Novel composition

Abstract

The present disclosure relates to amorphous solid dispersions comprising (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 and an additive, and to methods of making and using the dispersions.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 63 / 303,950, filed January 27, 2022, the contents of which are incorporated herein in their entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to amorphous solid dispersions comprising a PDE1 inhibitor, such as (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 in free base or pharma- ceutically acceptable salt form, and an excipient, compositions comprising the same, and methods of making and using the amorphous solid dispersions. [Background technology]

[0003] 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 disclosed in WO2009 / 075784 (U.S. Patent Application Publication No. 2010 / 0273754). The compounds have been found to be potent and selective PDE1 inhibitors useful for the treatment or prevention of 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; cancer, such as glioma and leukemia; and renal disorders, such as renal disease); and / or any disease or condition that can be alleviated by enhancing progesterone signaling. This list of disorders is illustrative and is not intended to be exhaustive.

[0004] Many pharmaceutical compounds can exist in various physical forms (e.g., liquid or solid in various crystalline, amorphous, polymorphic, hydrated or solvated forms), which can affect the stability, solubility, bioavailability or pharmacokinetics (e.g., absorption, distribution, metabolism, excretion, etc.) and / or bioequivalence of the drug, and it is crucial in drug development to identify a pharmaceutical compound in an optimal physical form (e.g., free base or salt in solid, liquid, crystalline, hydrated, solvated, amorphous or polymorphic form).

[0005] Amorphous forms of many drugs exhibit superior dissolution properties and in some cases different bioavailability patterns compared to crystalline forms. Amorphous solid dispersions are sometimes used for poorly soluble pharmaceutical compounds in development. These systems consist of an amorphous active pharmaceutical ingredient stabilized by a polymer or excipient, creating a system with improved physical and solution stability. Amorphous solid dispersions may therefore be used as a means to improve the solubility of active pharmaceutical ingredients.

[0006] However, amorphous solid dispersions have been shown to be prone to change during storage and therefore not stable over time. For example, an amorphous solid dispersion of a drug in an excipient may separate into drug-rich fractions and / or convert to one or more crystalline polymorphs over time. An ideal drug formulation should be as physically stable as possible in normal storage environments. Otherwise, such drug formulations may entail additional logistical requirements and / or burdensome limitations in prescription and patient use. A major problem with amorphous solid dispersions of drugs is that while the dispersions may show enhanced bioavailability of poorly soluble drugs when administered immediately after manufacture, in typical storage environments, the bioavailability typically decreases over time. Such solid dispersions are often physically unstable in that the drug present in the dispersion reverts to a crystalline form upon storage, especially at high temperatures and humidity. Thus, the dispersions cannot be used to provide adequate dosing of the drug, as the bioavailability of the drug changes over time.

[0007] Therefore, it is desirable to obtain a composition comprising (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 in free base or pharma- ceutical acceptable salt form and additives, which has improved properties, such as solubility and / or bioavailability.It is also desirable for such compositions to be stable for long periods of time. Summary of the Invention

[0008] The present invention provides compositions (e.g., amorphous solid dispersions) comprising (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 with improved properties, such as improved solubility and / or improved bioavailability. The present invention also provides compositions (i.e., amorphous solid dispersions) that are stable for extended periods of time.

[0009] In a first aspect, the disclosure provides an amorphous solid dispersion comprising (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 (Compound 1) in free base or pharma- ceutically acceptable salt form and an excipient. In certain embodiments, the additive is one or more of cellulose; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500-50,000 daltons, e.g., PEG 1000 or PEG 10000); monostearin; polyvinylpyrrolidone; PEG / PPG block copolymers (e.g., poloxamers (e.g., poloxamer 407, Pluronic F127)); ascorbic acid (i.e., L-ascorbic acid); butylated hydroxyanisole; sodium dodecyl sulfate; cyclodextrins (e.g., β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin); or combinations thereof. In various embodiments, the composition is stable for extended periods of time (e.g., under accelerated storage conditions, e.g., at 40° C. and 75% relative humidity, e.g., about 1 day, about 3 days, or about 7 days).

[0010] In a second aspect, the present disclosure provides a method for preparing an amorphous solid dispersion comprising (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 (Compound 1) and an additive, the method comprising the steps of: a) dissolving compound 1 in a first solvent b) dissolving the additive in a second solvent; c) combining the solutions from steps a) and b); and d) removing the solvent from the mixture. In certain embodiments, the solvent removal step comprises freeze-drying and / or evaporation. That is, the solvent removal step can comprise freezing the mixture at a temperature of 0°C or less, for example -10°C or less, for example -20°C or less, and then evaporating the solvent under reduced pressure (for example 0 bar), for example at room temperature.

[0011] In a third aspect, the present disclosure provides an amorphous solid dispersion comprising (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 (Compound 1) in free base or pharma- ceutically acceptable salt form and an excipient, comprising the steps of: a) dissolving compound 1 in a first solvent b) dissolving the additive in a second solvent; c) combining the solutions from steps a) and b); and d) removing the solvent from the mixture. The present invention provides a dispersion obtained or obtainable by a process comprising:

[0012] In a fourth aspect, the disclosure relates to a method for the treatment of a neurodegenerative disease; a psychiatric disorder; a circulatory or cardiovascular disorder; a respiratory or inflammatory disorder; a disease that may be alleviated by enhancing progesterone signaling, such as female sexual dysfunction; glaucoma, or elevated intraocular pressure; a traumatic brain injury; a cancer or tumor; a renal disorder; any disease or condition characterized by low levels of cAMP and / or cGMP in cells expressing PDE1 (or inhibition of the cAMP and / or cGMP signaling pathway); or any disease or condition characterized by reduced dopamine D1 receptor signaling activity. The present invention relates to a method for preventing or treating a patient, e.g., a human, suffering from a disorder selected from one or more of the following conditions, comprising administering to a patient in need of the prevention or treatment a therapeutically effective amount of an amorphous solid dispersion comprising (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 (Compound 1) and an additive. In certain embodiments, Compound 1 is administered in an amount of about 0.5 mg to about 300 mg, the amount being calculated as free base equivalent.

[0013] Additional features and advantages of various embodiments will be set forth in part in the description which follows, and in part will be apparent from the description and examples. The objectives and other advantages of the various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The term "amorphous" as used herein means a solid that does not have long-range crystalline order. The term "amorphous" refers to a solid in which the arrangement of molecules is disordered and does not have a discernible crystal lattice. The amorphous form of (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 (Compound 1) according to the present invention preferably contains less than about 10% by weight, preferably less than 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, and more preferably essentially free of the crystalline form of Compound 1. "Essentially free of crystalline forms of Compound 1" means that no crystalline polymorphic forms of Compound 1 are detectable within the limits of the X-ray powder diffractometer.

[0015] The term "dispersion" as used herein refers to a dispersion system in which one substance (dispersed phase) is dispersed throughout a second substance (i.e., continuous phase or medium) in discrete units. The size of the dispersed phase varies (e.g., colloidal particles range in size from nanometer scale to micron scale). For the amorphous solid dispersions of the present disclosure, the dispersed phase and the continuous phase are both solids. In pharmaceutical applications, the solid dispersion may contain crystalline drug (dispersed phase) in an amorphous additive (continuous phase), or amorphous drug (dispersed phase) in an amorphous additive (continuous phase). In some embodiments, it is envisioned that the amorphous solid dispersions of the present disclosure contain additives that constitute the dispersed phase, and the drug constitutes the continuous phase. In other embodiments, the dispersions contain amorphous Compound 1 or substantially amorphous Compound 1.

[0016] The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a drug and a polymer, but which may be other components such as surfactants or other pharmaceutical excipients, where Compound 1 is amorphous or substantially amorphous (e.g., substantially free of crystalline Compound 1), and the physical stability and / or dissolution and / or solubility of the amorphous drug is enhanced by the other components.

[0017] As used herein, the terms "crystal" or "crystals" or "crystalline" or "crystallinic" refer to any solid in which molecules, atoms, or ions have short- or long-range order in a fixed lattice arrangement.

[0018] The amorphous solid dispersion of the present disclosure may have a ratio of Compound 1 to additive of about 5:1 to 1:5. For example, in various embodiments, the ratio of Compound 1 to additive may be 1:2 to 2:1, such as 1:1, 1:2, or 2:1.

[0019] Unless further modified, the term "Compound 1" 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)-cyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one, having the following structure: [ka]

[0020] The crystallinity or morphology of the amorphous forms of the present disclosure may be determined by a number of methods, including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared absorption spectroscopy, and Raman spectroscopy.

[0021] The term "about" before a numerical value refers to an approximation that may vary depending on the desired properties sought to be obtained by the present application. Each numerical value described herein can be interpreted by taking into account at least ordinary rounding techniques. When referring to temperature, the term "about" refers to ±10°C, preferably ±5°C, preferably ±3°C of the reference temperature of the temperature value itself.

[0022] The amorphous solid dispersion of the present disclosure comprises a selective PDE1 inhibitor.Accordingly, the amorphous solid dispersion of the present disclosure is useful for treating PDE1-related disorders, for example, as described in WO2014 / 151409, WO2018 / 049417, WO2019 / 227004, WO2019 / 152697, WO2009 / 075784, WO2010 / 132127, WO2006 / 133261 and WO2011 / 153129 (the contents of each of which are incorporated by reference in their entirety).

[0023] 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.

[0024] In a first aspect, the present disclosure provides an amorphous solid dispersion (Dispersion 1) comprising (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 (Compound 1) and an additive. For example, the present disclosure provides the following embodiment of Dispersion 1: 1.1 Dispersion 1, wherein Compound 1 is in a free base or pharma- ceutically acceptable salt form. 1.2 Dispersion 1 or 1.1, wherein compound 1 is in free base form. 1.3 Any of the preceding dispersions wherein Compound 1 is in a salt form. 1.4 Any of the preceding dispersions wherein Compound 1 is in the phosphate salt form. 1.5 Any of the preceding dispersions wherein Compound 1 is in the monophosphate form. 1.6 Any of the preceding dispersions wherein the additive comprises cellulose; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); monostearin; polyvinylpyrrolidone; PEG / PPG block copolymers (e.g., poloxamer (e.g., poloxamer 407, Pluronic F127)); ascorbic acid (i.e., L-ascorbic acid); butylated hydroxyanisole; sodium dodecyl sulfate; cyclodextrin (e.g., β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin); or combinations thereof. 1.7 Any of the preceding dispersions wherein the additive comprises cellulose; hydroxypropyl cellulose; methyl cellulose; hydroxypropyl methylcellulose; sodium dodecyl sulfate; ascorbic acid (e.g., L-ascorbic acid); β-cyclodextrin; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); PEG / PPG block copolymers (e.g., poloxamer (e.g., poloxamer 407, e.g., Pluronic F127)); butylated hydroxyanisole; monostearin; or combinations thereof. 1.8 Any of the preceding dispersions wherein the additive comprises a member of the group selected from cellulose; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); monostearin; polyvinylpyrrolidone; PEG / PPG block copolymers (e.g., poloxamer (e.g., poloxamer 407, pluronic F127)); ascorbic acid (i.e., L-ascorbic acid); butylated hydroxyanisole; sodium dodecyl sulfate; cyclodextrins (e.g., β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin); and combinations thereof. 1.9 Any of the preceding dispersions wherein the additive comprises a member of the group selected from cellulose; hydroxypropyl cellulose; methyl cellulose; hydroxypropyl methyl cellulose; sodium dodecyl sulfate; ascorbic acid (e.g., L-ascorbic acid); β-cyclodextrin; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); PEG / PPG block copolymers (e.g., poloxamer (e.g., poloxamer 407, Pluronic F127)); butylated hydroxyanisole; monostearin; and combinations thereof. 1.10 Any of the preceding dispersions wherein the additive comprises one or more of: cellulose; cyclodextrin; polyvinylpyrrolidone; ascorbic acid (e.g., L-ascorbic acid), or combinations thereof. 1.11 Any of the preceding dispersions wherein the additive comprises one or more of cellulose, methylcellulose; hydroxypropyl methylcellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyvinylpyrrolidone (e.g., K85-K95); ascorbic acid (e.g., L-ascorbic acid); or combinations thereof. 1.12 Any of the preceding dispersions wherein the additive is selected from the group consisting of cellulose; methylcellulose; hydroxypropyl methylcellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyvinylpyrrolidone (e.g., K85-K95); ascorbic acid (e.g., L-ascorbic acid); and combinations thereof. 1.13 Any of the preceding dispersions wherein compound 1 and additive are present in a molar ratio of 1:5 to 5:1. 1.14 Any of the preceding dispersions wherein compound 1 and additive are present in a molar ratio of 1:2 to 2:1. 1.15 Any of the preceding dispersions wherein compound 1 and additive are present in a 1:1 molar ratio. 1.16 Any of the preceding dispersions wherein compound 1 and additive are present in a molar ratio of 1:2. 1.17 Any of the preceding dispersions wherein compound 1 and additive are present in a molar ratio of 2:1. 1.18 Any of the preceding dispersions wherein the amorphous solid dispersion is in powder form. 1.19 Any of the preceding dispersions where the amorphous solid dispersion is present as the active ingredient in a tablet, e.g., an orally disintegrating tablet (ODT), a sustained release tablet, an enteric coated tablet, a capsule, e.g., a sustained release capsule, an enteric coated capsule, a multiparticulate or an injectable suspension. 1.20 Any of the preceding dispersions, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of from about 0.5 mg to about 300 mg, said amount being calculated as the free base equivalent. 1.21 Any of the preceding dispersions, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of from about 1 mg to about 100 mg, said amount being calculated as the free base equivalent. 1.22 Any of the preceding dispersions, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of from about 10 mg to about 90 mg, said amount being calculated as the free base equivalent. 1.23 Any of the preceding dispersions, wherein Compound 1 is administered in an amount of from about 30 mg to about 90 mg, said amount being calculated as the free base equivalent. 1.24 Any of the preceding dispersions, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of about 10 mg, about 30 mg, or about 90 mg, said amount being calculated as the free base equivalent. 1.25 Any of the preceding dispersions, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of about 30 mg, said amount being calculated as the free base equivalent. 1.26 Any of the preceding dispersions, wherein the solid amorphous dispersion is stable for about 1 day, about 3 days, or about 7 days. 1.27 Any of the preceding dispersions, wherein the solid amorphous dispersion is stable under accelerated storage conditions (e.g., 40° C. and 75% relative humidity) for about 1 day, about 3 days, or about 7 days. 1.28 Any of the preceding dispersions wherein the amorphous solid dispersion is stable under accelerated storage conditions (e.g., 40° C. and 75% relative humidity) for about 7 days. 1.29 Any of the preceding dispersions in which the amorphous solid dispersion is formed by using freeze-drying. 1.30 Any of the preceding dispersions in which an amorphous solid dispersion is formed by using evaporation. 1.31 Any of the preceding dispersions wherein Compound 1 is in free base form and the excipient is selected from cellulose; hydroxypropyl cellulose; methyl cellulose; hydroxypropyl methyl cellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate phthalate; polyvinylpyrrolidone; and combinations thereof, and the molar ratio of Compound 1 to excipient is 1:1, 1:2 or 2:1, and optionally, the amorphous solid dispersion is formed by using lyophilization. 1.32 Any of the preceding dispersions wherein Compound 1 is in free base form and the additive is selected from cellulose; methylcellulose; hydroxypropylmethylcellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; L-ascorbic acid; and combinations thereof, and the molar ratio of Compound 1 to additive is 1:1, 1:2 or 2:1, and optionally, an amorphous solid dispersion is formed by using evaporation. 1.33 Any of the preceding dispersions, wherein Compound 1 is in the form of a phosphate salt (e.g., monophosphate salt), and the additive is selected from cellulose; methylcellulose; hydroxypropylmethylcellulose; cellulose acetate; and combinations thereof, and the molar ratio of Compound 1 to additive is 1:1, 1:2 or 2:1, and optionally, the amorphous solid dispersion is formed by using lyophilization. 1.34 Any of the preceding dispersions wherein compound 1 is in the form of a phosphate salt (e.g., monophosphate salt) and the additive is selected from cellulose; hydroxypropyl cellulose; methyl cellulose; hydroxypropyl methyl cellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyvinylpyrrolidone; and combinations thereof, and the molar ratio of compound 1 to additive is 1:1, 1:2 or 2:1, and optionally, an amorphous solid dispersion is formed by using evaporation. 1.35 Any of the preceding dispersions wherein Compound 1 is in a substantially amorphous solid form. 1.36 Any of the preceding dispersions wherein Compound 1 is amorphous and contains less than 10% by weight of a crystalline form of Compound 1. 1.37 Any of the preceding dispersions wherein Compound 1 is amorphous and contains less than 5% by weight of a crystalline form of Compound 1. 1.38 Any of the preceding dispersions wherein Compound 1 is amorphous and contains less than 1% by weight of a crystalline form of Compound 1. 1.39 Any of the preceding dispersions wherein Compound 1 is amorphous and contains less than 0.1% by weight of a crystalline form of Compound 1. 1.40 Any of the preceding dispersions wherein Compound 1 is amorphous and contains less than 0.01% by weight of a crystalline form of Compound 1. 1.41 Any of the preceding dispersions wherein Compound 1 is amorphous and essentially free of crystalline forms of Compound 1. 1.42 Any of the preceding dispersions in which the additive is amorphous.

[0025] In a second aspect, the disclosure provides a method for preparing an amorphous solid dispersion (e.g., Dispersion 1 or later) comprising (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 (Compound 1) and an additive, the method comprising the steps of: a) dissolving compound 1 in a first solvent b) dissolving the additive in a second solvent; c) combining the solutions from steps a) and b); and d) removing the solvent from the mixture. The present invention provides a method (Method 1), which includes the steps of:

[0026] For example, the present disclosure provides the following embodiments of Method 1: 1.1 Method 1, wherein the solid amorphous dispersion is according to any of Dispersion 1 onwards. 1.2 Method 1 or 1.1, wherein the first solvent comprises one or more of water, acetone, dichloromethane, an alcohol (e.g., methanol or ethanol), dioxane, tetrahydrofuran, acetonitrile, and combinations thereof. 1.3 Any of the preceding methods, wherein the first solvent is acetone; dichloromethane; dioxane; dioxane and methanol (e.g. in a 1:1 ratio); acetone and ethanol (e.g. in a 3:1 ratio); dioxane and water (e.g. in a 9:1 ratio); tetrahydrofuran and water (e.g. in a 9:1 ratio); methanol and water (e.g. in a 9:1 ratio); or acetonitrile and water (e.g. in a 9:1 ratio). 1.4 Any of the preceding methods, wherein the first solvent is acetone; dichloromethane; or acetone and ethanol (e.g., in a 3:1 ratio). 1.5 Any of the preceding methods, wherein the first solvent is tetrahydrofuran and water (eg, in a 9:1 ratio); methanol and water (eg, in a 9:1 ratio); or acetonitrile and water (eg, in a 9:1 ratio). 1.6 Any of the preceding processes, wherein the second solvent is water and / or methanol. 1.7 Any of the preceding methods, wherein the step of removing the solvent from the mixture comprises freeze-drying and / or evaporation. 1.8 The preceding method, wherein the removing step includes freeze-drying and evaporation. 1.9 The preceding process, wherein the removal step comprises freezing the mixture at a temperature of 0° C. or below, such as −10° C. or below, such as −20° C. or below, followed by evaporation of the solvent under reduced pressure (e.g. 0 bar), e.g. at room temperature. 1.10 The removal step comprises evaporating the solvent under reduced pressure (e.g. 0 bar), e.g. at room temperature. Any of methods 1 or 1.1-1.7.

[0027] In a third aspect, the present disclosure provides an amorphous solid dispersion comprising (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 (Compound 1) and an additive, as described in Dispersion 1 et seq., obtained or obtainable by the method described in Method 1 et seq.

[0028] In a fourth aspect, the present disclosure provides a method for producing a composition comprising: A. Neurodegenerative diseases (including Parkinson's disease, restless legs syndrome, 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 disorders, 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 heart 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, e.g., female sexual dysfunction; F. A disease or disorder, such as psychiatric illness, glaucoma, or elevated intraocular pressure; G. Traumatic brain injury; H. A cancer or tumor, e.g., a brain tumor, a glioma (e.g., ependymoma, astrocytoma, oligodendroglioma, brain stem glioma, optic nerve glioma, or a mixed glioma, e.g., oligoastrocytoma), an astrocytoma (e.g., glioblastoma multiforme), osteosarcoma, melanoma, leukemia, neuroblastoma, or leukemia; I. Renal disorders, such as renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis; J. Any 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. Any disease or condition characterized by decreased dopamine D1 receptor signaling activity The present disclosure further provides a method for preventing or treating a patient, e.g., a human, suffering from a disorder selected from the group consisting of the following, comprising administering to a patient in need of the prevention or treatment a therapeutically effective amount of an amorphous solid dispersion comprising (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 (Compound 1) and an additive, as described, for example, in Dispersion 1 and thereafter of the present disclosure (Method 2). For example, the present disclosure further provides the following embodiments: 2.1 Any of the preceding methods, wherein the amorphous solid dispersion is in powder form. 2.2 Any of the preceding processes, wherein the amorphous solid dispersion is present as the active ingredient in a tablet, e.g., an orally disintegrating tablet (ODT), a sustained release tablet, an enteric coated tablet, a capsule, e.g., a sustained release capsule, an enteric coated capsule, a multiparticulate or an injectable suspension. 2.3 Any of the preceding methods, wherein Compound 1 is administered in an amount of from about 0.5 mg to about 300 mg, said amount being calculated as the free base equivalent. 2.4 Any of the preceding methods, wherein Compound 1 is administered in an amount of from about 1 mg to about 100 mg, said amount being calculated as the free base equivalent. 2.5 Any of the preceding methods, wherein Compound 1 is administered in an amount of about 10 mg to about 90 mg, said amount being calculated as the free base equivalent. 2.6 Any of the preceding methods, wherein Compound 1 is administered in an amount of about 30 mg to about 90 mg, said amount being calculated as the free base equivalent. 2.7 Any of the preceding methods, wherein Compound 1 is administered in an amount of about 10 mg, about 30 mg, or about 90 mg, said amount being calculated as the free base equivalent. 2.8 Any of the preceding methods, wherein Compound 1 is administered in an amount of about 30 mg, said amount being calculated as the free base equivalent.

[0029] A pharmaceutical composition comprising Dispersion 1 et seq. for use as a medicament, for example for use in the manufacture of a medicament for the treatment or prevention of a disease as described in Method 2 et seq.

[0030] The present disclosure further provides Dispersions 1 et seq. for use in any of Methods 2 et seq.

[0031] The disclosure further provides the use of Dispersion 1 et seq. in the manufacture of a medicament for use in any of Methods 2 et seq.

[0032] Without being bound by theory, it is believed that the amorphous solid dispersion of the present disclosure is substantially homogeneous, with the amorphous PDE1 inhibitor being dispersed as homogeneously as possible throughout the additive. As used herein, "substantially homogeneous" means that there is little or no presence of purely amorphous regions in the solid dispersion. For example, the percentage of amorphous regions of the PDE1 inhibitor accounts for less than 10% of the amorphous solid dispersion, preferably less than 5% of the amorphous solid dispersion, more preferably less than 1% of the amorphous solid dispersion, and more preferably there are no such regions. Although there may be some drug-rich regions in the dispersion, the dispersion itself preferably has a single glass transition temperature, which indicates that the dispersion is substantially homogeneous. In contrast, a physical mixture of purely amorphous drug particles and purely amorphous additive particles generally exhibits two different glass transition temperatures.

[0033] Particle size and temperature drying range can be varied to produce an optimal solid dispersion. Smaller particle size generally improves solvent removal. Generally, particle size can vary from nanometer scale to micron scale.

[0034] The present disclosure further provides pharma- ceutically acceptable compositions comprising the amorphous solid dispersions described herein and, optionally, a pharma- ceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0035] It should also be understood that compound 1 may be present for treatment in free form or, where appropriate, as a pharma- ceutically acceptable derivative or prodrug thereof. In accordance with the present disclosure, a pharma- ceutically acceptable derivative or prodrug includes, but is not limited to, a pharma- ceutically acceptable salt, ester, salt of such an ester, or other adduct or derivative that, upon administration to a patient in need thereof, can provide, directly or indirectly, a compound as described elsewhere herein, or a metabolite or residue thereof.

[0036] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with human and / or animal tissues without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to a non-toxic salt or ester salt of Compound 1 that, upon administration to a recipient, is capable of directly or indirectly providing Compound 1 or an active metabolite or residue thereof.

[0037] Pharmaceutically acceptable salts of Compound 1 described herein include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharma-ceutically acceptable salts include fumarate, hydrochloride, (1-hydroxy-2)-naphthoate, benzosulfonate, phosphate, mesylate, tartrate, sulfate and hydrobromide salts.

[0038] The pharma- ceutically acceptable compositions of the present disclosure may further comprise a pharma- ceutically acceptable carrier, adjuvant or vehicle, which as used herein includes any solvent, diluent or other liquid vehicle, dispersing or suspending agent, surface active agent (i.e., surfactant), isotonicity agent, thickening or emulsifying agent, preservative, solid binder, lubricant, etc., appropriate for the particular dosage form desired. One of skill in the art will appreciate that any conventional carrier medium or excipient compatible with the amorphous solid dispersions of the present disclosure may be used in such compositions. Examples of materials which may be used as pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose. and cellulose acetate; powdered tragacanth; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffers, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition.

[0039] Non-limiting examples of suitable surfactants include fatty acid and alkyl sulfonates; commercially available surfactants such as sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; sodium lauryl sulfate (SLS); sodium dodecylbenzenesulfonate (SDBS), sodium dioctyl sulfosuccinate; dioxycholic acid sodium salt (DOSS); sorbitan monostearate; sorbitan tristearate; hexadecyltrimethylammonium bromide (HTAB); sodium N-lauroyl sarcosine; sodium oleate. sodium myristate; sodium stearate; sodium palmitate; Gelucir 44 / 14; ethylenediaminetetraacetic acid (EDTA); Vitamin Ed-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS); lecithin; monosodium glutamate monohydrate; Labrasol; PEG 8 caprylic / capric glyceride; Transcutol; diethylene glycol monoethyl ether; Solutol HS-15; polyethylene glycol / hydroxystearate; taurocholic acid; pluronic F68; pluronic F108; pluronic F127 (or other polyoxyethylene-polyoxypropylene copolymers); or saturated polyglycolized glycerides (Gelucirs®).

[0040] The addition of pH adjusters, such as acids, bases or buffers, may also be beneficial to retard dissolution or enhance the dissolution rate of the dispersion. The addition of matrix materials, surfactants, excipients, disintegrants or binders may be added as part of the dispersion itself or by granulation by wet, mechanical or other means.

[0041] Examples of other matrix materials, additives or diluents include lactose, mannitol, xylitol, crystalline cellulose, calcium diphosphate, starch, polyoxamers such as polyethylene oxide and hydroxypropylmethylcellulose. Examples of drug complexing agents include polyethylene glycol, caffeine, xanthene, gentisic acid and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose and croscarmellose sodium. Examples of binders include methylcellulose, crystalline cellulose, starch, and gums such as guar gum and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Exemplary pH adjusting agents include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide; and buffers which generally comprise a mixture of an acid and a salt of the acid.

[0042] In some embodiments, the composition may be coated with an enteric polymer to prevent or delay dissolution until the dosage form leaves the stomach.Exemplary enteric coating materials include HPMCAS, HPMCP, cellulose acetate phthalate, cellulose acetate trimellitate, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.

[0043] In addition to the additives or excipients described above, the use of any conventional materials and procedures for formulating and manufacturing various dosage forms with the compositions of the present disclosure known to those of skill in the art is potentially useful.

[0044] The pharma- ceutical acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (by powders, ointments or drops), bucally, as an oral or nasal spray, or the like.

[0045] In some embodiments, the composition of the present disclosure can be used in a wide variety of forms for oral administration of drugs.Exemplary dosage forms can be powder or granules that can be taken orally in a dry state or by adding water to reconstitute to form paste, slurry, suspension or solution; tablets, such as oral disintegrating tablets (ODT), sustained release tablets, enteric-coated tablets, capsules, such as sustained release capsules, enteric-coated capsules, multiparticulates or pills.Various additives can be mixed, ground or granulated with the composition of the present disclosure to form materials suitable for the above dosage forms.Potentially useful additives are generally classified into other matrix materials or diluents, surfactants, drug complexing or solubilizing agents, excipients, disintegrants, binders, lubricants and pH adjusting agents (e.g. acids, bases or buffers).

[0046] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as water, acetone, dichloromethane, alcohol (e.g., methanol or ethanol), dioxane, tetrahydrofuran, acetonitrile, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and combinations thereof.In addition to inert diluents, oral compositions can contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and aromas.

[0047] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can be, for example, sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions.Vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution.Also, sterile fixed oils are conventionally used as solvents or suspension media.

[0048] Other features and embodiments of the present disclosure will become apparent from the following examples, which are provided to illustrate the present disclosure, but not to limit the intended scope of the disclosure. EXAMPLES

[0049] Example 1: Preparation of an amorphous solid dispersion containing the free base using lyophilization 5 mg of compound 1 free base is dissolved in acetone (500 μl) or dichloromethane (500 μl) and the additive is dissolved in either water (500 μl) or methanol (500 μl) depending on solubility. The free base solution and the additive solution are added to each other. For experiments without water, a few drops of water are added. The samples are then stored in a freezer (-20°C) for 16 hours and then in vacuum (0 mbar, RT) for rapid evaporation of the solvent. Experiments are performed with molar ratios of free base to additive of 1:1, 1:2 and 2:1. The appearance is recorded and the XPDR is measured on the observed solids. Experiments marked "N / A" were not performed due to the immiscibility of dichloromethane and water. [Table 1] [Table 2] [Table 3]

[0050] The solids designated as "glass / oil" are amorphous but were not tested for stability. The solids designated as "amorphous" are stored at 40° C. and 75% relative humidity for one week and stability is confirmed by PXRD at various time points. The results confirmed that each of the solids designated as "amorphous" remained stable for one week under these accelerated storage conditions.

[0051] Example 2: Preparation of an amorphous solid dispersion containing free base using evaporation 5 mg of compound 1 free base is dissolved in acetone (500 μl), dichloromethane (500 μl) or acetone / ethanol (3:1), and the additive is dissolved in either water (500 μl) or methanol (500 μl) depending on solubility. The free base solution and the additive solution are added to each other. For experiments without water, a few drops of water are added. The samples were then stored in vacuum (0 mbar, RT) for rapid evaporation of the solvent. Experiments are performed with molar ratios of free base to additive of 1:1, 1:2 and 2:1. The appearance is recorded and the XPDR is measured on the observed solids. Experiments marked "N / A" were not performed due to the immiscibility of dichloromethane and water. [Table 4] [Table 5] [Table 6]

[0052] Solids labeled "glass / oil" are amorphous but were not tested for stability. Solids labeled "amorphous" are stored at 40° C. and 75% relative humidity for one week and stability is confirmed by PXRD at various time points. Several amorphous patterns are observed depending on the solvent and ratio. Stability experiments show transformation of crystalline patterns in some of the experiments. Products that remained amorphous are shown below. [Table 7]

[0053] Example 3: Preparation of an amorphous solid dispersion containing phosphate salt using freeze-drying 5 mg of the monophosphate of compound 1 are dissolved in acetonitrile / water (9:1) (500 μl) and the additive is dissolved either in water (500 μl) or in methanol (500 μl) depending on the solubility. The phosphate solution and the additive solution are added to each other. For experiments without water, a few drops of water are added. The samples are subsequently stored in a freezer (-20 °C) for 16 h and then in vacuum (0 mbar, RT) for rapid evaporation of the solvent. Experiments are carried out with molar ratios of phosphate to additive of 1:1, 1:2 and 2:1. The appearance is recorded and the XPDR is measured on the observed solids. [Table 8] [Table 9] [Table 10]

[0054] The solids designated as "glass / oil" are amorphous but were not tested for stability. The solids designated as "amorphous" are stored at 40° C. and 75% relative humidity for one week and stability is confirmed by PXRD at various time points. The results confirmed that each of the solids designated as "amorphous" remained stable for one week under these accelerated storage conditions.

[0055] Example 4: Preparation of an amorphous solid dispersion containing phosphate using evaporation 5 mg of compound 1 phosphate is dissolved in acetonitrile / water 9:1 (500 μl), tetrahydrofuran / water 9:1 (500 μl) or methanol / water 9:1 (500 μl) and the additive is dissolved in either water or methanol (500 μl) depending on the solubility. The phosphate solution and the additive solution are added to each other. The samples were subsequently stored in vacuum (0 mbar, RT) for rapid evaporation of the solvent. Experiments are carried out with phosphate to additive molar ratios of 1:1, 1:2 and 2:1. The appearance is recorded and the XPDR is measured on the observed solids. [Table 11] [Table 12] [Table 13]

[0056] Solids labeled "glass / oil" are amorphous but were not tested for stability. Solids labeled "amorphous" are stored at 40° C. and 75% relative humidity for one week and stability is confirmed by PXRD at various time points. Several amorphous patterns are observed depending on the solvent and ratio. Stability experiments show transformation of crystalline patterns in some of the experiments. Products that remained amorphous are shown below. [Table 14]

Claims

1. An amorphous solid dispersion comprising (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 (Compound 1) in free base or pharmaceutically acceptable salt form and an excipient.

2. 10. The amorphous solid dispersion of claim 1, wherein Compound 1 is in free base form.

3. 10. The amorphous solid dispersion of claim 1, wherein Compound 1 is in the form of a phosphate salt.

4. 2. The amorphous solid dispersion of claim 1, wherein the excipient comprises cellulose; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); monostearin; polyvinylpyrrolidone; PEG / PPG block copolymer (e.g., poloxamer (e.g., poloxamer 407, pluronic F127)); ascorbic acid (i.e., L-ascorbic acid); butylhydroxyanisole; sodium dodecyl sulfate; cyclodextrin (e.g., β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin); or combinations thereof.

5. 2. The amorphous solid dispersion of claim 1, wherein the excipient comprises cellulose; hydroxypropyl cellulose; methylcellulose; hydroxypropylmethylcellulose; sodium dodecyl sulfate; ascorbic acid (e.g., L-ascorbic acid); β-cyclodextrin; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyethylene glycol (e.g., polyethylene glycol having a molecular weight of 500 to 50,000 daltons, e.g., PEG 1000 or PEG 10000); PEG / PPG block copolymer (e.g., poloxamer (e.g., poloxamer 407, pluronic F127)); butylhydroxyanisole; monostearin; or combinations thereof.

6. 2. The amorphous solid dispersion of claim 1, wherein the excipient comprises cellulose, methylcellulose; hydroxypropylmethylcellulose; (2-hydroxypropyl)-β-cyclodextrin; cellulose acetate; cellulose acetate phthalate; polyvinylpyrrolidone (e.g., K85-K95); ascorbic acid (e.g., L-ascorbic acid); or a combination thereof.

7. 2. The amorphous solid dispersion of claim 1, wherein Compound 1 and the additive are present in a molar ratio of 1:5 to 5:1, such as a molar ratio of 1:2 to 2:1, such as a molar ratio of 1:1, 1:2, or 2:

1.

8. 10. The amorphous solid dispersion of claim 1, wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of about 0.5 mg to about 300 mg, calculated as a free base equivalent, optionally wherein the amorphous solid dispersion is a dosage form comprising Compound 1 in an amount of about 30 mg to about 90 mg, calculated as a free base equivalent.

9. 10. The amorphous solid dispersion of claim 1, wherein the amorphous solid dispersion is stable under accelerated storage conditions (e.g., 40°C and 75% relative humidity) for about 1 day, about 3 days, or about 7 days.

10. 2. The amorphous solid dispersion of claim 1, wherein Compound 1 is amorphous and comprises less than 10% by weight of a crystalline form of Compound 1, such as less than 5% by weight of a crystalline form of Compound 1, such as less than 1% by weight of a crystalline form of Compound 1, such as less than 0.1% by weight of a crystalline form of Compound 1, such as less than 0.01% by weight of a crystalline form of Compound 1, such as essentially free of a crystalline form of Compound 1.

11. 11. A method for producing an amorphous solid dispersion comprising (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 (Compound 1) according to any one of claims 1 to 10 and an additive, the method comprising the steps of: a) dissolving compound 1 in a first solvent b) dissolving the additive in a second solvent; c) combining the solutions from steps a) and b); and d) removing the solvent from the mixture. A method comprising:

12. 12. The method of claim 11, wherein the first solvent comprises one or more of water, acetone, dichloromethane, an alcohol (e.g., methanol or ethanol), dioxane, tetrahydrofuran, acetonitrile, and combinations thereof, and optionally the first solvent is acetone; dichloromethane; acetone and ethanol (e.g., in a 3:1 ratio); tetrahydrofuran and water (e.g., in a 9:1 ratio); methanol and water (e.g., in a 9:1 ratio); or acetonitrile and water (e.g., in a 9:1 ratio).

13. 12. The method of claim 11, wherein the second solvent is water and / or methanol.

14. 12. The method of claim 11, wherein the step of removing the solvent from the mixture comprises freeze-drying and / or evaporation, and optionally the removing step comprises freeze-drying and evaporation.

15. 12. The method of claim 11 , wherein the removing step comprises freezing the mixture at a temperature of 0° C. or below, such as −10° C. or below, for example −20° C. or below, followed by evaporation of the solvent under reduced pressure (e.g., 0 bar).

16. 12. The method of claim 11, wherein the removing step comprises evaporating the solvent under reduced pressure (e.g., 0 bar).

17. the below described: i. Neurodegenerative diseases (including Parkinson's disease, restless legs syndrome, tremors, dyskinesia, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders); ii. Psychiatric disorders (including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorders, sleep disorders such as narcolepsy, cognitive disorders such as those in schizophrenia, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction); iii. circulatory and cardiovascular disorders (including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, e.g., pulmonary arterial hypertension, and sexual dysfunction (including cardiovascular disease and related disorders)); iv. Respiratory and inflammatory disorders (including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases); v. Diseases that can be alleviated by enhancing progesterone signaling, such as female sexual dysfunction; vi. a disease or disorder, such as psychiatric disease, glaucoma, or elevated intraocular pressure; vii. Traumatic brain injury; viii. a cancer or tumor, such as a brain tumor, glioma (e.g., ependymoma, astrocytoma, oligodendroglioma, brain stem glioma, optic nerve glioma, or mixed glioma, e.g., oligoastrocytoma), astrocytoma (e.g., glioblastoma multiforme), osteosarcoma, melanoma, leukemia, neuroblastoma, or leukemia; ix. Kidney disorders, such as renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, and nephritis; x. any 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 xi. Any disease or condition characterized by decreased dopamine D1 receptor signaling activity 11. A pharmaceutical composition for preventing or treating a disorder selected from the group consisting of: (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 (Compound 1) in free base or pharmaceutically acceptable salt form according to any one of claims 1 to 10; and an excipient.