptable excipients.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s) and pharmaceutically acceptable excipients.
• composition is also intended to comprise a combination product, comprising a salt or salt form according to any one of claims 1 to 12, in combination with one or more other therapeutic agents (pharmaceutically active compounds) and preferably at least one pharmaceutically acceptable excipient.
• therapeutic agents include at least one or two or more selected from the following groups:
• angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof
• angiotensin converting enzyme (ACE) Inhibitor or a pharmaceutically acceptable salt thereof
• the therapeutic agent(s) may be in the free (non- salt) form or in the form of a pharmaceutically acceptable salt, respectively.
• a compound of the present invention may be administered either simultaneously, before or after the other therapeutic agent (active ingredient), either separately by the same or different route of administration or together in the same pharmaceutical formulation.
• the combination product may comprise the salt or salt form according to the invention in one, one or more other therapeutic agents in a separate formulation, but in the form of a kit of parts for the simultaneous or chronically staggered administration, or in one fixed combination.
• the combinations as described above can be administered to a subject via simul- taneous, separate or sequential administration (use).
• Simultaneous administration (use) can take place in the form of one fixed combination with two or three or more active ingredients , or by simultaneously administering two or three or more compounds that are formulated independently.
• Sequential administration(use) preferably means administration of one (or more) compounds or active ingredients of a combination at one time point, other compounds or active ingredients at a different time point, that is, in a chronically staggered manner, preferably such that the combination shows more efficiency than the single compounds administered independently (especially showing synergism).
• Separate administration preferably means administration of the compounds or active ingredients of the combination independently of each other at different time points, preferably meaning that two, or three or more compounds are administered such that no overlap of measurable blood levels of both compounds are present in an overlapping manner (at the same time).
• combinations of two or three or more of sequential, separate and simultaneous administrations are possible, preferably such that the combination compound-drugs show a joint therapeutic effect that exceeds the effect found when the combination compound-drugs are used independently at time intervals so large that no mutual effect on their therapeutic efficiency can be found, a synergistic effect being especially preferred.
• the pharmaceutical compositions contain a therapeutically effective amount of a salt or salt form of Compound A of the invention as defined above or below, either alone or in a combination with one or more therapeutic agents, e.g., each at an effective therapeutic dose as reported in the art, selected from the group consisting of an anties- trogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoiso- merase II inhibitor; a microtubule active agent; an alkylating agent; an anti-neoplastic anti-metabolite; a platin compound; a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a anti-angiogenic compound; a compound which induces cell differentiation processes; monoclonal antibodies; a cyclo- oxygenase inhibitor; a bisphosphonate; a heparanase inhibitor; a biological response modifier; an inhibitor of Ras
• the present invention provides: - a pharmaceutical composition or combination of the present invention for use as a medicament;
• a pharmaceutical composition or combination of the present invention for the delay of progression and/or treatment of a disorder or disease mediated by aldo- sterone synthase, or responsive to inhibition of aldosterone synthase, or characterized by abnormal activity or expression of aldosterone synthase.
• a pharmaceutical composition or combination of the present invention for the delay of progression and/or treatment of a disorder or disease mediated by aromatase, or responsive to inhibition of aromatase, or characterized by abnormal activity or expression of aromatase.
• a pharmaceutical composition or combination of the present invention for the delay of progression and/or treatment of a disorder or disease selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, sleep apnoea, atherosclerosis, syndrome X, obe- sity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction.
• a disorder or disease selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, sleep apnoea, atherosclerosis, syndrome X, obe- sity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and
• the salt(s) or salt form(s) of the present invention are useful as aldosterone synthase inhibitors (see e.g. WO 2007/024945 incorporated by reference herein regarding the diseases and disorders related to aldosterone synthase).
• the salt(s) or salt form(s) of the present invention as aldosterone synthase inhibitors are useful for treatment of a disorder or disease characterized by abnormal aldosterone synthase activity.
• the salt(s) or salt form(s) of the present invention are also useful for treatment of a disorder or disease selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, sleep apnoea, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction.
• the disorder or disease to be treated with a salt or salt form according to the inventions is especially selected from hypertension (essential or resistant), primary aldosteronism congestive heart failure and acute heart failure.
• diseases or disorders of specific interest are selected from the group consisting of heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, Cushing's disease, Cushing's syndrome, metabolic syndrome or hypercortisolemia.
• the disease is Cushing's disease
• Protic or an aprotic solvents may be selected from aqueous or non-aqueous solvents or solvent mixtures, e.g. comprising one or more selected from water, C 1-7 alkanols, C ⁇ 8 ketones, C -7 alkanediols, C 1-7 alkylnitriles, C -7 alkyl-C 2 - 7 alkanoates, with methanol, acetone, propylene glykol, ethyl acetate, or especially ethanol being especially preferred.
• aqueous or non-aqueous solvents or solvent mixtures e.g. comprising one or more selected from water, C 1-7 alkanols, C ⁇ 8 ketones, C -7 alkanediols, C 1-7 alkylnitriles, C -7 alkyl-C 2 - 7 alkanoates, with methanol, acetone, propylene glykol, ethyl acetate, or especially ethanol being especially preferred
• Anti-solvent is a solvent which when added to an existing solution of a substance reduces the solubility of the substance.
• anti-solvents are especially less polar (more hydrophilic) solvents than those used for dissolving Com- pound A before the addition of nitric acid or phosphoric acid, e.g. organic solvents that are at least to a certain extent (e.g. at least up to 10 vol %) miscible with water .
• Fig. 1-A shows the X-ray powder diffraction pattern of the initial phosphate salt Form A.
• Fig. 1-B shows the X-ray powder diffraction pattern of phosphate salt Form B.
• Fig. 1-C shows the X-ray powder diffraction pattern of phosphate salt Form C.
• Fig. 1-D shows the X-ray powder diffraction pattern of phosphate salt Form D.
• Fig. 1-E shows the X-ray powder diffraction pattern of phosphate salt Form E.
• Fig. 1-F shows the X-ray powder diffraction pattern of phosphate salt Form F.
• Fig. 1-G shows the X-ray powder diffraction pattern of phosphate salt Form G.
• Fig. 1-H shows the X-ray powder diffraction pattern of phosphate salt Form H.
• Fig. 2 shows the X-ray powder diffraction pattern of nitrate salt.
• Fig. 3 shows the X-ray powder diffraction pattern of chloride salt.
• Example 1 Phosphate salt of 4-(R)-(6,7-dihvdro-5H-pyrrolo[1.2-climidazol-5-yl)-3-fluoro- benzonitrile (Form A)
• the phosphate salt was soluble at the 0.1% target concentration and stable for 2 days at 50°C.
• the free base remained largely insoluble. It converted from a free flo- wing solid into an oily material within a short time after contact with water, and remained as such for the 2 day period at 50°C.
• Sorption/desorption isotherms were measured using the VT1 100 humidity microbalance (VTI Corporation, Hialeah, FL, USA). Measurements were carried out at 25°C. Samples were dried under N 2 flow at 25°C
• the hygroscopicity of the phosphate salt was found to be only 0% water uptake at 5 % RH and 0.9 % water uptake at 75 % relative humidity.
• the melting point was determined by TG/DTA as described above and was determined to be 210.2 °C
• the hygroscopicity (measured under the conditions mentioned in Example 1) of the nitrate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile was found to be 0 % water uptake at 5 % RH and 0.2 % at 75 % RH.
• the nitrate salt was soluble at the 0.1% target concentration and stable for 2 days at 50°C.
• the free base remained largely insoluble. It converted from a free flowing solid into an oily material within a short time after contact with water, and remained as such for the 2 day period at 50°C.
• the melting point of the nitrate was determined to be between 160 and 163 °C.
• Example 3 Further forms B to H of 4-(R)-(6,7-dihvdro-5H-pyrrolon,2-c1imidazol-5-yl)-3- fluoro-benzonitrile phosphate salt
• Form A of 4-(R)-(6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl)-3-fluoro-benzonitrile phosphate salt was equilibrated in IPA for 72 hours at 50°C. Sample was collected by filtration and allowed to air dry. A melting temperature of form B of 209.0°C was determined by TG/DTA.
• Table 3-1 shows the angle of refraction 2-Theta values (in degrees) for the XRDPs of Fig. 1-A to 1-H for Forms A to G in comparison to those for Form A, with characteristic peaks for each form in comparison to Form A being underlined: : Table 3-1
• the HCI salt showed excessive hygroscopicity, as is shown in the following table:

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