Cocrystals

Abstract

The present invention relates to co-crystals of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one and co-crystal formers, compositions containing same, and related methods of making and using said co-crystals.

Description

[Technical field]

[0001] The present disclosure relates to co-crystals of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one, compositions containing the same, and methods of making and using the co-crystals. [Background technology]

[0002] The compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one is disclosed in WO 2009 / 075784 (U.S. Patent Application Publication No. 2010 / 0273754). The compounds have been found to be potent, selective PDE1 inhibitors useful for treating or preventing disorders characterized by low levels of cAMP and / or cGMP in cells expressing phosphodiesterase 1 (PDE1) and / or reduced dopamine D1 receptor signaling activity (e.g., neurodegenerative disorders such as Parkinson's disease; cognitive impairment in schizophrenia; cardiovascular disorders such as cardiac hypertrophy, heart failure and hypertension; cancers such as glioma and leukemia; and renal disorders such as kidney disease); and / or diseases or conditions that can be ameliorated by enhancing progesterone signaling. This list of disorders is illustrative and is not intended to be exhaustive.

[0003] WO 2009 / 075784 discloses (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one in free base form and generally in pharma-ceutically acceptable salt form, but does not indicate specific salts having particular stability or desired properties. Since many pharmaceutical compounds can exist in different physical forms (e.g., liquid or solid in different crystalline, amorphous, polymorphic, hydrated or solvated forms) which can alter the stability, solubility, bioavailability or pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) and / or bioequivalence of the drug, identifying the optimal physical form (e.g., free base or salt in a solid, liquid, crystalline, hydrated, solvated, amorphous or polymorphic form) of the pharmaceutical compound is crucial in drug development. Summary of the Invention

[0004] In a first aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: A) (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1), in free form, in pharma- ceutically acceptable salt form or in prodrug form, including enantiomers, diastereoisomers and racemates; and B) Co-crystal former The subject of this study is a cocrystal containing [Cocrystal 1].

[0005] Accordingly, in its first aspect, the disclosure provides:

[0006] 1.1 Cocrystal 1, where compound 1 is in free base form or salt form.

[0007] 1.2 Cocrystal 1 or 1.1, where compound 1 is in the free base form.

[0008] 1.3 Any of the preceding co-crystals, wherein the co-crystal is anhydrous or solvated.

[0009] 1.4 Any of the above co-crystals, wherein the co-crystal is anhydrous.

[0010] 1.5 Any of the cocrystals 1.1 to 1.3, wherein the cocrystal is solvated.

[0011] 1.6 Any of the preceding co-crystals, wherein the ratio of compound 1 to co-crystal former is 1:0.5 to 1:3 (e.g., 1:0.5, 1:0.7, 1:1, or 1:2).

[0012] 1.7 The co-crystal former is selected from the group consisting of alanine, glutamic acid, 2-aminobutyric acid, urea, tyrosine, glycine, arginine, 6-hydroxynicotinamide, diethanolamine, 3-nitrophthalimide, isoleucine, histidine, bisacetylated ethylenediamide, nicotinamide, acetanilide, leucine, lysine, isonicotinamide, resorcinol, 4-nitrophthalimide, proline, serine, pyridinophthalimide, and 4-acetamidophenol. Any of the preceding co-crystals selected from benzamide, valine, threonine, tromethamine, hydroquinone, carbamazepine, phenylalanine, cysteine, 3-aminobutyric acid, piperazine, 4-acetamidophenol, tryptophan, methionine, 6-methylpyridine-3-carboxamide, succinimide, aspartic acid, asparagine, monoacetylated ethylenediamine, 4-methylacetanilide, glutamine, 2-pyridone, pyromellitic diimide, 1,2-dihydroxybenzene, amino-4,6-dimethylnicotinamide, and salts thereof.

[0013] 1.8 Any of the preceding co-crystals wherein the co-crystal former is selected from tyrosine, 3-nitro-phthalimide, pyridinophthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof.

[0014] 1.9 Any of the preceding co-crystals wherein the co-crystal former is selected from 3-nitro-phthalimide, diethanolamine, resorcinol, hydroquinone, and salts thereof.

[0015] 1.10 Any of the preceding co-crystals wherein the co-crystal former is 3-nitro-phthalimide.

[0016] 1.11 Cocrystal 1.10, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.8°, 16.3°, 17.0°, 17.4°, 18.6°, 19.1°, 19.6°, 20.8°, 21.4° and 21.5°, the XRPD pattern being measured on a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0017] 1.12 Either cocrystal 1.10 or 1.11, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​of 16.3°, 17.0°, 17.4°, 18.6° and 19.1°, said XRPD pattern being measured on a diffractometer using a copper anode, e.g., at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0018] 1.13 Cocrystals are listed in the following table: [Table 1] Any of cocrystals 1.10 to 1.12, which has a powder X-ray diffraction pattern including at least five peaks having 2θ angle values ​​selected from those described in, and the XRPD pattern is measured with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0019] 1.14 Any of cocrystals 1.10-1.13, wherein the cocrystal exhibits an X-ray powder diffraction pattern containing at least five peaks having d-spacing values ​​selected from those listed in the table of cocrystal 1.13.

[0020] 1.15 Any of cocrystals 1.10-1.14, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 11.32 Å, 5.45 Å, 5.21 Å, 5.09 Å, 4.77 Å, 4.65 Å, 4.52 Å, 4.27 Å, 4.14 Å and 4.12 Å.

[0021] 1.16 Any of cocrystals 1.10-1.15, wherein the cocrystal exhibits an X-ray powder diffraction pattern containing peaks having d-spacing values ​​of 5.45 Å, 5.21 Å, 5.09 Å, 4.77 Å, and 4.65 Å.

[0022] 1.17 Any of cocrystals 1.10-1.16, wherein the cocrystal exhibits an X-ray powder diffraction pattern corresponding to or substantially similar to that shown in Table or Figure 1 of the cocrystal 1.13.

[0023] 1.18 Any of cocrystals 1.10 to 1.17, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 110°C to 111°C, e.g., about 110.5°C.

[0024] 1.19 Any of cocrystals 1.10-1.18, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 2.

[0025] 1.20 Any of the cocrystals 1.10 to 1.19, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 86°C to 87°C, e.g., about 86.5°C.

[0026] 1.21 Any of cocrystals 1.10-1.20, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 3.

[0027] 1.22 Any of the cocrystals 1.10 to 1.21, wherein the cocrystal has a needle shape, for example, a needle shape having a length of 50 to 200 μm.

[0028] 1.23 Any of cocrystals 1.10-1.22, wherein the cocrystal comprises the free base form of compound 1 and a cocrystal former in a ratio of 1:0.5 and / or 1:1 (e.g., 1:0.7).

[0029] 1.24 Any of cocrystals 1.1-1.9, where the cocrystal former is diethanolamine.

[0030] 1.25 Cocrystal 1.24, which exhibits a powder X-ray diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.29°, 7.70°, 7.80°, 9.987°, 13.78°, 16.59°, 16.93°, 18.84°, 20.66° and 20.68°, said XRPD pattern being measured on a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0031] 1.26 Any of cocrystals 1.24 to 1.25, wherein the cocrystal exhibits a powder X-ray diffraction pattern including peaks having 2θ angle values ​​of 7.29°, 7.70°, 7.80°, 13.78° and 18.84°, and the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0032] 1.27 Cocrystals are shown in the following table: [Table 2] Any of cocrystals 1.24 to 1.26, comprising an X-ray powder diffraction pattern including at least five peaks having 2θ angle values ​​selected from those described in, wherein the XRPD pattern is measured at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å using a diffractometer using a copper anode.

[0033] 1.28 Any of cocrystals 1.24-1.27, wherein the cocrystal exhibits an X-ray powder diffraction pattern containing at least five peaks having d-spacing values ​​selected from those set forth in the table for cocrystal 1.27.

[0034] 1.29 Any of cocrystals 1.24 to 1.28, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 12.12 Å, 11.49 Å, 11.33 Å, 8.85 Å, 6.42 Å, 5.34 Å, 5.23 Å, 4.71 Å, 4.30 Å and 4.29 Å.

[0035] 1.30 Any of cocrystals 1.24-1.29, wherein the cocrystal exhibits a powder X-ray diffraction pattern containing peaks having d-spacing values ​​of 12.12 Å, 11.49 Å, 11.33 Å, 6.42 Å, and 4.71 Å.

[0036] 1.31 Any of cocrystals 1.24-1.30, wherein the cocrystal exhibits an X-ray powder diffraction pattern corresponding to or substantially similar to that shown in the Table or Figure 4 of cocrystal 1.24.

[0037] 1.32 Any of cocrystals 1.24 to 1.31, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 121°C to 122°C, e.g., about 121.7°C.

[0038] 1.33 Any of cocrystals 1.24-1.32, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 5.

[0039] 1.34 Any of the cocrystals 1.24 to 1.33, wherein the cocrystal has a needle shape, for example, a needle shape having a length of 5 to 40 μm.

[0040] 1.35 Any of cocrystals 1.24-1.34, wherein the cocrystal contains the free base form of compound 1 and a cocrystal former in a 1:1 ratio.

[0041] 1.36 Any of cocrystals 1.1-1.9, where the cocrystal former is resorcinol.

[0042] 1.37 Cocrystal 1.36, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.3°, 7.4°, 10.0°, 14.1°, 17.0°, 18.7°, 19.0°, 19.7°, 22.9° and 23.7°, said XRPD pattern being measured on a diffractometer using a copper anode, e.g., at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0043] 1.38 Any of cocrystals 1.36 to 1.37, wherein the cocrystal exhibits an X-ray powder diffraction pattern including peaks having 2θ angle values ​​of 7.3°, 7.4°, 17.0°, 19.0°, and 22.9°, and the XRPD pattern is measured on a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0044] 1.39 Cocrystals are shown in the following table: [Table 3] Any of the cocrystals 1.36 to 1.38, wherein the XRPD pattern comprises at least five peaks having 2θ angle values ​​selected from those described in, and the XRPD pattern is measured at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å using a diffractometer using a copper anode.

[0045] 1.40 Any of cocrystals 1.36-1.39, wherein the cocrystal exhibits an X-ray powder diffraction pattern containing at least five peaks having d-spacing values ​​selected from those set forth in the table for cocrystal 1.39.

[0046] 1.41 Any of the cocrystals 1.36 to 1.40, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 12.14 Å, 12.00 Å, 8.88 Å, 6.27 Å, 5.21 Å, 4.74 Å, 4.68 Å, 4.50 Å, 3.88 Å and 3.75 Å.

[0047] 1.42 Any of cocrystals 1.36-1.41, wherein the cocrystal exhibits a powder X-ray diffraction pattern containing peaks having d-spacing values ​​of 12.14 Å, 12.00 Å, 5.21 Å, 4.68 Å, and 3.88 Å.

[0048] 1.43 Any of cocrystals 1.36-1.42, wherein the cocrystal exhibits a powder X-ray diffraction pattern corresponding to or substantially similar to that shown in the table or FIG. 6 of the cocrystal 1.39.

[0049] 1.44 Any of the cocrystals 1.36-1.43, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern including endothermic peaks at about 160°C to 162°C, e.g., about 161°C, and about 167°C to 168°C, e.g., about 167.4°C.

[0050] 1.45 Any of the cocrystals 1.36-1.44, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 7.

[0051] 1.46 Any of the cocrystals 1.36 to 1.45, wherein the cocrystal has a needle shape, for example, a needle shape having a length of 20 to 100 μm.

[0052] 1.47 Any of cocrystals 1.36-1.46, wherein the cocrystal contains the free base form of compound 1 and a cocrystal former in a 2:1 ratio.

[0053] 1.48 Any of cocrystals 1.1 to 1.9, where the cocrystal former is hydroquinone.

[0054] 1.49 Cocrystal 1.48, wherein the cocrystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.26°, 7.42°, 9.94°, 17.21°, 18.41°, 18.38°, 19.44°, 19.47°, 23.08° and 23.73°, said XRPD pattern being measured on a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0055] 1.50 Any of cocrystals 1.48 to 1.49, wherein the cocrystal exhibits a powder X-ray diffraction pattern including peaks having 2θ angle values ​​of 7.26°, 7.42°, 9.94°, 17.21°, and 23.08°, and the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0056] 1.51 Cocrystals are shown in the following table: [Table 4] wherein the XRPD pattern is measured at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å using a diffractometer with a copper anode, and the XRPD pattern includes at least five peaks having 2θ angle values ​​selected from those described in the above, and the cocrystal is any of 1.48 to 1.50.

[0057] 1.52 Any of cocrystals 1.48 to 1.51, wherein the cocrystal exhibits an X-ray powder diffraction pattern containing at least five peaks having d-spacing values ​​selected from those listed in the table of cocrystal 1.51.

[0058] 1.53 Any of cocrystals 1.48 to 1.52, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 17.74 Å, 12.16 Å, 11.91 Å, 8.89 Å, 5.32 Å, 5.15 Å, 4.82 Å, 4.56 Å, 3.85 Å and 3.75 Å.

[0059] 1.54 Any of cocrystals 1.48 to 1.53, wherein the cocrystal exhibits a powder X-ray diffraction pattern containing peaks having d-spacing values ​​of 12.16 Å, 11.91 Å, 8.89 Å, 5.15 Å and 3.85 Å.

[0060] 1.55 Any of cocrystals 1.48-1.54, wherein the cocrystal exhibits a powder X-ray diffraction pattern corresponding to or substantially similar to that shown in the table or FIG. 8 of cocrystal 1.51.

[0061] 1.56 Any of the cocrystals 1.48 to 1.55, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 209°C to 210°C, for example, about 209.2°C.

[0062] 1.57 Any of the cocrystals 1.48 to 1.56, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 9.

[0063] 1.58 Any of the cocrystals 1.48 to 1.57, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern comprising endothermic peaks at about 128°C to 129°C, e.g., about 128.6°C; about 148°C to 150°C, e.g., about 149°C; and about 200°C to 201°C, e.g., 200.4°C.

[0064] 1.59 Any of the cocrystals 1.48 to 1.58, wherein the cocrystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG.

[0065] 1.60 Any of the cocrystals 1.48 to 1.59, wherein the cocrystal has a needle shape, for example, a needle shape having a length of 2 to 30 μm.

[0066] 1.61 Any of cocrystals 1.48-1.60, wherein the cocrystal contains the free base form of compound 1 and a cocrystal former in a 2:1 ratio.

[0067] 1.62 Any of the preceding co-crystals, wherein the co-crystal is in a single crystalline form and is free or substantially free of other forms, e.g., contains less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form.

[0068] 1.63 Any of the preceding co-crystals, wherein the co-crystal is a single crystalline form and is free or substantially free of other forms, e.g., contains less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of other crystalline forms.

[0069] 1.64 Any of the preceding co-crystals, wherein the co-crystal is in a single crystalline form and is free or substantially free of other forms, e.g., contains less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous and other crystalline forms.

[0070] 1.65 Any of the above co-crystals, wherein the co-crystal is formed according to method 1 et seq.

[0071] In a further aspect, the present disclosure also provides a method for preparing a co-crystal comprising (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1), in free form, pharma- ceutically acceptable salt form or prodrug form, including enantiomers, diastereoisomers and racemates, and a co-crystal former, comprising reacting Compound 1 with the co-crystal former and isolating the resulting co-crystal [Method 1].

[0072] In various embodiments, the present disclosure provides:

[0073] 1.1 Method 1, wherein compound 1 is in free base form or salt form.

[0074] 1.2 Method 1 or 1.1, wherein compound 1 is in free base form.

[0075] 1.3 Any of the preceding processes, wherein the co-crystal is anhydrous or solvated.

[0076] 1.4 Any of the preceding processes, wherein the co-crystal is anhydrous.

[0077] 1.5 Any of the preceding processes, wherein the co-crystal is solvated.

[0078] 1.6 Any of the preceding methods, wherein the ratio of compound 1 to co-crystal former in the resulting co-crystal is 1:0.5 to 1:3 (e.g., 1:0.5, 1:0.7, 1:1, or 1:2).

[0079] 1.7 Any of the preceding methods further comprising the step of dissolving Compound 1 in a first solvent comprising an alcohol and / or water.

[0080] 1.8 Any of the preceding methods further comprising the step of dissolving compound 1 in a solvent selected from ethanol, methanol, water, and combinations thereof.

[0081] 1.9 Any of the preceding methods further comprising the step of dissolving compound 1 in a solvent comprising methanol and water.

[0082] 1.10 The above process, wherein the molar ratio of methanol and water is 5:1 to 15:1.

[0083] 1.11 The process, wherein the molar ratio of methanol and water is 9:1.

[0084] 1.12 Any of the preceding methods further comprising the step of dissolving a co-crystal former in a second solvent.

[0085] 1.13 The process wherein the second solvent is an alcohol or water.

[0086] 1.14 Any of the preceding methods further comprising the step of dissolving a co-crystal former in a second solvent comprising ethanol, methanol, or water.

[0087] 1.15 The process wherein the second solvent is methanol or water.

[0088] 1.16 The method 1.12, wherein the second solvent is methanol.

[0089] 1.17 The method 1.12, wherein the second solvent is water.

[0090] 1.18 Any of Methods 1.12-1.17 further comprising combining the resulting solution comprising Compound 1 in the first solvent with the resulting solution comprising a co-crystal former and a second solvent.

[0091] 1.19 The co-crystal former is selected from the group consisting of alanine, glutamic acid, 2-aminobutyric acid, urea, tyrosine, glycine, arginine, 6-hydroxynicotinamide, diethanolamine, 3-nitrophthalimide, isoleucine, histidine, bisacetylated ethylenediamide, nicotinamide, acetanilide, leucine, lysine, isonicotinamide, resorcinol, 4-nitrophthalimide, proline, serine, pyridinophthalimide, and 4-acetamidophenol. Any of the preceding methods wherein the aryl ester is selected from benzamide, valine, threonine, tromethamine, hydroquinone, carbamazepine, phenylalanine, cysteine, 3-aminobutyric acid, piperazine, 4-acetamidophenol, tryptophan, methionine, 6-methylpyridine-3-carboxamide, succinimide, aspartic acid, asparagine, monoacetylated ethylenediamine, 4-methylacetanilide, glutamine, 2-pyridone, pyromellitic diimide, 1,2-dihydroxybenzene, amino-4,6-dimethylnicotinamide, and salts thereof.

[0092] 1.20 Any of the preceding processes wherein the co-crystal former is selected from tyrosine, 3-nitro-phthalimide, pyridinophthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof.

[0093] 1.21 Any of the preceding processes wherein the co-crystal former is selected from 3-nitro-phthalimide, diethanolamine, resorcinol, hydroquinone and salts thereof.

[0094] 1.22 Any of the preceding processes, wherein compound 1 is in free base form and the co-crystal former is 3-nitro-phthalimide.

[0095] 1.23 The process further comprising dissolving compound 1 in a mixture of methanol and water in a molar ratio of 9:1, dissolving 3-nitro-phthalimide in methanol, and mixing the two resulting solutions to form a reaction mixture.

[0096] 1.24 Any of the preceding processes wherein compound 1 is in free base form and the co-crystal former is diethanolamine.

[0097] 1.25 The process further comprising dissolving compound 1 in a mixture of methanol and water in a molar ratio of 9:1, dissolving diethanolamine in water, and mixing the two resulting solutions to form a reaction mixture.

[0098] 1.26 Any of the preceding methods, wherein compound 1 is in free base form and the co-crystal former is resorcinol.

[0099] 1.27 The process further comprising dissolving compound 1 in a mixture of methanol and water in a molar ratio of 9:1, dissolving resorcinol in water, and mixing the two resulting solutions to form a reaction mixture.

[0100] 1.28 Any of the preceding methods, wherein compound 1 is in free base form and the co-crystal former is hydroquinone.

[0101] 1.29 The process further comprising dissolving compound 1 in a mixture of methanol and water in a molar ratio of 9:1, dissolving hydroquinone in water, and mixing the two resulting solutions to form a reaction mixture.

[0102] 1.30 Any of the preceding methods, wherein compound 1 is reacted with a co-crystal former in a molar ratio of 2:1 to 1:2.

[0103] 1.31 The method, wherein compound 1 is reacted with a co-crystal former in a molar ratio of 1:1.

[0104] 1.32 Any of the preceding methods further comprising the step of heating the reaction mixture containing compound 1 and the co-crystal former to a temperature of, e.g., 30°C to 80°C, e.g., about 50°C.

[0105] 1.33 Any of the preceding processes further comprising the step of drying the reaction mixture, e.g., to a temperature between 0°C and 20°C, e.g., to a temperature of about 5°C.

[0106] 1.34 Any of the preceding methods, wherein the co-crystal is a co-crystal subsequent to Co-crystal 1.

[0107] The present disclosure further relates to a method for treating the following disorders: A. Neurodegenerative diseases, including Parkinson's disease, restless legs, tremors, dyskinesia, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; B. Psychiatric disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders, e.g., narcolepsy, cognitive disorders, e.g., cognitive impairment in schizophrenia, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction; C. Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke, congestive disease, hypertension, pulmonary hypertension, e.g., pulmonary arterial hypertension, and sexual dysfunction, including cardiovascular diseases and related disorders described in International Application No. PCT / US2014 / 16741, the contents of which are incorporated herein by reference; D. Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases; E. Diseases that may be alleviated by enhancing progesterone signaling, such as female sexual dysfunction; F. Diseases or disorders such as psychiatric illness, glaucoma, or elevated intraocular pressure; G. Traumatic brain injury; H. A cancer or tumor, such as a brain tumor, a glioma (e.g., an ependymoma, an astrocytoma, an oligodendroglioma, a brain stem glioma, an optic nerve glioma, or a mixed glioma, e.g., an oligoastrocytoma), an astrocytoma (e.g., a glioblastoma multiforme), an osteosarcoma, a melanoma, a leukemia, a neuroblastoma, or a leukemia; I. Renal disorders, such as renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis; J. A disease or condition characterized by low levels of cAMP and / or cGMP (or inhibition of the cAMP and / or cGMP signaling pathways) in cells expressing PDE1; and / or K. Diseases or conditions characterized by reduced dopamine D1 receptor signaling activity A method for preventing or treating a patient, e.g., a human, suffering from a disorder selected from the group consisting of: i. (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1), in free form, pharma- ceutically acceptable salt form or prodrug form, including enantiomers, diastereoisomers and racemates; and ii. Co-crystal formers Cocrystal containing [Cocrystal 1] For example, cocrystal 1 and subsequent cocrystals of the present disclosure administering a therapeutically effective amount of A preventive or therapeutic method [Method 2] is provided.

[0108] 2.1 A pharmaceutical composition comprising Cocrystal 1 or later for use as a medicament, e.g. for use in the manufacture of a medicament for the treatment or prevention of a disease as described in method 2.

[0109] 2.2 Use of cocrystal 1 or later in the treatment or prevention of a disease as described in Method 2.

[0110] 2.3 Method 2, wherein the co-crystal is administered to a patient in an amount equivalent to 1-300 mg of Compound 1 per day.

[0111] 2.4 Any of the preceding methods, wherein the co-crystal is administered to the patient in an amount equivalent to 15-180 mg of Compound 1 per day, e.g., 30-90 mg of Compound 1 per day, e.g., 30-60 mg of Compound 1 per day. [Brief description of the drawings]

[0112] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of the co-crystal of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1) and 3-nitro-phthalimide. [Diagram 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of the co-crystal of compound 1 with 3-nitro-phthalimide. [Diagram 3] FIG. 3 shows a differential scanning calorimetry (DSC) thermogram of the co-crystal of compound 1 with 3-nitro-phthalimide. [Figure 4] FIG. 4 shows the powder X-ray diffraction pattern of the co-crystal of Compound 1 and diethanolamine. [Diagram 5] FIG. 5 shows the differential scanning calorimetry (DSC) thermograph pattern of the co-crystal of Compound 1 with diethanolamine. [Figure 6] FIG. 6 shows the powder X-ray diffraction pattern of the co-crystal of Compound 1 and resorcinol. [Figure 7] FIG. 7 shows the differential scanning calorimetry (DSC) thermograph pattern of the co-crystal of Compound 1 with resorcinol. [Figure 8]FIG. 8 shows the powder X-ray diffraction pattern of the co-crystal of Compound 1 and hydroquinone. [Figure 9] FIG. 9 shows a differential scanning calorimetry (DSC) thermogram of the co-crystal of Compound 1 with hydroquinone. [Figure 10] FIG. 10 shows a differential scanning calorimetry (DSC) thermogram of the co-crystal of Compound 1 with hydroquinone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0113] As used herein, the term "crystal" or "crystals" or "crystalline" or "crystallinic" refers to a solid having short-range or long-range order of molecules, atoms, or ions in a fixed lattice arrangement. The cocrystals of the present disclosure may be in a single crystal form. Thus, the cocrystals of the present disclosure may be in a triclinic crystal form, a monoclinic crystal form, an orthorhombic crystal form, a tetragonal crystal form, a rhobohedral crystal form, a hexagonal crystal form, a cubic crystal form, or a mixture thereof. In particular, the cocrystals of the present disclosure are in a dry crystal form. In another embodiment, the cocrystals of the present disclosure are in a needle form. In certain embodiments, the cocrystals of the present disclosure are substantially free of other forms, e.g., free of amorphous forms or other crystalline forms.

[0114] The term "substantially free" of other crystalline forms refers to less than about 10% by weight of other forms or other crystalline forms, such as amorphous or other crystalline forms, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight.

[0115] In certain embodiments, the crystals of the present disclosure may contain trace amounts of solvent, for example in the form of a solvate, or may contain trace amounts of water, for example in the form of a hydrate. The cocrystals of the present disclosure are in a non-solvated form. In some embodiments, the crystals of the present disclosure are in a non-solvated and non-hydrated form. In some embodiments, the cocrystals of the present disclosure are in anhydrous form.

[0116] The co-crystals of the present disclosure may have a ratio of compound 1 to co-crystal former of about 5:1 to 1:5. For example, in various embodiments, the ratio of compound 1 to co-crystal former may be 1:2 to 2:1, such as 1:1, 1:0.5, 1:0.7, or 1:>1, such as 1:1.3 or 1:2. For example, the co-crystals of compound 1 and 3-nitro-phthalimide of the present disclosure may include compound 1 and 3-nitro-phthalimide in a ratio of 1:0.5 and / or 1:1 (e.g., 1:0.7). The co-crystals of compound 1 and diethanolamine of the present disclosure may include compound 1 and diethanolamine in a ratio of 1:1. The co-crystals of compound 1 and resorcinol of the present disclosure may include compound 1 and resorcinol in a ratio of 2:1. The co-crystals of compound 1 and hydroquinone of the present disclosure may include compound 1 and hydroquinone in a ratio of 2:1.

[0117] The term "solvate" refers to a crystalline solid adduct that contains a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal structure. Thus, the term "non-solvate" form herein refers to a co-crystal that does not contain or is substantially free of solvent molecules within the crystal structure of the present disclosure. Similarly, the term "non-hydrate" form herein refers to a co-crystal that does not contain or is substantially free of water molecules within the crystal structure of the present disclosure.

[0118] The term "amorphous" refers to a solid with a disordered arrangement of molecules and lacking a discernible crystal lattice.

[0119] Unless further modified, "Compound 1" has the following structure: [ka]

[0033] The compound refers to the free base form of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one, having the formula:

[0120] The crystallinity or morphology of the cocrystals of the present disclosure may be determined by a number of methods, including, but not limited to, single crystal X-ray diffraction, powder X-ray diffraction, polarized optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared adsorption spectroscopy, and Raman spectroscopy. Characterization of solvates or hydrates or lack thereof may also be determined by DSC and / or TGA.

[0121] It should be understood that the powder X-ray diffraction pattern or differential scanning calorimetry pattern of a given sample may vary slightly (standard deviation) depending on the equipment used, the time and temperature of the sample when measured, and standard experimental error. Therefore, the temperature, or 2θ values, d-spacing values, heights and relative intensities of peaks described in tables or figures herein have an acceptable level of deviation. For example, the values ​​may have an acceptable deviation of, for example, about 20%, 15%, 10%, 5%, 3%, 2% or 1%. In certain embodiments, the 2θ values ​​or d-spacing values ​​of the XRPD pattern of the crystal of the present disclosure may have an acceptable deviation of ±0.2° and / or ±0.2 Å. Furthermore, the XRPD pattern of the crystal of the present disclosure may be identified by characteristic peaks as recognized by those skilled in the art. For example, a crystal of the present disclosure may be identified by, for example, at least five characteristic peaks, e.g., at least three or at least five peaks, e.g., at least three or at least five 2θ values, and / or at least three or at least five d-spacing values, as described in the XRPD patterns described herein. Thus, the term "corresponding to or substantially similar to" that described in any of the tables or shown in any of the figures refers to a crystal having an XRPD with the major or characteristic peaks as described in the table / figure.

[0122] The term "about" in front of a numerical value refers to the numerical value itself ±20% of the numerical value, ±15% of the numerical value, ±10% of the numerical value, preferably ±5% of the numerical value, preferably ±3% of the numerical value, preferably ±2% of the numerical value, preferably ±1% of the numerical value. When referring to temperature, the term "about" refers to the temperature value itself ±10°C of the reference temperature, preferably ±5°C of the reference temperature, more preferably ±3°C of the reference temperature. In another example, when referring to a 2θ angle value, the term "about" refers to the numerical 2θ angle value itself ±0.2° of the reference 2θ angle value. In yet another example, when referring to a d-spacing value, the term "about" refers to the numerical 2θ angle value itself ±0.2Å of the reference d-spacing value.

[0123] The crystal of the present disclosure is a selective PDE1 inhibitor.Therefore, the crystal of the present disclosure is useful for treating PDE1-related disorders, for example, as described in International Publication No. WO 2014 / 151409, International Publication No. WO 2018 / 049417, International Publication No. WO 2019 / 227004, International Publication No. WO 2019 / 152697, International Publication No. WO 2009 / 075784, International Publication No. WO 2010 / 132127, International Publication No. WO 2006 / 133261 and International Publication No. WO 2011 / 153129 (each of which is incorporated herein by reference in its entirety).

[0124] The term "patient" includes humans and non-humans. In one embodiment, the patient is a human. In another embodiment, the patient is a non-human. EXAMPLES

[0125] Example 1: Free Base Crystals The preparation of the compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one is generally described in WO 2009 / 075784, which is incorporated herein by reference in its entirety. This compound can also be prepared as summarized in or similar to the reaction schemes 1 and 2 below.

[0126] [ka]

[0127] [ka]

[0128] Crystalline (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1) free base can be prepared, for example, according to the methods described in WO2014205354 A1, which is incorporated herein by reference in its entirety.

[0129] Example 2: 3-Nitro-phthalimide cocrystal 100mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (2000μl). 3-nitro-phthalimide coformer (1:1 molar ratio to compound 1 free base) is dissolved in methanol and added to the free base solution. The vial is then shaken at 50°C for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5°C and stored at this temperature for about 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0130] The obtained solid is dried under vacuum and first characterized by XRPD. Powder X-ray diffraction studies are carried out using a Bragg-Brentano type Bruker AXS D2 PHASER. The X-ray source is a Cu anode at 30 kV and 10 mA. The obtained XRPD is shown in Figure 1 and summarized in Table 1 below. The observed crystals are solvated as methanol solvates and are needle-shaped with a size of about 50-200 μm.

[0131] [Table 5]

[0132] XRPD data indicates that a crystalline structure was formed. Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 2, which shows an endothermic peak at 111°C.

[0133] The co-crystal formation was confirmed by 1H-NMR and FT-IR.

[0134] Example 3: 3-Nitro-phthalimide cocrystal 20 mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (400 μl). 3-nitro-phthalimide coformer (1:1 molar ratio to compound 1 free base) is dissolved in methanol (400 μl) and added to the free base solution. The vial is then shaken at 50° C. for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5° C. and stored at this temperature for approximately 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0135] Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 3, which shows an endothermic peak at 87°C.

[0136] Example 4: Diethanolamine Co-Crystals 100 mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (2000 μl). Diethanolamine coformer (1:1 molar ratio to compound 1 free base) is dissolved in water and added to the free base solution. The vial is then shaken at 50° C. for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5° C. and stored at this temperature for approximately 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0137] The obtained solid is dried under vacuum and first characterized by XRPD. Powder X-ray diffraction studies are carried out using a Bragg-Brentano type Bruker AXS D2 PHASER. The X-ray source is a Cu anode at 30 kV, 10 mA. The obtained XRPD is shown in Figure 4 and summarized in Table 2 below. The observed crystals are anhydrous and needle-shaped with a size of about 5-40 μm.

[0138] [Table 6]

[0139] XRPD data indicates that a crystalline structure is formed. Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 5, which shows an endothermic peak at 122°C.

[0140] The co-crystal formation is confirmed by 1H-NMR and FT-IR. 1H-NMR shows that the co-crystal contains a 1:1 ratio of free base and co-former.

[0141] Example 5: Resorcinol Cocrystals 100 mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (2000 μl). A resorcinol coformer (1:1 molar ratio to compound 1 free base) is dissolved in water and added to the free base solution. The vial is then shaken at 50° C. for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5° C. and stored at this temperature for approximately 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0142] The obtained solid is dried under vacuum and first characterized by XRPD. Powder X-ray diffraction studies are carried out using a Bragg-Brentano type Bruker AXS D2 PHASER. The X-ray source is a Cu anode at 30 kV, 10 mA. The obtained XRPD is shown in Figure 6 and summarized in Table 3 below. The observed crystals are anhydrous and needle-shaped with a size of about 20-100 μm.

[0143] [Table 7]

[0144] XRPD data indicates that a crystalline structure is formed. Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 7, which shows endothermic peaks at 161°C and 167°C.

[0145] The co-crystal formation is confirmed by 1H-NMR and FT-IR. 1H-NMR shows that the co-crystal contains a 2:1 ratio of free base and co-former.

[0146] Example 6: Hydroquinone Cocrystal 100 mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (2000 μl). Hydroquinone coformer (1:1 molar ratio to compound 1 free base) is dissolved in water and added to the free base solution. The vial is then shaken at 50° C. for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5° C. and stored at this temperature for approximately 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0147] The obtained solid is dried under vacuum and first characterized by XRPD. Powder X-ray diffraction studies are carried out using a Bragg-Brentano type Bruker AXS D2 PHASER. The X-ray source is a Cu anode at 30 kV and 10 mA. The obtained XRPD is shown in Figure 8 and summarized in Table 4 below. The observed crystals are anhydrous and needle-shaped with a size of about 2-30 μm.

[0148] [Table 8]

[0149] XRPD data indicates that a crystalline structure is formed. Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 9, which shows an endothermic peak at 208°C.

[0150] The co-crystal formation is confirmed by 1H-NMR and FT-IR. 1H-NMR shows that the co-crystal contains a 2:1 ratio of free base and co-former.

[0151] Example 7: Hydroquinone Cocrystal 20 mg of compound 1 free base is added to a vial and dissolved in a 9:1 mixture of methanol and water (400 μl). Hydroquinone coformer (1:1 molar ratio to compound 1 free base) is dissolved in water (400 μl) and added to the free base solution. The vial is then shaken at 50° C. for 3 hours. The resulting clear solution is transferred to a cooling plate cooled to 5° C. and stored at this temperature for approximately 16 hours. The remaining liquid is absorbed into filter paper and stored under vacuum until completely dry.

[0152] Differential scanning calorimetry is performed on a Mettler Toledo TGA / DSC-3+ STARe System equipped with a 34-position autosampler. 5-10 mg of sample is placed in a pre-weighed aluminum crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 ml / min is maintained over the sample. STARe Software v15.00 build 8668 is used for the measurements. The resulting DSC curve is shown in Figure 10, which shows endothermic peaks at 129°C, 149°C and 200°C.

[0153] Example 8: Cocrystal solubility comparison The aqueous solubility of the cocrystals is determined by preparing saturated solutions containing the individual cocrystals in water. The saturated solutions are shaken at room temperature for 24 hours. At two time points (2 hours and 24 hours), samples are taken, filtered, diluted (acetonitrile / water 1:1) and then measured by liquid chromatography. The results are summarized in Table 5 below.

[0154] [Table 9]

[0155] After 24 hours, the solubilities of diethanolamine and resorcinol are very low. Hydroquinone is shown to be completely insoluble. Only the free base-3-nitrophthalimide cocrystal showed a solubility of 1.10 mg / mL at 24 hours, a significant increase over the solubility of the free base of 0.001 mg / mL.

Claims

1. A) (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1), in free form, pharmaceutically acceptable salt form, or prodrug form, including enantiomers, diastereoisomers, and racemates; and B) Co-crystal formers A co-crystal comprising: Optionally, the co-crystal wherein Compound 1 is in free base form.

2. 10. The co-crystal of claim 1, wherein the co-crystal is anhydrous or solvated.

3. Co-crystal formers include alanine, glutamic acid, 2-aminobutyric acid, urea, tyrosine, glycine, arginine, 6-hydroxynicotinamide, diethanolamine, 3-nitrophthalimide, isoleucine, histidine, bisacetylated ethylenediamide, nicotinamide, acetanilide, leucine, lysine, isonicotinamide, resorcinol, 4-nitrophthalimide, proline, serine, pyridinophthalimide, and 4-acetamidophenol.

3. The co-crystal of claim 1 or 2, wherein the co-crystal is selected from benzamide, valine, threonine, tromethamine, hydroquinone, carbamazepine, phenylalanine, cysteine, 3-aminobutyric acid, piperazine, 4-acetamidophenol, tryptophan, methionine, 6-methylpyridine-3-carboxamide, succinimide, aspartic acid, asparagine, monoacetylated ethylenediamine, 4-methylacetanilide, glutamine, 2-pyridone, pyromellitic diimide, 1,2-dihydroxybenzene, amino-4,6-dimethylnicotinamide, and salts thereof; optionally, the co-crystal former is selected from tyrosine, 3-nitro-phthalimide, pyridinophthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof; and further optionally, the co-crystal former is selected from 3-nitro-phthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof.

4. 4. The co-crystal of claim 3, wherein the co-crystal former is 3-nitro-phthalimide.

5. 5. The cocrystal of claim 4, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.8°, 16.3°, 17.0°, 17.4°, 18.6°, 19.1°, 19.6°, 20.8°, 21.4°, and 21.5°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å; optionally, the cocrystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​of 16.3°, 17.0°, 17.4°, 18.6°, and 19.1°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

6. 5. The co-crystal of claim 4, wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising an endothermic peak at about 110°C to 111°C, e.g., about 110.5°C, or wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising an endothermic peak at about 86°C to 87°C, e.g., about 86.5°C.

7. 4. The co-crystal of claim 3, wherein the co-crystal former is diethanolamine.

8. 8. The cocrystal of claim 7, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.29°, 7.70°, 7.80°, 9.987°, 13.78°, 16.59°, 16.93°, 18.84°, 20.66°, and 20.68°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å; optionally, the cocrystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​of 7.29°, 7.70°, 7.80°, 13.78°, and 18.84°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

9. 8. The co-crystal of claim 7, wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising an endothermic peak at about 121°C to 122°C, for example, about 121.7°C.

10. 4. The co-crystal of claim 3, wherein the co-crystal former is resorcinol.

11. 11. The cocrystal of claim 10, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.3°, 7.4°, 10.0°, 14.1°, 17.0°, 18.7°, 19.0°, 19.7°, 22.9°, and 23.7°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å; optionally, the cocrystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​of 7.3°, 7.4°, 17.0°, 19.0°, and 22.9°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

12. 11. The co-crystal of claim 10, wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising endothermic peaks at about 160°C to 162°C, e.g., about 161°C, and about 167°C to 168°C, e.g., about 167.4°C.

13. 4. The co-crystal of claim 3, wherein the co-crystal former is hydroquinone.

14. 14. The cocrystal of claim 13, wherein the cocrystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.26°, 7.42°, 9.94°, 17.21°, 18.41°, 18.38°, 19.44°, 19.47°, 23.08°, and 23.73°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a2 of 1.5444 Å; optionally, the cocrystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​of 7.26°, 7.42°, 9.94°, 17.21°, and 23.08°, wherein the XRPD pattern is measured with a diffractometer using a copper anode, for example at a wavelength α1 of 1.5406 Å and a2 of 1.5444 Å.

15. 14. The co-crystal of claim 13, wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising an endothermic peak at about 209°C to 210°C, for example, about 209.2°C, or wherein the co-crystal exhibits a differential scanning calorimetry (DSC) pattern comprising endothermic peaks at about 128°C to 129°C, for example, about 128.6°C; about 148°C to 150°C, for example, about 149°C; and about 200°C to 201°C, for example, 200.4°C.

16. A method for producing a co-crystal comprising (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopento[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound 1), in free form, pharmaceutically acceptable salt form, or prodrug form, including enantiomers, diastereoisomers, and racemates, and a co-crystal former, the method comprising the steps of reacting Compound 1 with the co-crystal former and isolating the resulting co-crystal.

17. 17. The method of claim 16, further comprising dissolving Compound 1 in a first solvent comprising an alcohol and / or water.

18. 18. The method of claim 17, wherein the first solvent is selected from ethanol, methanol, water, and combinations thereof (e.g., methanol and water).

19. 20. The method of claim 17, further comprising dissolving a co-crystal former in the second solvent.

20. 20. The method of claim 19, wherein the second solvent is selected from ethanol, methanol, and water.

21. 20. The method of claim 19, further comprising combining the resulting solution comprising Compound 1 in the first solvent with the resulting solution comprising the co-crystal former and the second solvent.

22. Co-crystal formers include alanine, glutamic acid, 2-aminobutyric acid, urea, tyrosine, glycine, arginine, 6-hydroxynicotinamide, diethanolamine, 3-nitrophthalimide, isoleucine, histidine, bisacetylated ethylenediamide, nicotinamide, acetanilide, leucine, lysine, isonicotinamide, resorcinol, 4-nitrophthalimide, proline, serine, pyridinophthalimide, and 4-acetamidophenol.

17. The method of claim 16, wherein the co-crystal former is selected from benzamide, valine, threonine, tromethamine, hydroquinone, carbamazepine, phenylalanine, cysteine, 3-aminobutyric acid, piperazine, 4-acetamidophenol, tryptophan, methionine, 6-methylpyridine-3-carboxamide, succinimide, aspartic acid, asparagine, monoacetylated ethylenediamine, 4-methylacetanilide, glutamine, 2-pyridone, pyromellitic diimide, 1,2-dihydroxybenzene, amino-4,6-dimethylnicotinamide, and salts thereof; optionally, the co-crystal former is selected from tyrosine, 3-nitro-phthalimide, pyridinophthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof; and further optionally, the co-crystal former is selected from 3-nitro-phthalimide, diethanolamine, resorcinol, hydroquinone, threonine, and salts thereof.

23. 17. The method of claim 16, further comprising heating the reaction mixture containing compound 1 and the co-crystal former, e.g., to a temperature of 30°C to 80°C, e.g., to a temperature of about 50°C.

24. 17. The method of claim 16, further comprising drying the reaction mixture, for example to a temperature of 0°C to 20°C, for example to a temperature of about 5°C.

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