formulation

Abstract

The present invention relates to a solid dosage form comprising 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), at least one of a first diluent and / or binder, and a lubricant; a process for making the solid dosage form; and the use of the solid dosage form in the treatment of disease.

Description

[Technical Field]

[0001] The present invention relates to solid dosage forms of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. [Background technology]

[0002] 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (also referred to herein as "Compound A") is an allosteric activator of the enzyme beta-glucocerebrosidase (GCase) that is being developed as a potential treatment for Parkinson's disease patients with mutations in the GBA1 gene (GBA-PD).

[0003] Compound A exists in four polymorphic forms: Form A (used in previous Phase I clinical trials), Form B (the thermodynamically most stable form at room temperature), Form C (a metastable form), and Form D (a hydrated form). Previous clinical trials of Compound A used an oral dosage form containing polymorphic Form A.

[0004] Although polymorphic Form B is the most thermodynamically stable, its solid state remains susceptible to hydrolysis and thermal degradation (including thermal degradation to other polymorphic forms, e.g., Form A). It is therefore sensitive to processing conditions commonly used during the preparation of oral dosage forms.

[0005] Furthermore, Compound A exhibits insufficient technical properties for formulation and industrial processing. For example, it has a small particle size, a low bulk density (0.25 g / mL), a low Hausner ratio (1.45), a compressibility index (31), and does not pass through a 10 mm diameter orifice. Furthermore, it exhibits low solubility. This makes it difficult to process and dissolve into clinical or commercial dosage forms such as tablets or capsules.

[0006] Because of these difficulties, early clinical studies used drugs in capsule dosage forms that consisted of filling capsules with precise amounts of compound manually or with non-expandable instruments, a process that was very slow, variable, and not scalable for larger clinical studies or for commercial purposes.

[0007] Therefore, there is a need to provide a robust, reproducible, stable solid dosage form of Compound A and a manufacturing process for producing the same. Summary of the Invention

[0008] In a first aspect of the present invention, a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, and i) a first diluent and / or binder, and ii) Lubricants A solid dosage form comprising at least one of: 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has X-ray peaks at diffraction angles (2θ): 5.7±0.2, 11.8±0.2, 14.4±0.2, 17.2±0.2, 22.2±0.2, 27.2±0.2, 32.5±0.2, or a mixture thereof, preferably 4.0±0.2, 10.9±0.2, 12.3±0.2, 16.2±0.2, 20.2±0.2, 21.1±0.2, 21.5±0.2, 24.7±0.2, 27.6±0.2 A solid dosage form is provided which is a crystalline form characterized by a powder diffraction pattern, or wherein the solid dosage form is characterized by an X-ray powder diffraction pattern comprising a peak at a diffraction angle (2θ): 12.2±0.2.

[0009] In a second aspect of the present invention, a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, and i) a first diluent and / or binder, and ii) Lubricants A solid dosage form comprising at least one of: A solid dosage form is provided in which 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is in a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.7±0.2, 11.8±0.2, 14.4±0.2, 17.2±0.2, 22.2±0.2, 27.2±0.2, 32.5±0.2; or the solid dosage form is characterized by an X-ray powder diffraction pattern comprising peaks (2θ) at 5.6±0.2 and 17.1±0.2.

[0010] A preferred process for forming oral dosage forms is direct powder compression, also known as direct compaction. Direct compression requires less equipment than granulation processes. To provide a direct compression / fill formulation, raw materials must be premixed to provide a uniform tablet and reduce the possibility of segregation. However, compounds with poor technical properties, such as bulk density, particle size, or flow rate, are difficult to process using direct compression / fill. Furthermore, direct compression / filling also makes it difficult to ensure uniformity of compound content in the final matrix. Crystalline Forms A and B of Compound A exhibit very poor technical properties for use in direct compression / fill processes. To obtain a compressible, flowable powder, the inclusion of a first diluent and / or binder and / or lubricant is necessary.

[0011] The solid dosage form of the first aspect of the present invention can be formulated using pure compression without the need to add heat or moisture to the composition, and therefore Compound A in such solid dosage forms does not undergo significant polymorphic transformation to less stable forms.

[0012] In a further embodiment of the first aspect of the present invention, the solid dosage form is characterized by an X-ray diffraction pattern that does not include peaks at diffraction angles (2θ): 5.6±0.2 and 17.1±0.2.

[0013] Peaks at diffraction angles (2θ) 5.6±0.2 and 17.1±0.2 indicate the presence of Form A polymorph of Compound A in the solid dosage form. If the presence of the Form B identifying peak at 12.2°±0.2 is confirmed, and both Form A identifying peaks are also confirmed, then the solid dosage form contains a mixture of both Forms A and B.

[0014] In a further embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, meaning that the crystalline Compound A used to prepare the solid dosage form has been micronized to reduce particle size.

[0015] The particle size (distribution) of micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide can be measured using any method known to those skilled in the art. For example, laser light scattering can be used using dry measurements at 1.0 bar air pressure and 35% feed rate. Particle size can be defined using the parameters D10, D50, and / or D90, or any combination thereof. Parameter D90 is the size distribution. It indicates the point in a fabric below which 90% of the total volume of material in a sample is "contained." For example, if D90 is 60 μm, this means that 90% of the sample has a particle size of 60 μm or less. D50 is defined as the size point below which 50% of the material is contained. Similarly, D10 is the size below which 10% of the material is contained. Possible values ​​for D10, D50, and D90 are defined below. They may be used alone or in combination.

[0016] With the above in mind, in the following description, use of the phrase "micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D90" refers to a particle size where 90% of the total volume of material in a sample is equal to or less than that particle size. For example, the phrase "micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D90:≦100 μm" means that at least 90% of the total volume of material in a sample has a particle size of 100 μm or less. Similarly, the phrase "micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D50 between 1 μm and 60 μm" means that 50% of the total volume of material in a sample has a particle size of between 1 μm and 60 μm. Furthermore, the phrase "micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D10 >= 0.3 μm" means that less than 10% of the total volume of material in a sample has a particle size of less than 0.3 μm.

[0017] Preferably, the particle size of the micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is the particle size of the material used to prepare the solid dosage form. Preferably, this is the particle size of the material prior to preparing the solid dosage form.

[0018] In a further embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size D50 of 1 μm to 60 μm, preferably 3 μm to 50 μm, or more preferably 5 μm to 30 μm.

[0019] In another embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size D10: ≧0.3 μm, preferably ≧0.5 μm, more preferably ≧1 μm.

[0020] In a further embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D90:≦100 μm, preferably ≦80 μm, more preferably ≦60 μm.

[0021] In a further embodiment of the first or second aspect, the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D10: ≧0.3 μm, D50: 1 μm to 60 μm, and D90: ≦100 μm. Preferably, the 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size of D10: ≧0.5 μm, D50: 2 μm to 50 μm, and D90: ≦80 μm, or even more preferably D10: ≧1 μm, D50: 5 μm to The particle size is 30 μm, and D90:≦60 μm.

[0022] If the particle size of the active compound is too large, the pharmacological properties of the active compound may be impaired. For example, large particles may take a long time to dissolve in the intestinal fluids of the patient's gastrointestinal tract, and the compound may have low oral bioavailability. Furthermore, dosage uniformity (e.g., uniformity of Compound A within or within a tablet) may be impaired. If the particle size of Compound A is too small, it may be difficult to prepare tablets. For example, small particles may have poor properties or poor compression characteristics, which may make it difficult to produce tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have insufficient hardness, poor content uniformity, and / or poor mass uniformity. This is particularly important when the manufacturing process is direct compression or capsule filling.

[0023] In a further embodiment of the first or second aspect, the solid dosage form comprises: a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, b) a first diluent and / or binder; and c) Lubricants Includes:

[0024] Surprisingly, the inclusion of diluents and / or binders and lubricants ensures that the mixture has improved flowability, content uniformity, and solubility. Good flowability is necessary to ensure good filling of compression dies for tableting. Insufficient filling of the dies leads to uneven filling and thus to unevenness in the resulting solid dosage form.

[0025] In further embodiments of the first or second aspect, the solid dosage form further comprises a disintegrant. In some embodiments, the solid dosage form further comprises a disintegrant and a glidant. In some embodiments, the solid dosage form comprises a glidant.

[0026] Disintegrants improve the dissolution of Compound A in the patient's gastrointestinal tract and improve the dissolution of the active ingredient in the dosage form. Glidants further improve the flowability of the blend before compression, allowing for uniform filling of the die and easy processing.

[0027] In a further embodiment of the first or second aspect, the solid dosage form comprises a second diluent.

[0028] The inclusion of a second diluent improves the stability of the composition at high temperatures and humidity.

[0029] The range of component ratios can be important to the stability of the resulting composition.

[0030] In further embodiments of the first or second aspect, the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A) in an amount of about 1% to about 60% by weight, preferably about 1% to about 50% by weight, more preferably about 2% to about 40% by weight, and even more preferably about 3% to about 30% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount of about 1% to about 20% by weight, preferably about 1% to about 10% by weight, and even more preferably about 1% to about 5% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount of about 3% to about 5% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount of about 10% to about 40% by weight, preferably about 15% to about 35% by weight, or more preferably about 20% to about 30% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount of about 23% to about 27% by weight. The composition contains Compound A in an amount of about 30% to about 60% by weight, preferably about 35% to about 55% by weight, or more preferably about 40% to about 50% by weight.

[0031] In some embodiments, the solid dosage form has a unit dose of Compound A of about 1 mg to about 200 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 1 mg to about 150 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 1 mg to about 100 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 2 mg to about 90 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 5 mg to about 80 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 1 mg to about 30 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 2 mg to about 20 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 5 mg to about 15 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 10 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 20 mg to about 100 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 30 mg to about 90 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 40 mg to about 80 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 50 mg to about 70 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 60 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 50 mg to about 150 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 70 mg to about 130 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 80 mg to about 120 mg. In some embodiments, the solid dosage form has a unit dose of Compound A of about 90 mg to about 110 mg.

[0032] In further embodiments of the first or second aspect, the solid dosage form comprises a first diluent and / or binder, wherein the first diluent and / or binder is present in an amount of about 20% to about 98% by weight, preferably about 30% to about 80% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 10% to about 40% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 20% to about 50% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 30% to about 60% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 40% to about 70% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 50% to about 80% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 60% to about 90% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 70% to about 98% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 45% to about 55% by weight. In some embodiments, the first diluent and / or binder is present in an amount of about 70% to about 80% by weight.

[0033] In further embodiments of the first or second aspect, the solid dosage form comprises a first diluent, wherein the first diluent is present in an amount of about 20% to about 98% by weight, preferably about 30% to about 80% by weight. In some embodiments, the first diluent is present in an amount of about 10% to about 40% by weight. In some embodiments, the first diluent is present in an amount of about 20% to about 50% by weight. In some embodiments, the first diluent is present in an amount of about 30% to about 60% by weight. In some embodiments, the first diluent is present in an amount of about 40% to about 70% by weight. In some embodiments, the first diluent is present in an amount of about 50% to about 80% by weight. In some embodiments, the first diluent is present in an amount of about 60% to about 90% by weight. In some embodiments, the first diluent is present in an amount of about 70% to about 98% by weight. In some embodiments, the first diluent is present in an amount of about 45% to about 55% by weight. In some embodiments, the first diluent is present in an amount of about 70% to about 80% by weight. It is present in an amount of about 80% by weight.

[0034] The amount of first diluent and / or binder may affect the release characteristics of Compound A. Increasing the concentration of binder may improve tablet properties, particularly hardness and friability, but may slow the release of Compound A in patients.

[0035] In further embodiments of the first or second aspect, the solid dosage form comprises a second diluent, wherein the second diluent is present in an amount of about 3% to about 30% by weight, preferably less than about 10% by weight. In some embodiments, the second diluent is present in an amount of about 0.1% to about 60% by weight, preferably about 0.2% to about 40% by weight, or more preferably about 0.5% to about 30% by weight. In some embodiments, the second diluent is present in an amount of about 1% to about 60% by weight, preferably about 1% to about 40% by weight, or more preferably about 1% to about 30% by weight. In some embodiments, the second diluent is present in an amount of about 0.1% to about 15% by weight, preferably about 0.2% to about 10% by weight, or more preferably about 0.5% to about 5% by weight. In some embodiments, the second diluent is present in an amount of about 10% to about 50% by weight, preferably about 10% to about 40% by weight, or more preferably about 15% to about 35% by weight. In some embodiments, the second diluent is present in an amount of about 5% to about 15% by weight, preferably about 8% to about 12% by weight.

[0036] The amount of the second diluent present in the solid dosage form affects the compression characteristics, i.e., hardness, disintegration, and friability. If the amount of the second diluent is too high, the solid dosage form becomes difficult to compress. If the second diluent is not present in a sufficiently high concentration, the stability of the solid dosage form decreases.

[0037] In some embodiments, the solid dosage form comprises about 40% to about 98% total amount of diluent by weight. In some embodiments, the solid dosage form comprises about 50% to about 98% total amount of diluent by weight. In some embodiments, the solid dosage form comprises about 60% to about 98% total amount of diluent by weight. In some embodiments, the solid dosage form comprises about 70% to about 98% total amount of diluent by weight.

[0038] In further embodiments of the first or second aspect, the solid dosage form comprises a glidant, wherein the glidant is present in an amount of about 0.3% to about 5% by weight, preferably about 0.5% to about 2% by weight. In some embodiments, the glidant is present in an amount of about 0.1% to about 10% by weight, preferably about 0.1% to about 8% by weight, more preferably about 0.25% to about 7% by weight, or even more preferably about 0.2% to about 6% by weight. In some embodiments, the glidant is present in an amount of up to about 10% by weight, preferably up to about 8% by weight, more preferably up to about 7% by weight, or even more preferably up to about 6% by weight.

[0039] The amount of glidant used in a solid dosage form can be important: too much can adversely affect the flowability of the powder mixture by hindering its flow, while too little can cause punch sticking.

[0040] In further embodiments of the first or second aspect, the solid dosage form comprises a disintegrant, wherein the disintegrant is present in an amount of about 1% to about 20% by weight, preferably about 2% to about 10% by weight, and more preferably about 3% to about 7% by weight. In some embodiments, the disintegrant is present in an amount of about 0.1% to about 30% by weight, preferably about 0.1% to about 25% by weight, or more preferably about 0.5% to about 25% by weight. In some embodiments, the disintegrant is present in an amount of about 0.1% to about 5% by weight, preferably about 0.5% to about 5% by weight. In some embodiments, the disintegrant is present in an amount of about 5% to about 30% by weight, preferably about 5% to about 25% by weight. In some embodiments, the disintegrant is present in an amount of up to about 30% by weight, preferably up to about 25% by weight, or more preferably up to about 20% by weight. In some embodiments, the disintegrant is present in an amount of about 0.1% to about 5% by weight, preferably about 0.5% to about 5% by weight. In some embodiments, the disintegrant is present in an amount of up to about 15% by weight, preferably up to about 10% by weight. In some embodiments, the disintegrant is present in an amount of up to about 5% by weight.

[0041] The concentration of disintegrant affects the technical properties of the tablet, ie, hardness and disintegrability, which are important for controlling the dissolution rate of Compound A in the patient.

[0042] In further embodiments of the first or second aspect, the solid dosage form comprises a lubricant, wherein the lubricant is present in an amount of about 5% to about 10% by weight, more preferably about 1% to about 5% by weight. In some embodiments, the lubricant is present in an amount of about 0.1% to about 15% by weight, preferably about 0.1% to about 12% by weight, or even more preferably about 0.2% to about 12% by weight. In some embodiments, the lubricant is present in an amount of about 0.1% to about 7% by weight, preferably about 0.1% to about 6% by weight, or even more preferably about 0.2% to about 5% by weight. In some embodiments, the lubricant is present in an amount of about 0.5% to about 4% by weight, preferably about 1% to about 3% by weight. In some embodiments, the lubricant is present in an amount of about 4% to about 12% by weight, preferably about 5% to about 12% by weight, or even more preferably about 6% to about 12% by weight. In some embodiments, the lubricant is present in an amount of up to about 15% by weight, preferably up to about 12% by weight, or more preferably up to about 10% by weight, hi some embodiments, the lubricant is present in an amount of up to about 7% by weight, preferably up to about 6% by weight, or more preferably up to about 5% by weight.

[0043] The amount of lubricant affects the flowability of the mixture of ingredients. Many failures in pharmaceutical manufacturing operations are caused by problems related to lubrication. For example, if the concentration of lubricant is too high, the stability of Compound A may be adversely affected, the hardness of the dosage form may be reduced, compression may be affected, and the rate of disintegration and dissolution of the dosage form may be increased. If the concentration of lubricant is too low, the ingredients may not be mixed well, resulting in uneven distribution of Compound A in the solid dosage form.

[0044] In a further embodiment of the first or second aspect, the solid dosage form further comprises a coating.

[0045] The inclusion of a coating on the solid dosage form protects Compound A from environmental moisture and provides improved aesthetics. Additionally, the coating improves the color of the resulting solid dosage form. Examples of suitable coatings for use in one embodiment of the present invention include capsule coatings and / or film coatings.

[0046] In further embodiments of the first or second aspect, the solid dosage form includes a binder, and the binder may be present in an amount of about 1% to about 20% by weight, preferably about 2% to about 10% by weight, or more preferably about 3% to about 7% by weight. In some embodiments, the binder may be present in an amount of about 0.1% to about 40% by weight, preferably about 0.2% to about 30% by weight, more preferably about 0.5% to about 25% by weight, or even more preferably about 0.5% to about 25% by weight. In some embodiments, the binder may be present in an amount of about 0.5% to about 20% by weight, preferably about 0.5% to about 15% by weight, or more preferably about 0.5% to about 10% by weight. In some embodiments, the binder may be present in an amount of about 10% to about 40% by weight, preferably about 15% to about 35% by weight, or even more preferably about 18% to about 32% by weight. In some embodiments, the binder may be present in an amount of up to about 40% by weight, preferably up to about 30% by weight, and more preferably up to about 25% by weight, hi some embodiments, the binder may be present in an amount of up to about 20% by weight, up to about 15% by weight, or up to about 10% by weight.

[0047] In a further embodiment of the first or second aspect, the first and / or second diluents independently have a particle size D50 of less than 500 μm, preferably less than 300 μm, more preferably less than 200 μm.

[0048] The particle size of the diluent affects the flow characteristics of the mixture before compression. D50 is the corresponding particle size when the cumulative percentage reaches 50%. D50 is sometimes referred to as the median particle size. For example, for a powder sample with D50 = 250 μm, 50% of the particles are larger than 250 μm and 50% of the particles are smaller than 250 μm. D50 particle size can be measured by any suitable means known in the art, such as dynamic light scattering (DLS), laser diffraction, sieve analysis, dynamic image analysis (DIA), and static image analysis (SIA).

[0049] In a further embodiment of the first or second aspect, the first and / or second diluent independently have a moisture content of less than about 15%, preferably less than about 7%, and further, the first diluent and / or the second diluent have a bulk density of greater than 0.15 g / ml, more preferably greater than or equal to 0.25 g / ml.

[0050] Compound A is susceptible to degradation and / or polymorphic changes upon hydration. Therefore, it is important to control the water content of any solid dosage form.

[0051] In a further embodiment of the first or second aspect, the first and / or second diluent are independently a sugar, e.g., sugar, sucrose, powdered sucrose, fructose, lactose, powdered hydrogenated maltose starch syrup, or syrup), and maltose; sugar alcohols such as D-mannitol, D-sorbitol, xylitol, erythritol, and maltitol; starches such as corn starch, wheat starch, maize starch, and potato starch; starch derivatives such as dextrin and β-cyclodextrin (e.g., starches in which some of the d-glucopyranosyl units in the molecule have been modified, including pregelatinized starch); cellulose or its derivatives such as microcrystalline cellulose, powdered cellulose, and ethyl cellulose; phosphate derivatives (e.g., calcium phosphate, sodium phosphate, potassium phosphate, magnesium phosphate, and ammonium phosphate (monobasic, dibasic, and tribasic)), cellulose, or mixtures thereof. Co-process diluents combining one or more diluents, such as Prosovol®, cellacotse®, combilac®, Disintequik®, and CompactCel®. In some embodiments, the first and / or second diluents are independently selected from cellulose or a derivative thereof, starch or a derivative thereof, lactose, and a phosphate derivative (e.g., calcium phosphate). In some embodiments, the first and / or second diluents are independently selected from microcrystalline cellulose, pregelatinized starch, corn starch, lactose, and a phosphate derivative (e.g., calcium phosphate). Preferably, the first diluent and the second diluent are independently polymeric diluents. In one example, the first diluent is microcrystalline cellulose. In one example, the second diluent is a starch derivative, more preferably, the second diluent is pregelatinized starch.

[0052] Surprisingly, microcrystalline cellulose and pregelatinized starch have been found to be particularly good at stabilizing the dosage forms of the present invention.

[0053] In a further embodiment of the first and second aspects, the glidant is an anhydrous glidant. Preferably, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, PEG6000, or mixtures thereof, preferably the glidant is talc or colloidal silicon dioxide, more preferably the glidant is colloidal silicon dioxide.

[0054] Compound A is susceptible to degradation due to hydration. Therefore, it is important to control the water content in any solid dosage form. The inclusion of an anhydrous glidant can improve the water content of the solid dosage form. The moisture in the mold is limited.

[0055] In a further embodiment of the first and second aspects, the glidant is about 10 ml 2 / g, more preferably about 100m 2 / g (measured using the Branauer-Emmett-Teller (BET) method).

[0056] Glidants are suggested to improve the flowability of the API by occupying the space between powder particles and reducing contact between individual particles of the API.

[0057] The BET method for measuring the surface area of ​​a material forms part of the general knowledge of those skilled in the art. Briefly, the surface area of ​​a material is determined by the physical adsorption of a gas (typically nitrogen, krypton, or argon) onto the sample surface at cryogenic temperatures.

[0058] In further embodiments of the first or second aspect of the invention, the glidant is selected from colloidal silicon dioxide, talc, magnesium silicate, polyethylene glycol (e.g., PEG 6000, PEG 10,000, etc.), a PEG derivative, or a mixture thereof. In some embodiments, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, magnesium silicate, a PEG derivative, or a mixture thereof. Preferably, the glidant is polyethylene glycol (e.g., PEG 6000, PEG 10,000, etc.), talc, or colloidal silicon dioxide. Preferably, the glidant is talc or colloidal silicon dioxide. In one example, the glidant is colloidal silicon dioxide.

[0059] In a further embodiment of the first or second aspect of the present invention, the particle size of the disintegrant is D90 less than about 500 μm, preferably D90 less than about 300 μm, and more preferably D90 less than about 150 μm. D90 is the particle size corresponding to the cumulative percentage reaching 90%. For example, for a powder sample with D90=500 μm, 90% of the particles are less than 500 μm, and 10% of the particles are greater than 500 μm. D90 particle size can be measured by any suitable means known in the art, such as dynamic light scattering (DLS), laser diffraction, sieve analysis, dynamic image analysis (DIA), and static image analysis (SIA).

[0060] The particle size of the disintegrant affects the disintegration time of the solid dosage form and also affects the flowability of the blend before compression: for example, a larger particle size improves the flowability of the blend before compression, but shortens the disintegration time of the resulting solid dosage form.

[0061] In a further embodiment of the first or second aspect of the present invention, the disintegrant is selected from the group consisting of starch or its derivatives, such as wheat starch, potato starch, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, and hydroxypropyl starch; cellulose or its derivatives, such as microcrystalline cellulose, carboxymethylcellulose (carmellose), carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, and low-substituted hydroxypropylcellulose; crospovidone; alginic acid; and bentonite, or a mixture thereof.Preferably, the disintegrant is crospovidone, croscarmellose sodium, or sodium starch glycolate.Preferably, the disintegrant is crospovidone or sodium starch glycolate.In one example, the disintegrant is crospovidone.

[0062] In a further embodiment of the first or second aspect of the invention, the lubricant is selected from the group consisting of magnesium stearate, stearic acid, aluminum stearate, calcium stearate, sodium stearyl fumarate, carnauba wax; glycerol esters of fatty acids; hydrogenated oils; yellow wax; white wax; talc; and polyethylene glycol (macrogol, e.g., macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 4000, and Macrogol 6000), or mixtures thereof. In some embodiments, the lubricant is magnesium stearate, sodium stearyl fumarate, or stearic acid. Preferably, the lubricant is magnesium stearate or sodium stearyl fumarate. In one example, the lubricant is magnesium stearate. In a further example, the lubricant is sodium stearyl fumarate.

[0063] The inclusion of magnesium stearate improves the flow of the mixture in the compressor.

[0064] In further embodiments of the first or second aspect of the present invention, the solid dosage form further comprises a binder. In some embodiments, the binder is selected from the group consisting of copolyvidone, povidone, polyvinyl alcohol, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, pregelatinized corn starch, partially pregelatinized starch, gelatin, acrylic acid-based polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, and aminoalkyl methacrylate copolymer RS, sodium alginate, purified gelatin, hydrolyzed gelatin powder, carboxyvinyl polymer, or a mixture thereof. In some embodiments, the binder is povidone, methylcellulose, or hypromellose. In some embodiments, the binder is povidone or hypromellose. Preferably, the binder is povidone or methylcellulose, more preferably povidone.

[0065] In some embodiments, solid dosage forms according to the present invention may include the following ingredients, ranges expressed as weight percent of the total composition: A1)-Compound A: 1~50% -First diluent: 20~98% - Lubricant: 0.1~15% A2)-Compound A: 1~30% -First diluent: 50~98% - Lubricant: 0.1~15% B) -Compound A: 1~50% - Binder: 0.5~30% - Lubricant: 0.1~15% C1)-Compound A: 1~50% -First diluent: 20~98% - Binder: 0.5~30% - Lubricant: 0.1~15% C2)-Compound A: 1~50% -First diluent: 20~90% -Binder: 0.5~25% - Lubricant: 0.1~15% D1)-Compound A: 1~50% -First diluent: 20~98% - Second diluent: 0.1~60% - Lubricant: 0.1~15% D2)-Compound A: 1~50% -First diluent: 20~90% -Second diluent: 0.5~40% - Lubricant: 0.1~15% E1)-Compound A: 1~50% -First diluent: 20~98% - Second diluent: 0.1~60% - Binder: 0.5~30% - Lubricant: 0.1~15% E2)-Compound A: 1~50% -First diluent: 30~90% -Second diluent: 1~40% -Binder: 0.5~25% - Lubricant: 0.1~15% F) -Compound A: 20~30% -First diluent: 60~80% - Lubricant: 0.1~10% G) -Compound A: 1~10% -First diluent: 80~98% - Lubricant: 0.1~10% H) -Compound A: 1~10% -First diluent: 60~80% -Second diluent: 10~30% - Lubricant: 0.1~10% I) -Compound A: 1~10% -First diluent: 70~90% -Second diluent: 1~10% - Binder: 0.5~5% - Lubricant: 5~15% J) -Compound A: 1~10% -First diluent: 90~98% - Lubricant: 0.1~5% K) -Compound A: 1~10% -First diluent: 50~70% -Second diluent: 20~40% - Lubricant: 1~10% L) -Compound A: 1~10% -First diluent: 75~98% - Lubricant: 0.1~5% M) -Compound A: 1~10% -First diluent: 30~45% -Second diluent: 10~30% - Binder: 0.5~5% - Lubricant: 5~15% N) -Compound A: 1~10% -First diluent: 60~80% -Second diluent: 0.1~10% - Lubricant: 1~10% O) -Compound A: 30~55% -First diluent: 20~40% -Second diluent: 0.1~10% - Lubricant: 1~10% P) -Compound A: 1~10% -First diluent: 50~70% -Second diluent: 0.1~10% - Lubricant: 5~15% Q) -Compound A: 1~10% -First diluent: 40~60% -Second diluent: 20~40% -Binder: 2~15% - Lubricant: 1~10% R) -Compound A: 1~10% -First diluent: 20~45% -Second diluent: 10~30% -Binder: 10~30% - Lubricant: 0.1~10% S) - Compound A: 1~10% -First diluent: 70~85% -Second diluent: 0.1~10% - Lubricant: 0.1~10% T) -Compound A: 1~10% -First diluent: 35~55% -Second diluent: 20~40% -Binder: 10~30% - Lubricant: 0.1~10% U) -Compound A: 1~10% -First diluent: 40~60% -Second diluent: 10~30% - Lubricant: 0.1~10% V) -Compound A: 1~10% -First diluent: 75~98% - Lubricant: 0.1~10% W) -Compound A: 1~10% -First diluent: 50~70% -Second diluent: 20~40% - Lubricant: 1~10% X) -Compound A: 1~10% -First diluent: 75~98% -Second diluent: 0.5~10% - Lubricant: 1~10% Y) Compound A: 1 to 10% -First diluent: 75~98% - Lubricant: 1~10% Z) - Compound A: 1~10% -First diluent: 50~75% -Second diluent: 15~30% - Lubricant: 0.1~10%

[0066] In some embodiments of the above solid dosage forms A) through Z), the first and second diluents (if present) may be selected from microcrystalline cellulose, starch, pregelatinized starch, lactose, and calcium phosphate. The binder (if present) may be selected from povidone and hypromellose. The lubricant may be magnesium stearate, sodium stearyl fumarate, or the like. The hydroxybenzoate may be selected from ethanol, methylcellulose, and stearic acid.

[0067] Additionally, in some embodiments of the above solid dosage forms A) through Z), the solid dosage form may include a disintegrant selected from, for example, crospovidone, croscarmellose sodium, and sodium starch glycolate.

[0068] Additionally, in some embodiments of the solid dosage forms A) through Z) above, the solid dosage form may include a glidant selected from, for example, colloidal silicon dioxide, polyethylene glycol (e.g., PEG 10,000), and talc.

[0069] The above solid dosage forms A) to Z) are exemplary embodiments, but other descriptions of solid dosage forms can be similarly applied to the above solid dosage forms A) to Z). For example, other descriptions similarly apply to the selection of possible components corresponding to each excipient type (first diluent, second diluent, binder, lubricant). Furthermore, when alternative ranges for each component (compound A, first diluent, second diluent, binder, lubricant) are shown in other descriptions, these can be substituted for the ranges shown in the above solid dosage forms A) to Z).

[0070] In certain embodiments, solid dosage forms according to the present invention may include the following ingredients, ranges expressed as weight percent of the total composition: -Compound A: 1~50% -First diluent: 20~98% -Second diluent: 0~40% - Lubricant: 0.1~15% -Binder: 0~30% -Disintegrant: 0~30% -Glidant: 0~10%

[0071] In the specific embodiments described above, alternative ranges for each component found elsewhere in this description can be substituted for the ranges shown in the specific embodiment.

[0072] In some embodiments, the mixture of excipients in the solid dosage form does not consist solely of about 86%-87% calcium phosphate, about 2.5%-3.5% corn starch, and about 6%-7% magnesium stearate, because such a mixture may impart unusual dissolution characteristics to the solid dosage form. In certain embodiments, the mixture of excipients in the solid dosage form does not consist solely of about 86.36% calcium phosphate, about 3% corn starch, and about 6.38% magnesium stearate.

[0073] In further embodiments, the present invention may include other ingredients, examples of which may include surfactants, pH adjusters, preservatives, flavor enhancers, antioxidants, buffers, chelating agents, solvents, stiffening agents, sweeteners, glazing agents, and flavoring agents.

[0074] In an embodiment of the first or second aspect of the invention, for the solid dosage form, the drug release (average 6 units) in Apparatus 2 (USP) at 100 rpm in 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate, pH 4.5 at 37°C is greater than about 60% in 90 minutes, preferably greater than about 60% in 60 minutes, and even more preferably greater than about 70% in 60 minutes.

[0075] The USP dissolution test is a standard dissolution test.

[0076] In an embodiment of the first or second aspect of the invention, the product can be stored for 6 months at 40°C and 75% relative humidity. After incubation, greater than about 50% of Compound A is present as Form B, preferably greater than about 80% is present as Form B, and even more preferably greater than about 90% is present as Form B, where Form B is identified by the presence of a peak (2θ) 12.2±0.2 in an X-ray diffraction pattern, and Form A is identified by the presence of peaks (2θ) 5.6±0.2 and 17.1±0.2 in an X-ray diffraction pattern.

[0077] In embodiments of the first or second aspects of the invention, less than about 10% decomposition products of Compound A are produced, more preferably less than about 5% decomposition products, and even more preferably less than about 3% decomposition products, after 6 months of storage at 40°C and about 75% relative humidity, after 18 months of storage at 25°C and about 65% relative humidity, and / or after 21 days of storage at 70°C and 85% relative humidity.

[0078] A third aspect of the present invention provides a method for producing a solid dosage form, such as a solid dosage form of the first or second aspect of the invention, comprising: a) mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; and i. wetting the resulting mixture with a solvent such as ethanol or acetone to obtain wet granules, drying the resulting granules, and roller compacting the resulting mixture to obtain granules; ii. compressing the mixture to form tablets; and iii. a) or filling the mixture obtained in step i) into capsules. A method is provided, comprising:

[0079] Alternatively, there is provided a method for producing a solid dosage form, such as a solid dosage form of the first or second aspect of the invention, comprising the steps of: a) mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; b) optionally granulating the resulting mixture to obtain granules; and c) compressing the mixture obtained in a) or the granules of b) to form tablets, or filling the mixture obtained in a) or the granules of b) into capsules. A method is provided, comprising:

[0080] The granulation step in the above process may comprise wet granulation with a granulating liquid such as water, ethanol, or acetone. After wet granulation with a granulating liquid, the granules may be dried.

[0081] The granulation step in the above process can include dry granulation, which involves compressing the mixture to obtain granules, which can be by roller compaction or compression.

[0082] The wet granulation process described above (e.g., step i)) produces roughly spherical granules that have better flow properties than powders. Without being bound by theory, spherical particles flow well and are easier to compress, meaning that lower pressures can be used when compressing into solid dosage forms. Furthermore, the wet granulation process prevents the components of a homogeneous powder mixture from separating during processing, transportation, handling, and storage, reducing intra- and inter-batch variability.

[0083] Unlike granulation or other methods, the use of the direct compression method described above (e.g., step ii)) requires fewer equipment and manufacturing steps. This reduces the associated labor costs, processing time, and energy consumption. Another important advantage of the direct compression process is that it is a dry procedure that does not require a drying step, so there are no concerns related to heat and moisture. To reduce losses of the active ingredient that adhere to the sides of the mixer, the API is compressed. It is important to pre-coat the mixer with the excipients before addition.

[0084] The formation of capsules described in step iii) is a simple process that does not require complex equipment. The use of capsules also protects Compound A from moisture or pressure, since no liquid or heat needs to be added.

[0085] In a further embodiment of the third aspect of the invention, the method comprises directly compressing the mixture produced in step a).

[0086] In certain embodiments of the method for producing a solid dosage form, the method comprises: mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; wetting the resulting mixture with a solvent such as water, ethanol, or acetone to obtain wet granules, and drying the resulting granules; and compressing the mixture to form tablets Includes:

[0087] In another embodiment of the method for producing a solid dosage form, the method comprises: mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; roller compacting the resulting mixture to obtain granules; and compressing the mixture to form tablets Includes:

[0088] In a further embodiment of the method for producing a solid dosage form, the method comprises: mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; dry granulating the resulting mixture to obtain granules; and compressing the mixture to form tablets Includes:

[0089] In another embodiment of the method for producing a solid dosage form, the method comprises: mixing a predetermined amount of compound A with a composition according to any one of the first or second aspects above in a mixer; and compressing the mixture to form tablets Includes:

[0090] In a further embodiment of the third aspect of the invention, the method comprises: i) adding further excipients to the mixer after step a) Further includes:

[0091] If the excipients have a high water content or are not chemically compatible with Compound A, it may be useful to mix Compound A with the other excipients before adding them to the mixer.

[0092] In a further embodiment of the third aspect of the present invention, the mixing time for each individual step is from about 1 to about 60 minutes, preferably from about 1 to about 30 minutes. Each individual step may have the same or different mixing time.

[0093] In a further embodiment of the third aspect of the present invention, the mixing speed for each individual step is from about 1 rpm to about 60 rpm, preferably from about 5 rpm to about 25 rpm. The mixers may have the same or different mixing speeds.

[0094] In a further embodiment of the third aspect of the invention, the method comprises: ii) coating the resulting solid dosage form Further includes:

[0095] In further embodiments of the third aspect of the invention, micronized Compound A is used in the mixing step of the method. In some embodiments, the method further comprises micronizing the particles of Compound A to obtain a suitable particle size. Preferably, the particle size of the micronized Compound A is as described above. Preferably, micronization occurs before the mixing step.

[0096] Processing the crystalline compound to a defined particle size can be performed by any suitable method known to those skilled in the art. For example, the crystalline compound can be micronized. This can be done by jet milling, mechanical milling, fluid milling, crushing, or grinding. In certain embodiments, jet milling is used.

[0097] As discussed above with respect to the first and second aspects, the particle size of Compound A may affect the properties of the resulting formulation.

[0098] The present invention also provides a solid dosage form obtainable by the above process. In particular, the solid dosage form may be obtainable by any of the processes described in relation to the third aspect of the present invention.

[0099] In a fourth aspect of the invention, there is provided a solid dosage form according to the first or second aspect of the invention for use in the treatment of a disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, disease with Lewy bodies, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorders, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

[0100] In a fifth aspect of the present invention, there is provided a method of treating a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma. The method comprises administering to a patient in need thereof a therapeutically effective amount of a solid dosage form described in the first or second aspect of the present invention. In one embodiment, the disease is Parkinson's disease.

[0101] In a sixth aspect of the present invention, there is provided a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size defined as follows: a) D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm, b) D10 is ≧0.3 μm, preferably ≧0.5 μm, or more preferably ≧1 μm, and / or c) D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm.

[0102] In certain embodiments, the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a D10 of ≧1 μm, a D50 of 5 μm to 30 μm, and a D90 of ≦60 μm, preferably a D10 of ≧0.5 μm, a D50 of 2 μm to 50 μm, and a D90 of ≦80 μm, and even more preferably a D10 of ≧0.3 μm, a D50 of 1 μm to 60 μm, and a D90 of ≦1 μm. It has a particle size of 00 μm.

[0103] D10, D50, and D90 are as defined above for the expression "micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of . . . . " on pages 3-4. The particle size of micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide can be measured using any method known to those skilled in the art, such as laser light scattering using dry measurement at an air pressure of 1.0 bar and a feed rate of 35%.

[0104] As discussed above with respect to the first and second aspects, the particle size of the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide can affect the properties of any resulting pharmaceutical composition. If the particle size of the active compound is too large, the pharmacological properties of the active compound may be impaired. For example, large particles may take a long time to dissolve in the intestinal fluids in the patient's gastrointestinal tract, and the compound may have low oral bioavailability. Furthermore, dosage uniformity (e.g., uniformity of Compound A within or within a tablet) may be impaired. If the particle size of Compound A is too small, it may be difficult to prepare tablets. For example, small particles may have poor properties or poor compression characteristics, which may make it difficult to produce tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have insufficient hardness, exhibit poor content uniformity, and / or exhibit poor mass uniformity, which is particularly important when the manufacturing process is direct compression or capsule filling.

[0105] In a further embodiment of the sixth aspect of the present invention, the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is prepared by micronizing crystalline particles of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[0106] In a further embodiment of the sixth aspect of the invention, micronization is carried out by jet milling, mechanical milling, fluid milling, crushing or grinding. Preferably, jet milling is used.

[0107] Further Pharmaceutical Compositions In another aspect, related to the various aspects and embodiments described above, there is provided a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and at least one pharmaceutically acceptable carrier or excipient. The crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size (prior to manufacturing the pharmaceutical composition) defined as follows: a) D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm, b) D10 is ≧0.3 μm, preferably ≧0.5 μm, or more preferably ≧1 μm, and / or c) D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm.

[0108] Furthermore, 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexane and mixing a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with at least one pharmaceutically acceptable carrier or excipient, wherein the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size defined as follows: a) D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm, b) D10 is ≧0.3 μm, preferably ≧0.5 μm, or more preferably ≧1 μm, and / or c) D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm

[0109] Further provided is a method for preparing a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, the method comprising mixing a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with at least one pharmaceutically acceptable carrier or excipient, wherein the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size defined as follows: a) D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm, b) D10 is ≧0.3 μm, preferably ≧0.5 μm, or more preferably ≧1 μm, and / or c) D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm

[0110] Preferably, the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is Form A or Form B. More preferably, the crystalline form is Form B. Form B is identified by the presence of a peak at 12.2±0.2 2θ in an X-ray diffraction pattern, and Form A is identified by the presence of peaks at 5.6±0.2 and 17.1±0.2 2θ in an X-ray diffraction pattern.

[0111] As described below, pharmaceutical compositions may be specially formulated for administration in liquid or solid form, including liquid or solid forms adapted for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., buccal, sublingual, and / or targeted for systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., as a sterile solution or suspension or sustained-release formulation, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection; (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) vaginal or rectal administration, e.g., as a pessary, cream, or foam; (5) sublingual; (6) ophthalmic; (7) transdermal; or (8) nasal administration.

[0112] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human or animal) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0113] Pharmaceutical compositions include those that are administered orally, nasally, topically (including buccal and sublingually), rectally, vaginally, and / or non-oral. The compositions are conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the host being treated and the particular method of administration.

[0114] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect, and generally ranges from about 0.1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent, of one hundred percent.

[0115] Methods of preparing these compositions include the step of bringing into association a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with the carrier and, optionally, one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0116] Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of the crystalline form of Compound A as the active ingredient. The pharmaceutical composition may also be administered as a bolus, electuary, or paste.

[0117] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges and the like), the active ingredient is combined with one or more pharmaceutically acceptable carriers by any method well known in the art of pharmacy and / or described herein.

[0118] Liquid dosage forms for oral administration of the crystalline form of Compound A include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0119] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0120] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0121] Pharmaceutical compositions for rectal or vaginal administration may be provided as suppositories, which contain the compound of the invention. They can be prepared by mixing one or more with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity, releasing the active compound.

[0122] Pharmaceutical compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0123] Dosage forms for topical or transdermal administration of the active compound include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0124] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0125] Powders and sprays can contain, in addition to the active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0126] Transdermal patches have the additional advantage of providing controlled delivery of active compounds into the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0127] Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated.

[0128] Pharmaceutical compositions suitable for parenteral administration contain the active compound in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0129] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0130] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the addition of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the composition. Furthermore, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0131] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug by subcutaneous injection or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility.The absorption rate of a drug depends on the dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, the delayed absorption of a drug form administered parenterally can be achieved by dissolving or suspending the drug in an oil vehicle.

[0132] Injectable depot forms are prepared by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. [Brief explanation of the drawings]

[0133] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of crystalline polymorphic Form A of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. [Figure 2] FIG. 2 is an X-ray powder diffraction pattern of crystalline polymorphic Form B of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. [Figure 3] FIG. 3 is an X-ray diffraction diagram of a coated solid dosage form containing 10 mg of crystalline polymorphic Form B of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and starch 1500. [Figure 4] FIG. 4 is an X-ray diffraction diagram of a solid dosage form containing 60 mg of crystalline polymorphic Form B of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. DETAILED DESCRIPTION OF THE INVENTION

[0134] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical chemistry, organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques may be found in various publications, including those of Raymond C. Rowe, Paul J. Sheskey, and Marian E. Quinn, Handbook of Pharmaceutical Excipients, 6 th Edition(2009).Pharmaceutical Press.1 Lambert High Street,London SE1 / JN,UK;100 South Atkinson Road,Suite 200,Grayslake,IL 60030-7820,USA.European Pharmacopoeia;current edition United States Pharmacopoeia,The National Formulary current editions, “Comprehensive Organic Synthesis” (BMTrost & I. Fleming, eds., 1991-1992); "Current protocols in molecular biology" (F.M. Ausubel et al., eds., 1987, and periodic updates); and "Current protocols in immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated by reference in its entirety. and is incorporated herein by reference.

[0135] Various aspects of the present invention are presented in the following sections; however, an aspect of the present invention described in a particular section is not limited to any particular section.

[0136] definition To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0137] As used herein, the terms "a" and "an" mean "one or more" and include pluralities unless the context is inappropriate.

[0138] The present invention also encompasses isotopically labeled forms of Compound A that are identical to Compound A described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0139] As used herein, the term "solid dosage form" refers to a combination of an active agent with at least one carrier or excipient, inert or active (i.e., having a pharmacological effect), which makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic applications.

[0140] 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A) has the following structure: [ka]

[0141] The above-mentioned compound in crystalline form can be further characterized according to its specific crystalline form. In certain embodiments, the compound is crystalline polymorph form A. In other certain embodiments, the compound is crystalline polymorph form B.

[0142] A summary of the physicochemical properties of Compound A is shown in Table 1.

[0143] [Table 1]

[0144] Crystalline Form A may be characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.7±0.2, 11.5±0.2, 11.8±0.2, and 12.8±0.2. In certain embodiments, such a crystalline form of the compound may be characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.7±0.2, 11.5±0.2, 11.8±0.2, 12.8±0.2, 17.2±0.2, 18.7±0.2, 19.6±0.2, 22.3±0.2, and 27.3±0.2.

[0145] In certain embodiments, the compound of crystalline polymorph Form A is characterized by an X-ray powder diffraction pattern shown in Table 2 in terms of diffraction angles 2θ and optionally interplanar distances d, and relative intensities (expressed as a percentage of the most intense peak).

[0146] [Table 2]

[0147] The relative intensity of the peak at the above diffraction angle (2θ) is at least 20% relative to the most intense peak in the X-ray powder diffraction pattern.

[0148] Crystalline polymorph Form A of the compound may be characterized by an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0149] In certain embodiments, the crystalline polymorph Form A of the compound is characterized by an X-ray powder diffraction pattern shown in Table 3 in terms of diffraction angles 2θ and, optionally, relative intensities (expressed as a percentage relative to the most intense peak).

[0150] [Table 3]

[0151] The compound of crystalline polymorph Form A may exist in the monoclinic system and have the P21 / c space group. The compound of crystalline polymorph Form A may be characterized by the crystallographic unit cell parameters shown in Table 4.

[0152] [Table 4]

[0153] In other embodiments, the crystalline polymorph form A of the compound has substantially the same X polymorphism as shown in FIG. It is characterized by a X-ray powder diffraction pattern.

[0154] Crystalline Form B is characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 4.0±0.2, 10.9±0.2, 12.3±0.2, and 16.2±0.2. In certain embodiments, the crystalline form of the compound is characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 4.0±0.2, 10.9±0.2, 12.3±0.2, 16.2±0.2, 20.2±0.2, 21.1±0.2, 21.5±0.2, 24.7±0.2, 27.6±0.2.

[0155] In certain embodiments, the crystalline polymorph Form B of the compound is characterized by an X-ray powder diffraction pattern shown in Table 5 in terms of diffraction angles 2θ and optionally interplanar distances d, and relative intensities (expressed as a percentage of the most intense peak).

[0156] [Table 5]

[0157] The relative intensity of the peak at the above diffraction angle (2θ) is at least 20% relative to the most intense peak in the X-ray powder diffraction pattern.

[0158] Crystalline polymorph Form B of the compound may be characterized by an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0159] The crystalline form of the compound may be characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 4.2±0.2, 10.9±0.2, 11.5±0.2, and 12.4±0.2. In certain embodiments, the crystalline form of the compound comprises peaks at diffraction angles (2θ): 4.2±0.2, 10.9±0.2, 11.5±0.2, 12.4±0.2, 16.3±0.2, 21.5±0.2, 22.3±0.2, 22.4±0.2, 22.9±0.2, and 23.0±0.2. The compound may be characterized by an X-ray powder diffraction pattern containing a peak.

[0160] The compound of crystalline polymorph form B may be characterized by its X-ray powder diffraction pattern shown in Table 6 in terms of diffraction angles 2θ and, where appropriate, relative intensities (expressed as a percentage relative to the most intense peak).

[0161] [Table 6]

[0162] The crystalline polymorph form B of the compound may exist in the monoclinic system and have the P21 / c space group. The crystalline polymorph form B of the compound may be characterized by the crystallographic unit cell parameters shown in Table 7.

[0163] [Table 7]

[0164] Compound A can be prepared according to the method described in WO 2019 / 126776, the contents of which are incorporated herein by reference. Briefly, the method includes: 1. Mixing a compound of formula (I), a base, and a solvent to prepare a reaction mixture, wherein formula (I) is represented as follows: [ka] 2. adding an n-pentyl alkylating agent to the reaction mixture to produce a compound of formula (II); [ka] 3. Exposing a compound of formula (II) to an acid HX to obtain a compound of formula (III); [ka] (wherein X is an anion) 4. subjecting a compound of formula (III) to hydrogenation conditions to obtain a compound of formula (IV); [ka] (wherein X is an anion) 5. Mixing a compound of formula (IV) and benzyl bromide in the presence of a base (B) and a solvent (S) to produce a compound of formula V, wherein formula (V) is represented as follows: [ka] or 6. Mixing a compound of formula (VII) with an amide coupling reagent in the presence of a solvent (SI) to form an amide coupling reaction mixture, and then adding a compound of formula (IV) to the amide coupling reaction mixture to obtain a mixture comprising a compound of formula (VIII), wherein the compound of formula (IV) is represented as follows: [ka] (wherein X is an anion) Formula (VII) is represented as follows: [ka] Formula (VIII) is represented as follows: [ka]

[0165] Crystalline Forms A and B of Compound A can be prepared by a variety of methods.

[0166] In one approach to preparing a crystalline form of the compound of Formula (VIII), the method comprises adding water to a mixture containing the compound of Formula (VIII) to obtain a crystalline solid form of the compound of Formula (VIII). The volume of water added ranges from about 0.5 to about 3 times the volume of the mixture containing the compound of Formula (VIII). In certain examples, the volume of water added is approximately equal to the volume of the mixture containing the compound of Formula (VIII).

[0167] The method further comprises the steps of: (i) isolating the compound of formula (VIII) in crystalline solid form, thereby obtaining an isolated crystalline compound of formula (VIII); and (ii) washing the isolated crystalline compound of formula (VIII) one or more times with a solvent (S2) containing water and dimethylformamide (wherein the volume ratio of water to dimethylformamide in the solvent (S2) is in the range of 3:1 to 5:1) to obtain a purified, isolated crystalline compound of formula (VIII).

[0168] Polymorphic form A The following protocol can be used to make crystalline polymorph Form A. The method comprises the following steps: (i) isolating the compound of formula (VIII) in solid form, thereby obtaining an isolated compound of formula (VIII); (ii) reacting the isolated compound of formula (VIII) with C 5~8 Alkanes and (C 1~4 alkyl)-CO2-(C 1~4 alkyl) to form a mixture, and then heating the mixture to a temperature of at least 65 degrees Celsius to obtain a heated mixture; (iii) cooling the heated mixture of step (ii) to a temperature of less than 55 degrees Celsius to obtain a cooled mixture; (iv) aging the cooled mixture of step (iii) to obtain a compound of formula (VIII) in crystalline solid form; and (v) isolating the compound of formula (VIII) in crystalline solid form to obtain an isolated crystalline compound of formula (VIII).

[0169] C 5~8 The alkane may be heptane. 1~4 alkyl)-CO2-(C 1~4 The alkyl) may be ethyl acetate.

[0170] Polymorphic form B The following protocol can be used to make crystalline polymorph Form B. The method comprises the following steps: a. isolating the compound of formula (VIII) produced in section C in solid form to obtain an isolated compound of formula (VIII); b. The isolated compound of formula (VIII) is heated to a temperature of about 20°C to about 50°C (C 1~4 Archi )-CO2-(C 1~4 alkyl) esters, saturated fatty alcohols, or (C 1~4 alkyl)-CO-(C 1~4 forming a mixture by dissolving the compound in a (alkyl) ketone solvent; c. adding an alkane solvent to the mixture of step (ii) and cooling the mixture to a temperature of about 0° C. to about 25° C.; d. Aging the cooled mixture of step (iii) to obtain a compound of formula (VIII) in crystalline solid form; and e. isolating the compound of Formula (VIII) in a first crystalline solid form to obtain an isolated first crystalline compound of Formula (VIII), i.e., Form B.

[0171] C 5~8 The alkane may be heptane. 5~8 The alkane may be methylcyclohexane. 1~4 alkyl)-CO2-(C 1~4(C alkyl) may be ethyl acetate. 1~4 alkyl)-CO2-(C 1~4 The saturated alcohol may be 1-pentanol. The saturated alcohol may be isopentanol. (C 1~4 alkyl)-CO-(C 1~4 (C alkyl) may be methyl ethyl ketone. 1~4 alkyl)-CO-(C 1~4 The alkyl) may be methyl isobutyl ketone (MIBK).

[0172] Further processing of compound A The crystalline polymorphic form of Compound A preferably falls within a predetermined particle size distribution. If the Compound A particles obtained from synthesis are not of an appropriate particle size, the crystalline polymorphic form of Compound A can be further processed to a predetermined particle size. Processing the crystalline compound to a defined particle size can be carried out by any suitable method known to those skilled in the art. For example, the crystalline compound can be micronized. This can be carried out by jet milling, mechanical milling, fluid milling, crushing, or grinding.

[0173] One method for pulverizing the crystalline particles of Compound A is to use a jet mill. Jet mills use high-speed jets of compressed air or inert gas to crush the material by causing particles to collide with each other. If desired, Compound A can be sieved before pulverization, for example, using a 20 mesh sieve.

[0174] Diluent The terms "filler" and "diluent" are used interchangeably herein. It is generally known that the term "filler" is used in the context of capsule formulations, and the term "diluent" is used in the context of tablet formulations. Diluents function as bulking agents in pharmaceutical tablets, increasing weight and improving content uniformity. Diluents provide better tablet properties, such as improved cohesion and flowability. Diluents should be non-toxic, commercially available in acceptable grades, physiologically inert, and physically and chemically stable by themselves and in combination with the active pharmaceutical ingredient (API).

[0175] Other names for diluents include carriers, fillers, and volumizing agents. Not all solid dosage forms require diluents. Examples of suitable diluents include calcium carbonate (Barcroft™, Cal-Carb™, CalciPure™, Destab™, MagGran™, Millicarb™, Pharma-Carb™, Precarb™, Sturcal™, Vivapres Ca™), calcium phosphate dibasic anhydrous (A-TAB™, Di-Cafos AN™, Emcompress Anhydrous™, Fujicalin™), calcium phosphate, dibasic dihydrate (Cafos™, Calipharm™, Calstar™, Di-Cafos™, Emcomp™), and dicalcium phosphate, dibasic dihydrate (Cafos™, Calipharm™, Calstar™, Di-Cafos™, Emcomp™). ress™), tricalcium phosphate (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium sulfate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™, USG Terra Alba™), powdered cellulose (Arbocel™, Elcema™, Sanacel™, Solka-Floc™), silicified microcrystalline cellulose (ProSolv™), cellulose acetate, compressible sugar (Di-Pac™), powdered sugar, dextran (Candex™, Emdex™), dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofin™, Lycadex™). PF™, Roferose™, Tab fine D-IOO™), fructose (Advantose™, Fructamyl™, Fructofin™, Krystar™), kaolin (Lion™, Sim90™), lactitol (Finlac ACX™, Finlac DC™, Finlac MCX™), lactose (Lactose® 80, Aero Flo20™, Aero Flo65(TM), Anhydrox(TM), CapsuLac(TM), Fast-Flo(TM), FlowLac(TM), GranuLac(TM), InhaLac(TM), Lactochem(TM), Lactohale(TM), Lactopress(TM), Microfine(TM), Microtose (Trademark), Pharmatose (Trademark), PrismaLac (Trademark), Respitose (Trademark), SacheLac (Trademark), SorboLac (Trademark), Super-Tab (Trademark), Tablettose (Trademark), Wyndale (Trademark), Zeparox (Trademark)), Magnesium Carbonate, Magnesium Oxide (MagGran MO (trademark)), maltodextrin (C *Dry MD (trademark), Glucidex (trademark), Glucodry (trademark), Lycatab DSH (trademark), Maldex (trademark), Maltagran (trademark), Maltrin (trademark), Maltrin QD (trademark), Paselli MD 10 PH (trademark), Star-Dri (trademark), Advantose 100 (trademark), Mannogem (trademark), Pearlitol (trademark), Avicel PH (trademark), Celex (trademark), Celphere (trademark), Ceolus KG (trademark), Emcocel (trademark), Ethispheres (trademark), Fibrocel (trademark), Pharmacel (trademark), Tabulose (trademark), Vivapur (trademark), Litesse (trademark), Dow Corning Q7-2243 LVA (trademark), Cow Corning Q7-2587 (trademark), Sentry Simethicone (trademark), Kelcosol (trademark), Keltone (trademark), Protanal (trademark), Alberger (trademark), Liponec 70-NC (trademark), Liponic 76-NCv, Meritol (trademark), Neosorb (trademark), Sorbifin (trademark), Sorbitol Instant (trademark), Sorbogem (trademark), Aytex P (trademark), Fluftex W (trademark), Instant Pure-Cote (trademark), Melojel (trademark), Meritena Paygel55 (trademark), Perfectamyl D6PH (trademark), Pure-Bind (trademark), Pure-Cote (trademark), Pure-Dent (trademark), Pure-Gel (trademark), Pure-Set (trademark), Purity21 (trademark), Purity826 (trademark), Tablet White (trademark), Alpha Chemical Denpon (Instastarch (trademark), Lycatab C (trademark), Lycatab PGS (trademark), Merigel (trademark), National 78-1551 (trademark), Pharma-Gel (trademark), Prejel (trademark), Sepistab ST200 (trademark), SpressB820(TM), Starch 1500G(TM), Tablitz(TM), Unipure LD(TM), Unipu re WG220™), sucrose, trehalose, isomalt (GaleniQ), and xylitol (Klinit™, Xylifm™, Xylitab™, Xylisorb™, Xylitolo™), or mixtures thereof.

[0176] Preferred diluents include lactose, starch, starch derivatives (eg, pregelatinized starch), phosphoric acid derivatives, cellulose, or mixtures thereof.

[0177] More preferably, the first diluent and the second diluent are independently polymeric diluents, preferably the first diluent is microcrystalline cellulose and / or the second diluent is a starch derivative, more preferably the second diluent is pregelatinized starch.

[0178] A particularly preferred diluent is microcrystalline cellulose. Examples include Avicel® pH 101 and Avicel® pH 102. In some embodiments, Avicel® pH 102 is preferred.

[0179] Binder Binders, which are excipients, hold the components of a formulation together, for example, in a tablet. Binders ensure that tablets, powders, granules, etc. can be formed with the necessary mechanical strength. Furthermore, they provide bulk to low-active-dose tablets. Examples of binders can be dry or liquid.

[0180] Suitable binders for inclusion in the compositions of the present invention include acacia, alginic acid (Kelacid™, Protacid™, Satialgine H8™), carbomer (Acritamer™, Carbopol™, Pemulen™, Ultrez™), sodium carboxymethylcellulose (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel™, Tylose™), ceratonia (Meyprofleur™), cottonseed oil, dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofm™, Lycedex™), and the like. PF(TM), Roferose(TM), TabfmeD-100(TM)), gelatin(Cryogel(TM), Instagel(TM), Solugel(TM)), guar gum(Galactosol(TM), Mepr ogat(TM), Meyprodor(TM), Meyprofm(TM), Meyproguar(TM)), hydrogenated vegetable oil type I (Akofine(TM), Lubritab(TM), Sterotex(TM), Dynasan P[omicron]O (trademark), Softisan154 (trademark), Hydrocote (trademark), Lipovol (trademark), HS-K (trademark), Sterotex HM (trademark)), hydroxyethyl cellulose (Alcoramnosan (trademark), Cellosize (trademark), Idroramnosan (trademark), Liporamnosan (trademark), Natrosol (trademark), Tylose PHA™), hydroxyethyl methylcellulose (Culminal™, Tylopur MH™, Tylopur MHB™, TyloseMB™, Tylose MH™, Tylose MHB™), hydroxypropyl cellulose (Klucel™, Methocel™, Nisso HPC™), low-substituted hydroxypropyl cellulose, hypromellose (BenecelMHPC(TM), Methocel(TM), Metolose(TM), Pharmacoat(TM), Spectracel(TM), Spectracel15(TM)), Tylopur(TM)), Magnesium aluminum silicate (Carrisorb(TM), Gelsorb(TM), Magnabite(TM), Neusilin(TM) ), Pharmsorb™, Veegum™), maltodextrin (C *Dry MD (trademark), Glucidex (trademark), Glucodry (trademark), Lycatab DSH (trademark), Maldex (trademark), Maltagran (trademark), Maltrin (trademark), Maltrin QD (trademark), Paselli MD10PH (trademark), Star-Dri (trademark), Advantose100 (trademark), Benecel (trademark), Culminal MC (trademark), Methocel (trademark), Metolose (trademark), Avicel PH (trademark), Celex (trademark), Celphere (trademark), Ceolus KG (trademark), Emcocel (trademark), Ethispheres (trademark), Fibrocel (trademark), Pharmacel (trademark), Tabulose (trademark), Vivapur (trademark), Litesse (trademark), Polyox (trademark), Eastacryl 30D (trademark), Eudragit (trademark), Kollicoat MAE30D (trademark), Kollicoat MAE30DP (trademark), Kolidon (trademark), Plasdone (trademark), Kelcosol (trademark), Keltone (trademark), Protanal (trademark), Aytex (trademark) P (trademark), FluftexW (trademark), Instant Pure-Cote (trademark), Melojel (trademark), Meritena Paygel55 (trademark), Perfectamyl D6PH (trademark), Pure-Bind (trademark), Pure-Cote (trademark), Pure-Dent (trademark), Pure-Gel (trademark), Pure-Set (trademark), Purity21 (trademark), Purity826 (trademark), Tablet White (trademark), Alpha Chemical Denpon (Instastarch (trademark), Lycatab C (trademark), Lycatab PGS (trademark), Merigel (trademark), National78-1551 (trademark), Pharma-Gel (trademark), Prejel (trademark), Sepistab ST200 (trademark), Spress B820 (trademark), Starch1500G (trademark), Tablitz (trademark), Unipure LD (trademark), UnipureWG220™), stearic acid (Crodacid™, Emersol Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), sucrose, and zein, or mixtures thereof.

[0181] Glidants Glidants are typically fine powders that facilitate the movement of powders or granules in manufacturing machines (e.g., hoppers) prior to compaction, compression, or encapsulation. By increasing the flow rate of the powder or granules, tablets are produced with less variation in weight and more consistent dosing of the drug substance.

[0182] The ability of a glidant to enhance the movement of powders or granules in the hopper in a tablet press and into the tablet die is due to the ability of the glidant particles to locate in the interpowder / intergranule spaces, thus reducing the overall surface charge present on the mixture, reducing friction between particles of the mixture, filling gaps on the surface and further increasing the rate of movement and flow.

[0183] Glidants are typically hydrophobic, and therefore care must be taken to ensure that the concentration of glidant used in the formulation does not adversely affect tablet disintegration and drug dissolution.

[0184] The concentration of glidant added to the dry powder blend of excipients and active ingredients can be important because above a certain concentration the glidant itself can inhibit good flow.

[0185] Suitable glidants include tricalcium phosphate (Tri-Cafos™, TRI-CAL™, TRITAB™), calcium silicate, powdered cellulose (Arbocel™, Elcema™, Sanacel™, Solka-Floc™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Sil M-5P™, WackerHDK™, Syloid™), magnesium silicate, magnesium trisilicate, starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Pagel 55™, Perfectamyl Examples of suitable glidants include D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™, PEG 6000, PEG 10000, and talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™), or mixtures thereof. Preferably, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, magnesium silicate, or mixtures thereof; more preferably, the glidant is talc or colloidal silicon dioxide. In one example, the glidant is colloidal silicon dioxide.

[0186] Disintegrant Disintegrants or disintegrating agents are materials found in some solid dosage forms. They are added to the formulation to counteract cohesive forces that arise during compression, thus promoting the breakdown of the tablet into granules so that the drug is readily available to the patient upon contact with moisture. The mechanism by which disintegrants perform their function is not yet fully understood.

[0187] Disintegrants may enable tablet disintegration by increasing the porosity and wettability of the compressed tablet matrix, or may facilitate tablet disintegration by increasing internal pressure within the tablet matrix.

[0188] The concentration of disintegrant can be directly related to the rate of disintegration until a maximum rate of disintegration is reached, after which the rate of disintegration decreases with increasing concentration of disintegrant.

[0189] Suitable disintegrants include alginic acid (Kelacid™, Protacid™, Satialgine H8™), tricalcium phosphate (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium carboxymethylcellulose (ECG505™, Nymcel ZSC™), sodium carboxymethylcellulose (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel Tylose CB™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Sil M-5P™, Wacker HDK™, Syloid™), croscarmellose sodium (Ac-Di-Sol™, Explocel™, Nymcel ZSX™, Pharmacel XL™, Primellose™, Solutab™, Vivasol™), crospovidone (Kollidon CL™, Kollidon CL-M™, Polyplasdone XL™, Polyplasdone XL-IO™), docusate sodium, guar gum (Galactosol™, Meprogat™, Meyprodor™, Meyprofin™, Meyproguar™), low-substituted hydroxypropyl cellulose, magnesium aluminum silicate (Carrisorb™, Gelsorb™) , Magnabite™, Neusilin™, Pharmsorb™, Veegum™), methylcellulose (Benecel™, Culminal MC™, Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, Celex™, Celphere™, Ceolus KG™, Emcoel™, Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), povidone (Kollidon™, Plasdone™), sodium alginate (Kelcosol™, Keltone™, Protanal™), sodium starch glycolate (Explotab™, Primojel™, Vivastar P™), polacrilin potassium (Amberlite IRP88(TM)), silicified microcrystalline cellulose (ProSolv(TM)), starch (AytexP(TM), Fluftex W(TM), InstantPure-Cote(TM), Melojel(TM), Meritena(TM), Paygel55(TM), Perfectamyl D6PH(TM), Pure-Bind(TM), Pure-Cote(TM), Pure-Dent(TM), Pure-Gel(TM), Pure-Set(TM), Purity21(TM), Purity826(TM), Tablet White(TM)), or pregelatinized starch (Instanstarch(TM), Lycatab C(TM), Lycatab PGS(TM), Merigel(TM), National78-1551(TM), Pharma-Gel(TM), Prejel(TM), Sepistab ST200(TM), Spress B820(trademark)), Starch1 500G™, Tablitz™, Unipure LD™, Unipure WG220™, or mixtures thereof.

[0190] Preferred examples of disintegrants for use in the present invention include crospovidone, croscarmellose sodium, sodium starch glycolate, or mixtures thereof, and preferably the disintegrant is crospovidone or sodium starch glycolate. In one example, the disintegrant is crospovidone.

[0191] lubricant As the name suggests, lubricants reduce friction between the powder mixture and the die wall during compression and ejection. Lubricants also prevent the mixed powder / granules from sticking to the processing areas of the tablet press, especially the punches and dies. In some cases, lubricants reduce interparticle friction, thus improving the flow rate of the powder or granules. The best lubricants are those with low shear strength but a strong tendency to agglomerate perpendicular to the shear line.

[0192] Powder flow during tablet production is important because the powder must flow easily and uniformly into the tablet die to ensure uniform tablet weight and the production of tablets with consistent and reproducible properties. Smaller particles, such as Compound A particles, which have low density and irregular surfaces and shapes, flow less well than dense, large, smooth, spherical particles. Particle shape and surface morphology affect interparticle contact; therefore, increasing the contact area can increase friction, thereby decreasing flow. Because boundary layer lubricants form a film around particles, these lubricants can affect friction by altering interparticle contact, thereby affecting powder flow.

[0193] Inadequate lubrication during tablet manufacturing can result in tablets with uneven surfaces. Conversely, using too much lubricant can create tablets with poor disintegration and dissolution rates.

[0194] Preferred lubricants for use in the present invention include those selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, or mixtures thereof. In one example, the lubricant is magnesium stearate.

[0195] coating Pharmaceutical film coating is considered an important part of the manufacture of solid pharmaceutical dosage forms because it improves the physical and chemical stability of the dosage form and modifies the release characteristics of the drug. Several techniques are available to achieve coating. The most common techniques are film coating, sugar coating, microencapsulation, and compression coating. Film coating is preferably used in the present invention.

[0196] Treatment method The solid dosage forms described herein may be useful for the treatment of a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

[0197] Described herein are methods for treating a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form described herein.

[0198] The amount or dose of the solid dosage form administered should be sufficient to alleviate the disease in vivo. The dose will be determined by the potency of the particular formulation and the weight of the subject being treated.

[0199] The dosage of a solid dosage form is also determined by the presence, nature, and extent of any side effects that may accompany the administration of a particular formulation. Typically, a physician will determine the dosage of a composition for treating each individual subject, taking into account various factors such as age, body weight, general health, diet, sex, the compound / formulation to be administered, the route of administration, and the severity of the condition being treated. Suitable dosages can be determined by those skilled in the art. As non-limiting examples, the total dosage of Compound A in a solid dosage form of the present invention can be about 2 to about 500 mg, about 5 to about 300 mg, about 10 mg to about 200 mg, and about 20 mg to about 100 mg. In preferred embodiments, the total amount of Compound A in a solid dosage form of the present invention is about 10 mg, about 30 mg, or about 60 mg. [Example]

[0200] The following examples are not intended to be limiting.

[0201] Example 1 Bulk and tapped densities, Carr index, compressibility index, Hausner ratio, true density, porosity, relative solids content, and flow rate were obtained for micronized Compound A. The results are summarized in Table 8.

[0202] Compound A was micronized using a PM6 jet mill with the following process parameters: feed rate - 20%, controlled feed pressure - 0.4 MPa (target 4 bar, range: 3.5-5.5 bar), and milling pressure - 0.4 MPa (target 4 bar, range: 3.5-5.5 bar). Particle size was measured using a Malvern Mastersizer 3000 using laser light scattering.

[0203] [Table 8]

[0204] Solid Dosage Forms - Properties Unless otherwise stated, the prepared solid dosage forms were characterized using the following methods:

[0205] [Table 9]

[0206] Example 2 - Preparation of an active ingredient-free solid dosage form Solid dosage forms containing ingredients according to Table 9 were prepared according to the following protocol.

[0207] The particle size of microcrystalline cellulose and crospovidone was calibrated using a 500 μm sieve. The particles that passed through the sieve were placed in a Biconic mixer at 21 rpm for 15 minutes. The particle size of magnesium stearate was calibrated using a 250 μm sieve. The particles that passed through the sieve were placed in a Biconic mixer and mixed for an additional 5 minutes at 21 rpm. The bulk density of the resulting mixture was measured to be 0.37 g / mL. The resulting mixture was passed through an eccentric-type tablet press using 11 x 5.7 mm oval concave punches and compressed.

[0208] [Table 10]

[0209] The resulting tablets had the following properties: Appearance: White, oval, biconvex tablet with one score line on each side ·Hardness: 119N Disintegration: Less than 2 minutes

[0210] Example 3 - Batch 210115-L containing 60 mg of Compound A Tablets having the composition set forth in Table 10 below were prepared according to the following method: Compound A, Avicel® pH102, and crospovidone were separately calibrated by passing them through a 500 μm sieve. 50% of Avicel® pH102 was placed in a Biconic mixer and mixed for 5 minutes at 21 rpm. The remaining 50% of Compound A and Avicel® pH102 were placed in the mixer and mixed for 15 minutes at 21 rpm. Crospovidone was added, and the mixture was mixed for 15 minutes at 21 rpm. Finally, magnesium stearate, calibrated by passing it through a 250 μm sieve, was added and mixed for 5 minutes at 21 rpm. The resulting mixture had a bulk density of 0.33 g / mL. The mixture was compressed in an eccentric tablet press using oval concave punches measuring 11 × 5.7 mm.

[0211] [Table 11]

[0212] Example 4 - Batch 210117-L containing 60 mg of Compound A A solid dosage form was prepared with the ingredients in Table 11 below. The solid dosage form was prepared using the same method as in Example 3. The bulk density of the mixture is 0.38 g / mL.

[0213] [Table 12]

[0214] The solid dosage form had the following properties: Appearance: White, oval, biconvex tablet with one score line on each side ·Hardness: 189N Disintegration: Less than 1 minute Compression: Regular filling of the die with sufficient mass uniformity (RSD<2%)

[0215] Example 5 - Batch 210124-L - 10 mg of Compound A Following the methods of Examples 3 and 4, solid dosage forms having the compositions set forth in Table 12 below were prepared, with the following minor modifications: To ensure optimal mixture uniformity, the duration of the first and second mixing (addition of Compound A) was extended to 30 minutes and the mixer speed was increased to 25 rpm for all mixtures. The resulting mixtures had a bulk density of 0.38 g / mL.

[0216] [Table 13]

[0217] The solid dosage form had the following properties: Appearance: White, oval, biconvex tablet with one score line on each side ·Hardness: 234N Collapse: <2 minutes Friability: <0.2% Compression: Regular filling of the die with sufficient mass uniformity (RSD<2%) Dosage uniformity:

[0218] [Table 14]

[0219] Tablets with suitable technical properties and mass uniformity were obtained. Considering hydrolysis as one of the main degradation pathways of Compound A, pregelatinized starch (Starch® 1500) was added to the formulation. It is hygroscopic, absorbing moisture and reducing the risk of degradation due to humidity.

[0220] Example 6 - Batch 210142-L - 10 mg of Compound A Solid dosage forms having the compositions in Table 13 were prepared according to the following method: Compound A, Avicel® pH102, Aerosil® 200, Starch® 1500, and crospovidone particle sizes were calibrated using a 500 μm sieve. A portion of the Avicel® pH102 and 50% of the Aerosil® 200 were mixed in a Biconic mixer at 25 rpm for 30 minutes. Compound A and the remaining Avicel® pH102, Starch® 1500, 50% of the Aerosil® 200, and crospovidone were added to the mixture and mixed at 25 rpm for 30 minutes.

[0221] Magnesium stearate was sieved using a 250 μm sieve and added to the mixer, which was then mixed for 5 minutes at 25 rpm. The resulting mixture had a density of 0.39 g / mL. The mixture was compressed in an eccentric tablet press using 11×5.7 mm oval concave punches.

[0222] [Table 15]

[0223] The resulting tablets had the following properties: Appearance: White, oval, biconvex tablet with one score line on each side ·Hardness: 182N Collapse: <1 minute Friability: <0.2% Compression: Regular filling of the die ensures excellent mass uniformity (RSD≦2%) Dosage uniformity:

[0224] [Table 16]

[0225] Tablets with adequate technical properties and mass uniformity were obtained.

[0226] Batches 210124-L and 210142-L are produced by a robust and reproducible manufacturing process and are tablets that meet all critical quality attributes as defined above.

[0227] Example 7 - Batch 230012-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0228] [Table 17]

[0229] The resulting mixture had the following properties: Bulk density: 0.42g / mL Tap density: 0.54g / mL ·Fluidity (sec / 100g): 13.6 (15mm)

[0230] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0231] The resulting tablets had the following properties: Weight uniformity (RSD): 1.21% ·Hardness: 118N Disintegration: <30 minutes Solubility at 60 minutes: 63%

[0232] Example 8 - Batch 230013-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0233] [Table 18]

[0234] The resulting mixture had the following properties: Bulk density: 0.37g / mL Tap density: 0.53g / mL ·Fluidity (sec / 100g): 11.8 (15mm)

[0235] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0236] The resulting tablets had the following properties: Weight uniformity (RSD): 0.65% ·Hardness: 319N Decay: >120 minutes Solubility at 60 minutes: 89.1%

[0237] Example 9 - Batch 230014-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0238] [Table 19]

[0239] The resulting mixture had the following properties: Bulk density: 0.58g / mL Tap density: 0.79g / mL ·Fluidity (sec / 100g): 5.6 (15mm)

[0240] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0241] The resulting tablets had the following properties: Weight uniformity (RSD): 1.04% ·Hardness: 55N Disintegration: Less than 2 minutes Solubility in 60 minutes: 88%

[0242] Example 10 - Batch 230015-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0243] [Table 20]

[0244] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0245] The resulting tablets had the following properties: Weight uniformity (RSD): 0.89% Collapse: <3 minutes Solubility in 60 minutes: 88%

[0246] Example 11 - Batch 230016-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0247] [Table 21]

[0248] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0249] The resulting tablets had the following properties: Weight uniformity (RSD): 1.5% Disintegration: <2 minutes Solubility in 60 minutes: 98%

[0250] Example 12 - Batch 230017-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0251] [Table 22]

[0252] The resulting mixture had the following properties: Bulk density: 0.33g / mL Tap density: 0.44g / mL ·Fluidity (sec / 100g): 15.6 (15mm)

[0253] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0254] The resulting tablets had the following properties: Weight uniformity (RSD): 0.95% ·Hardness: 148N Collapse: <1 minute Solubility in 60 minutes: 96%

[0255] Example 13 - Batch 230018-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0256] [Table 23]

[0257] The resulting mixture had the following properties: Bulk density: 0.36g / mL Tap density: 0.52g / mL

[0258] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0259] The resulting tablets had the following properties: Weight uniformity (RSD): 1.34% ·Hardness: 132N Collapse: <1 minute Solubility at 60 minutes: 53%

[0260] Example 14 - Batch 230019-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0261] [Table 24]

[0262] The resulting mixture had the following properties: Bulk density: 0.74g / mL Tap density: 1.01g / mL

[0263] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0264] The resulting tablets had the following properties: Weight uniformity (RSD): 1.05% Collapse: <1 minute Solubility in 60 minutes: 95%

[0265] Example 15 - Batch 230020-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0266] [Table 25]

[0267] The mixture was punched eccentrically using an oval concave punch with dimensions of 11 x 5.7 mm. Compressed in a tablet press.

[0268] The resulting tablets had the following properties: Weight uniformity (RSD): 0.50% ·Hardness: 223N Disintegration: <30 minutes Solubility at 60 minutes: 82%

[0269] Example 16 - Batch 230021-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0270] [Table 26]

[0271] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0272] The resulting tablets had the following properties: Weight uniformity (RSD): 0.96% ·Hardness: 102N Collapse: <5 minutes Solubility in 60 minutes: 97%

[0273] Example 17 - Batch 230022-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0274] [Table 27]

[0275] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0276] The resulting tablets had the following properties: Weight uniformity (RSD): 0.72% ·Hardness: 307N Collapse: <5 minutes Solubility in 60 minutes: 89%

[0277] Example 18 - Batch 230023-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0278] [Table 28]

[0279] The resulting mixture had the following properties: Bulk density: 0.46g / mL Tap density: 0.60g / mL

[0280] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0281] The resulting tablets had the following properties: Weight uniformity (RSD): 1.96% ·Hardness: 124N Decay: <50 minutes Solubility in 60 minutes: 95%

[0282] Example 19 - Batch 230024-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0283] [Table 29]

[0284] The resulting mixture had the following properties: Bulk density: 0.4g / mL Tap density: 0.5g / mL

[0285] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0286] The resulting tablets had the following properties: Weight uniformity (RSD): 0.78% ·Hardness: 124N Collapse: <1 minute Solubility at 60 minutes: 104%

[0287] Example 20 - Batch 230025-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0288] [Table 30]

[0289] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0290] The resulting tablets had the following properties: Weight uniformity (RSD): 1.08% ·Hardness: 30N Collapse: <5 minutes Solubility at 60 minutes: 106%

[0291] Example 21 - Batch 230026-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0292] [Table 31]

[0293] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0294] The resulting tablets had the following properties: Weight uniformity (RSD): 0.59% Collapse: <1 minute Solubility in 60 minutes: 92%

[0295] Example 22 - Batch 230027-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0296] [Table 32]

[0297] The resulting mixture had the following properties: ·Fluidity (sec / 100g): 4.6 (15mm) 16.6 (10 mm)

[0298] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0299] The resulting tablets had the following properties: Weight uniformity (RSD): 0.46% ·Hardness: 50N Collapse: <2 minutes Solubility at 60 minutes: 13%

[0300] It was felt that the above solubility results were artificially low because the tablets did not disintegrate appreciably in the dissolution vessel due to insufficient tablet wetting caused by excessive mixing of magnesium stearate (however, the disintegration test showed values ​​of less than 2 minutes and the tablet hardness was relatively low). This result did not accurately reflect the properties of this solid dosage form. It was found that slightly lowering the magnesium stearate content significantly increased the solubility.

[0301] Example 23 - Batch 240022-L The excipients were simply mixed and then directly compressed to obtain solid dosage forms with the compositions detailed in the table below:

[0302] [Table 33]

[0303] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0304] The resulting tablets had the following properties: ·Hardness: 30N Collapse: <2 minutes Solubility at 60 minutes: 88.6%

[0305] Example 24 - Batch 240006-L Solid dosage forms having the compositions detailed in the table below were obtained by wet granulation using purified water as the granulating liquid.

[0306] [Table 34]

[0307] The resulting mixture had the following properties: Bulk density: 0.4g / mL Tap density: 0.5g / mL

[0308] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0309] The resulting tablets had the following properties: Weight uniformity (RSD): 1.44% ·Hardness: 115N Collapse: <2 minutes Solubility in 60 minutes: 92%

[0310] Example 25 - Batch 240014-L Solid dosage forms were obtained by dry granulation with the compositions detailed in the table below:

[0311] [Table 35]

[0312] The resulting mixture had the following properties: Bulk density: 0.56g / mL Tap density: 0.70g / mL

[0313] The mixture was compressed in an eccentric type tablet press using oval concave punches measuring 11 x 5.7 mm.

[0314] The resulting tablets had the following properties: Weight uniformity (RSD): 1.00% ·Hardness: 89N Collapse: <2 minutes Solubility in 60 minutes: 98%

[0315] Example 26 - Stability Study To evaluate the stability of the drug, batch formulations (having the compositions shown in Tables 14, 15, 16, and 17) were prepared and subjected to stress studies. For formulations containing pregelatinized starch (Starch® 1500), it was decided to reduce its proportion in the active formulation to 10%, and the introduction of Compound A compensated for the reduced amount of microcrystalline cellulose and improved the compression properties of the final blend. For the placebo, the proportion of pregelatinized starch (Starch® 1500) was maintained at 20%. Since preventing discrimination between doses was a major concern, film-coated tablets were also prepared and tested for stability. The formulations were sealed in HDPE bottles and stored at 70°C and 70°C / 80% RH for 21 days.

[0316] [Table 36]

[0317] [Table 37]

[0318] [Table 38]

[0319] [Table 39]

[0320] The results are shown in Table 18 below.

[0321] [Table 40]

[0322] All batches are manufactured using a robust and reproducible manufacturing process and the tablets meet all critical quality attributes as previously defined.

[0323] A matrix design was established to assess the stability of the formulations at T0, T11, and T21 days. The formulations were tested for appearance, assay, and purity.

[0324] ·T0 days Appearance: White, oval, biconvex tablet with one score line on each side for all formulations tested.

[0325] [Table 41]

[0326] Results were obtained using HPLC. All tablets showed good assay results with values ​​between 95 and 105.

[0327] [Table 42]

[0328] T11th Appearance: For the film-coated formulations tested (FADU and FADY), white oval biconvex tablets with one score line on each side were stored at 70°C and 70°C / 80%RH. For the uncoated formulations tested (FADZ and FAEC), yellowish oval tablets with one score line on each side were stored at 70°C and 70°C / 80%RH.

[0329] [Table 43]

[0330] [Table 44]

[0331] ·T21st Appearance: For the film-coated formulations tested (FADU and FADY), one tube was placed on each side. White, oval, biconvex tablets with a score line on each side were stored at 70°C and 70°C / 80% RH. For the uncoated formulations tested (FADZ and FAEC), yellowish, oval tablets with one score line on each side were stored at 70°C and 70°C / 80% RH.

[0332] [Table 45]

[0333] [Table 46]

[0334] Example 27 - X-ray diffraction of polymorphic forms of Compound A (Form A and Form B) The methods described herein or, for example, the methods described in WO 2019 / 126776 can be used to prepare crystalline polymorphic form A and crystalline polymorphic form B.

[0335] A Rigaku MiniFlex benchtop X-ray diffractometer was set up with the following instrument parameters:

[0336] [Table 47]

[0337] 1. Set the XRPD instrument parameters as described in Table 25. 2. Spread the powder sample evenly in the sample holder. 3. Place a glass plate on top of the sample and compress it with your fingertips. 4. Place the sample in the instrument's autosampler. 5. Perform XRPD analysis. 6. Evaluate the resulting diffraction pattern.

[0338] Example 28 - X-ray diffraction of solid dosage tablets Using the above method, the following tablets were prepared: Film-coated tablets (FADX) containing 10 mg of Compound A (results shown in Figure 3) Tablets containing 60 mg of Compound A (FAEA) (results shown in Figure 4)

[0339] A Rigaku MiniFlex benchtop X-ray diffractometer was set up with the following instrument parameters:

[0340] [Table 48]

[0341] Tablet samples were prepared and analyzed in the following manner: 1. Crush 10 sample tablets to obtain a fine, homogeneous powder. 2. Set the XRPD instrument parameters as described in Table 25. 3. Spread the powder sample evenly in the sample holder. 4. Place a glass plate on top of the sample and compress it with your fingertips. 5. Place the sample in the instrument's autosampler. 6. Perform XRPD analysis. 7. Evaluate the resulting diffraction pattern.

[0342] The results are shown in Figures 3 and 4.

[0343] Qualitative visual evaluation of the diffractogram of the sample obtained after the assay confirmed the presence of a peak identifying Form B at about 12.2° 2θ, along with the absence of peaks identifying Form A at about 5.6° 2θ and 17.1° 2θ.

[0344] The presence of a Form B identifying peak at about 12.2° 2θ, coupled with the absence of both Form A identifying peaks at about 5.6° 2θ and about 17.1° 2θ, confirms the identity of Form B of Compound A, and Form A is absent.

[0345] If the presence of a Form B identifying peak at about 12.2 2θ is confirmed, along with the presence of Form A identifying peaks at both about 5.6 and about 17.1 2θ, then Compound A is present in both Form A and Form B.

[0346] If the presence of identifying peaks for Form B is not confirmed and the presence of identifying peaks for Form A is confirmed, then Compound A is present only in the form of Form B.

[0347] conclusion Thus, the solid dosage forms of the present invention exhibit high stability and high polymorphic purity.

[0348] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments, therefore, are to be considered in all respects as illustrative and not restrictive of the invention described herein. Accordingly, the scope of the invention is indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

[0349] Embodiments of the present invention: In addition to the various aspects and embodiments of the invention described above, the present invention is further defined by the following embodiments:

[0350] 1.a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (compound A), and i) a first diluent and / or binder; and ii) Lubricants A solid dosage form comprising at least one of the following, characterized by an X-ray powder diffraction pattern comprising a peak at a diffraction angle (2θ): 12.2±0.2.

[0351] 2.a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (compound A), and i) a first diluent and / or binder; and ii) Lubricants A solid dosage form comprising at least one of: 1. A solid dosage form, wherein 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is in a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.7±0.2, 11.8±0.2, 14.4±0.2, 17.2±0.2, 22.2±0.2, 27.2±0.2, 32.5±0.2.

[0352] 3. The solid dosage form of embodiment 1 or embodiment 2, wherein the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[0353] 4. The solid dosage form of any one of the preceding embodiments, wherein said solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D50: 1 μm to 60 μm.

[0354] 5. The solid dosage form of embodiment 4, wherein the D50 is between 3 μm and 50 μm.

[0355] 6. The solid dosage form of embodiment 4, wherein the D50 is 5 μm to 30 μm.

[0356] 7. The solid dosage form of any one of the preceding embodiments, wherein said solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D10: ≧0.3 μm.

[0357] 8. The solid dosage form of embodiment 7, wherein the D10 is ≧0.5 μm.

[0358] 9. The solid dosage form of embodiment 7, wherein the D10 is ≧1 μm.

[0359] 10. The solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide.

[0360] 11. The solid dosage form of embodiment 10, wherein the D90 is ≦80 μm.

[0361] 12. The solid dosage form of embodiment 10, wherein the D90 is ≦60 μm.

[0362] 13. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having particle sizes of D10: ≧0.3 μm, D50: 1 μm to 60 μm, and D90: ≦100 μm.

[0363] 14. The solid dosage form of embodiment 13, wherein the 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size of D10: ≧0.5 μm, D50: 2 μm to 50 μm, and D90: ≦80 μm.

[0364] 15. The solid dosage form of embodiment 13, wherein the 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has a particle size of D10: ≧1 μm, D50: 5 μm to 30 μm, and D90: ≦60 μm.

[0365] 16. The solid dosage form comprises: a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, b) a first diluent and / or binder; and c) lubricants, 2. The solid dosage form of any one of the preceding embodiments, comprising:

[0366] 17. The solid dosage form comprises: i) disintegrants and glidants, and / or ii) a second diluent 2. The solid dosage form of any one of the preceding embodiments, further comprising:

[0367] 18. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide in an amount of about 1% to about 60% by weight.

[0368] 19. The solid dosage form of embodiment 18, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide in an amount of about 2% to about 40% by weight.

[0369] 20. The solid dosage form of embodiment 18, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide in an amount of about 3% to about 30% by weight.

[0370] 21. The solid dosage form of any of the previous embodiments, wherein the solid dosage form comprises a first diluent and / or binder, and the first diluent and / or binder is present in an amount of about 20% to about 98% by weight.

[0371] 22. The solid dosage form of embodiment 21, wherein the solid dosage form comprises a first diluent and / or binder, and wherein the first diluent and / or binder is present in an amount of about 30% to about 80% by weight.

[0372] 23. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a second diluent, and wherein the second diluent is present in an amount of about 1% to about 40% by weight.

[0373] 24. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a second diluent, and wherein the second diluent is present in an amount of about 2% to about 40% by weight.

[0374] 25. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a second diluent, and wherein the second diluent is present in an amount of about 3% to about 30% by weight.

[0375] 26. The solid dosage form of embodiment 25, wherein the solid dosage form comprises a second diluent, wherein the second diluent is present in an amount of less than about 10% by weight.

[0376] 27. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a glidant, and wherein the glidant is present in an amount of about 0.25% to about 7% by weight.

[0377] 28. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a glidant, and wherein the glidant is present in an amount of about 0.3% to about 5% by weight.

[0378] 29. The solid dosage form of embodiment 27, wherein the solid dosage form comprises a glidant, and wherein the glidant is present in an amount of about 0.5% to about 2% by weight.

[0379] 30. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and wherein the disintegrant is present in an amount of about 0.5% to about 25% by weight.

[0380] 31. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and wherein the disintegrant is present in an amount of about 1% to about 20% by weight.

[0381] 32. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and wherein the disintegrant is present in an amount of about 2% to about 10% by weight.

[0382] 33. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and wherein the disintegrant is present in an amount of about 3% to about 7% by weight.

[0383] 34. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a lubricant, and wherein the lubricant is present in an amount of about 0.1% to about 15% by weight.

[0384] 35. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a lubricant, and wherein the lubricant is present in an amount of about 0.1% to about 12% by weight.

[0385] 36. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a lubricant, and wherein the lubricant is present in an amount of about 5% to about 10% by weight.

[0386] 37. The solid dosage form of embodiment 36, wherein the solid dosage form comprises a lubricant, and wherein the lubricant is present in an amount of about 1% to about 5% by weight.

[0387] 38. The solid dosage form comprises a binder, and the binder is present in an amount of from about 0.5% to about 30% by weight.

[0023] The solid dosage form of any one of the preceding embodiments, wherein

[0388] 39. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a binder, and wherein the binder is present in an amount of about 1% to about 20% by weight.

[0389] 40. The solid dosage form of embodiment 39, wherein the solid dosage form comprises a binder, and wherein the binder is present in an amount of about 2% to about 10% by weight.

[0390] 41. The solid dosage form of embodiment 39, wherein the solid dosage form comprises a binder, and wherein the binder is present in an amount of about 3% to about 7% by weight.

[0391] 42. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form further comprises a coating.

[0392] 43. The solid dosage form of embodiment 42, wherein the coating comprises a capsule coating or a film coating.

[0393] 44. The solid dosage form of embodiment 42, wherein the coating comprises a film coating.

[0394] 45. The solid dosage form of any one of the preceding embodiments, wherein the first diluent and / or second diluent independently have a particle size D50 of less than 500 μm.

[0395] 46. ​​The solid dosage form of embodiment 45, wherein the first diluent and / or the second diluent independently have a particle size D50 of less than 300 μm.

[0396] 47. The solid dosage form of embodiment 45, wherein the first diluent and / or second diluent independently have a particle size D50 of less than 200 μm.

[0397] 48. The solid dosage form of any one of the preceding embodiments, wherein the first diluent and / or second diluent independently have a moisture content of less than about 15%.

[0398] 49. The solid dosage form of embodiment 48, wherein the first diluent and / or second diluent independently have a moisture content of less than about 7%.

[0399] 50. The solid dosage form of any of the previous embodiments, wherein the first and / or second diluents are independently selected from the group consisting of lactose, starch, starch derivatives, cellulose, calcium phosphate, or mixtures thereof.

[0400] 51. The solid dosage form of any one of the preceding embodiments, wherein the first and / or second diluents are independently selected from the group consisting of lactose, starch, starch derivatives, cellulose, or mixtures thereof.

[0401] 52. The solid dosage form of embodiment 51, wherein the first diluent and second diluent are, independently, polymeric diluents.

[0402] 53. The solid dosage form of embodiment 51, wherein the first diluent is microcrystalline cellulose and / or the second diluent is a starch derivative.

[0403] 54. The solid formulation of embodiment 51, wherein the second diluent is pregelatinized starch. shape.

[0404] 55. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a glidant, and the glidant is an anhydrous glidant.

[0405] 56. The solid dosage form of embodiment 55, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, PEG6000, or a mixture thereof.

[0406] 57. The solid dosage form of embodiment 55, wherein the glidant is talc or colloidal silicon dioxide.

[0407] 58. The solid dosage form of embodiment 55, wherein the glidant is colloidal silicon dioxide.

[0408] 59. The solid dosage form comprises a glidant, and the glidant has a viscosity of about 10 ml as measured using the BET method. 2 1. The solid dosage form of any one of the preceding embodiments, having a surface area of ​​greater than 1000 nm / g.

[0409] 60. The solid dosage form comprises a glidant, and the glidant has a viscosity of about 100 ml as measured using the BET method. 2 60. The solid dosage form of embodiment 59, having a surface area of ​​more than 1000 mg / g.

[0410] 61. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is less than 500 μm.

[0411] 62. The solid dosage form of embodiment 61, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is less than 300 μm.

[0412] 63. The solid dosage form of embodiment 61, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is less than 150 μm.

[0413] 64. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a disintegrant, and the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, or a mixture thereof.

[0414] 65. The solid dosage form of embodiment 64, wherein the disintegrant is crospovidone or sodium starch glycolate.

[0415] 66. The solid dosage form of embodiment 64, wherein the disintegrant is crospovidone.

[0416] 67. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form comprises a lubricant, and the lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, or mixtures thereof.

[0417] 68. The solid dosage form of embodiment 67, wherein the lubricant is magnesium stearate.

[0418] 69. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form further comprises a binder, and the binder is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, pregelatinized maize starch, gelatin, or a mixture thereof.

[0419] 70. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form further comprises a binder, the binder being selected from the group consisting of povidone, hypromellose, pregelatinized maize starch, or a mixture thereof.

[0420] 71. The solid dosage form of embodiment 70, wherein the binder is povidone or methylcellulose.

[0421] 72. The solid dosage form of embodiment 70, wherein the binder is povidone.

[0422] 73. The solid dosage form of any one of the preceding embodiments, wherein the drug release (average 6 units) is greater than about 60% in 90 minutes in Apparatus 2 (USP) at 100 rpm using 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate and having a pH of 4.5 at 37°C.

[0423] 74. The solid dosage form of embodiment 73, wherein the drug release (average 6 units) at 100 rpm in Apparatus 2 (USP) using 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate and having a pH of 4.5 at 37°C is greater than about 50% in 60 minutes.

[0424] 75. The solid dosage form of embodiment 73, wherein the drug release (average 6 units) is greater than about 60% in 60 minutes in Apparatus 2 (USP) using 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate and having a pH of 4.5 at 37°C at 100 rpm.

[0425] 76. The solid dosage form of embodiment 73, wherein the drug release (average 6 units) at 100 rpm in Apparatus 2 (USP) using 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate and having a pH of 4.5 at 37°C is greater than about 70% in 60 minutes.

[0426] The solid dosage form of any one of the preceding embodiments, wherein after 6 months of storage at 77.40°C and 75% HR, greater than about 50% of Compound A is present as Form B, wherein Form B is identified by the presence of peaks (2θ) 12.2 in an X-ray diffraction pattern, and Form A is identified by the presence of peaks (2θ) 5.6 and 17.1 in an X-ray diffraction pattern.

[0427] 78. The solid dosage form of embodiment 77, wherein after 6 months of storage at 40°C and 75% HR, greater than about 80% of Compound A is present as Form B, which is identified by the presence of peaks (2θ) 12.2 in an X-ray diffraction pattern, and Form A is identified by the presence of peaks (2θ) 5.6 and 17.1 in an X-ray diffraction pattern.

[0428] 79. The solid dosage form of embodiment 77, wherein after 6 months of storage at 40°C and 75% HR, greater than about 90% of Compound A is present as Form B, which is identified by the presence of peaks (2θ) 12.2 in an X-ray diffraction pattern, and Form A is identified by the presence of peaks (2θ) 5.6 and 17.1 in an X-ray diffraction pattern.

[0429] 80. The solid dosage form of any one of the preceding embodiments, wherein less than about 10% degradants are produced after storage at 40°C and 75% HR for 6 months, after storage at 25°C and 65% HR for 18 months, and after storage at 70°C and 85% HR for 21 days.

[0430] 81. The solid dosage form of embodiment 80, wherein the solid dosage form produces less than about 5% decomposition products after 6 months of storage at 40°C and 75% HR, after 18 months of storage at 25°C and 65% HR, and after 21 days of storage at 70°C and 85% HR.

[0431] 82. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form produces less than about 3% degradants after storage at 40°C and 75% HR for 6 months, after storage at 25°C and 65% HR for 18 months, and after storage at 70°C and 85% HR for 21 days.

[0432] 83. A method for producing a solid dosage form according to any one of embodiments 1 to 82, comprising: a) mixing a predetermined amount of compound A and at least one of a first diluent, a second diluent, a lubricant, a glidant, a disintegrant, and a binder in a mixer; b) optionally granulating the resulting mixture to obtain granules; and c) Compressing the mixture obtained in a) or the granules of b) to form tablets, or filling the mixture obtained in a) or the granules of b) into capsules. A method comprising:

[0433] 84.a) mixing a predetermined amount of compound A and at least one of a first diluent and / or binder, a lubricant, a glidant, a disintegrant, a second diluent, and a binder in a mixer; and i) wetting the mixture obtained in step a) with a solvent such as ethanol or acetone to obtain wet granules, drying the obtained granules, and subsequently roller compacting the obtained mixture to obtain granules; ii) compressing the mixture of step a) to form tablets; and iii) filling the mixture obtained from step a) or step i) into capsules. 84. A method for producing a solid dosage form according to any one of embodiments 1 to 82 described in claim 83, comprising any one of:

[0434] 85. The method of embodiment 83 or 84, wherein the method comprises directly compressing the mixture obtained in step a).

[0435] 86. The method of any one of embodiments 83-85, wherein the method further comprises adding additional excipients to the mixer after step a).

[0436] 87. The method of any one of embodiments 83-86, wherein the method further comprises coating the obtained solid dosage form.

[0437] 88. The method of any one of embodiments 83-87, wherein the amount of Compound A is micronized Compound A, preferably having a particle size as defined below: a. D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm; b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm.

[0438] 89. The method of any one of embodiments 83-87, wherein the method further comprises micronizing the particles of Compound A to obtain a suitable particle size, preferably, the particle size is as defined below: a. D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm; b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm.

[0439] 90. A solid dosage form obtained by the method according to any one of embodiments 83 to 89.

[0440] 91. The solid dosage form of any one of embodiments 1-82 for use in treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease, disease with Lewy bodies, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

[0441] 92. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size defined below. a. D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably 5 μm to 30 μm; b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm

[0442] 93. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D10: ≧0.3 μm, D50: 1 μm to 60 μm, and D90: ≦100 μm, preferably a particle size of D10: ≧0.5 μm, D50: 2 μm to 50 μm, and D90: ≦80 μm, even more preferably a particle size of D10: ≧1 μm, D50: 5 μm to 30 μm, and D90: ≦60 μm.

[0443] 94. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to embodiment 92 or 93, obtained by micronizing crystalline particles of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[0444] 95. The crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 94, wherein the micronization is carried out by jet milling, mechanical milling, fluid milling, crushing, or grinding.

[0445] 96. The crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 95, wherein the crystalline form is form A or form B.

[0446] 97. A pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 96 and at least one pharmaceutically acceptable carrier or excipient.

[0447] 98. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 96, in combination with at least one pharmaceutically acceptable carrier or excipient. A pharmaceutical composition obtained by a process comprising the step of mixing.

[0448] 99. The pharmaceutical composition of embodiment 97 or 98, wherein the composition is a solid dosage form.

[0449] 100. A method for preparing a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, comprising mixing the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 96 with at least one pharmaceutically acceptable carrier or excipient.

[0450] 101. The solid dosage form of any one of embodiments 1 to 82 and 90, the crystalline form of any one of embodiments 92 to 96, or the pharmaceutical composition of any one of embodiments 97 to 99, for use in treating a disease selected from the group consisting of Gaucher disease, Parkinson's disease, disease with Lewy bodies, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

[0451] The solid dosage form, crystalline form, or pharmaceutical composition of embodiment 101, wherein the disease is Parkinson's disease, e.g., GBA-PD.

Claims

1. a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), and i) a first diluent and / or binder; and ii) Lubricants A solid dosage form comprising at least one of: A solid dosage form characterized by an X-ray powder diffraction pattern including a peak at diffraction angle (2θ): 12.2±0.

2.

2. a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), and i) a first diluent and / or binder; and ii) Lubricants A solid dosage form comprising at least one of:

1. A solid dosage form, wherein 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide is in a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.7±0.2, 11.8±0.2, 14.4±0.2, 17.2±0.2, 22.2±0.2, 27.2±0.2, 32.5±0.

2.

3. 3. The solid dosage form of claim 1 or 2, wherein the solid dosage form comprises micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

4. the solid dosage form comprising: D50: particle size of 1 μm to 60 μm, preferably 3 μm to 50 μm, or more preferably 5 μm to 30 μm, and / or D10: a particle size of ≧0.3 μm, preferably ≧0.5 μm, or more preferably ≧1 μm, and / or 4. The solid dosage form of any one of claims 1 to 3, comprising micronized 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size of D90:≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm.

5. 5. The solid dosage form of claim 1, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having particle sizes of D10: ≧1 μm, D50: 5 μm to 30 μm, and D90: ≦60 μm, preferably D10: ≧0.5 μm, D50: 2 μm to 50 μm, and D90: ≦80 μm, even more preferably D10: ≧0.3 μm, D50: 1 μm to 60 μm, and D90: ≦100 μm.

6. the solid dosage form comprising: a) 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, b) a first diluent and / or binder; and c) Lubricant 6. The solid dosage form of any one of claims 1 to 5, comprising:

7. the solid dosage form comprising: i) disintegrants and glidants, and / or ii) a second diluent 7. The solid dosage form of any one of claims 1 to 6, further comprising:

8. 8. The solid dosage form of any one of claims 1 to 7, wherein the solid dosage form comprises 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide in an amount of about 1% to about 60% by weight, preferably about 2% to about 40% by weight, and more preferably about 3% to about 30% by weight.

9. 9. The solid dosage form of any one of claims 1 to 8, wherein the solid dosage form comprises a first diluent and / or binder, the first diluent and / or binder being present in an amount of from about 20% to about 98% by weight, preferably from about 30% to about 80% by weight.

10. 10. The solid dosage form of any one of claims 1 to 9, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount of from about 3% to about 30% by weight, preferably less than about 10% by weight.

11. 11. The solid dosage form of any one of claims 1 to 10, wherein the solid dosage form comprises a glidant, wherein the glidant is present in an amount of from about 0.3% to about 5% by weight, preferably from about 0.5% to about 2% by weight.

12. 12. The solid dosage form of any one of claims 1 to 11, wherein the solid dosage form comprises a disintegrant, wherein the disintegrant is present in an amount of from about 1% to about 20% by weight, preferably from about 2% to about 10% by weight, and more preferably from about 3% to about 7% by weight.

13. 13. The solid dosage form of any one of claims 1 to 12, wherein the solid dosage form comprises a lubricant, wherein the lubricant is present in an amount of from about 5% to about 10% by weight, more preferably from about 1% to about 5% by weight.

14. 14. The solid dosage form of any one of claims 1 to 13, wherein the solid dosage form comprises a binder, and wherein the binder is present in an amount of from about 1% to about 20% by weight, preferably from about 2% to about 10% by weight, and more preferably from about 3% to about 7% by weight.

15. A solid dosage form according to any one of claims 1 to 14, wherein the solid dosage form further comprises a coating, preferably wherein the coating comprises a capsule coating or a film coating.

16. 16. The solid dosage form of any one of claims 1 to 15, wherein the solid dosage form further comprises a film coating.

17. 17. A solid dosage form according to any one of claims 1 to 16, wherein the first diluent and / or second diluent independently have a particle size D50 of less than 500 μm, preferably less than 300 μm, more preferably less than 200 μm.

18. 18. The solid dosage form of any one of claims 1 to 17, wherein the first diluent and / or second diluent independently have a moisture content of less than about 15%, preferably less than about 7%.

19. The first diluent and / or second diluent are independently selected from the group consisting of lactose, starch, starch derivatives, cellulose, or mixtures thereof, preferably the first diluent and second diluent are independently polymeric diluents, more preferably 19. The solid dosage form of any one of claims 1 to 18, wherein the first diluent is microcrystalline cellulose and / or the second diluent is a starch derivative, most preferably the second diluent is pregelatinized starch.

20. 20. A solid dosage form according to any one of claims 1 to 19, wherein the solid dosage form comprises a glidant, preferably an anhydrous glidant.

21. 21. The solid dosage form of any one of claims 1 to 20, wherein the solid dosage form comprises a glidant, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, PEG 6000, or a mixture thereof, preferably wherein the glidant is talc or colloidal silicon dioxide, more preferably wherein the glidant is colloidal silicon dioxide.

22. The solid dosage form comprises a glidant, and the glidant has a viscosity of about 10 ml as measured using the BET method. ２ / g, more preferably about 100m ２ 22. A solid dosage form according to any one of claims 1 to 21, having a surface area of ​​more than 1 / g.

23. 23. The solid dosage form according to any one of claims 1 to 22, wherein the solid dosage form comprises a disintegrant, the particle size D90 of the disintegrant being less than 500 μm, preferably less than 300 μm, more preferably less than 150 μm.

24. 24. The solid dosage form of any one of claims 1 to 23, wherein the solid dosage form comprises a disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, or a mixture thereof, preferably the disintegrant is crospovidone or sodium starch glycolate, more preferably the disintegrant is crospovidone.

25. 25. The solid dosage form according to any one of claims 1 to 24, wherein the solid dosage form comprises a lubricant, the lubricant being selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, or mixtures thereof, preferably magnesium stearate.

26. 26. The solid dosage form of any one of claims 1 to 25, further comprising a binder selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, pregelatinized maize starch, gelatin, or mixtures thereof, preferably the binder is povidone or methylcellulose, more preferably povidone.

27. 27. The solid dosage form of any one of claims 1 to 26, wherein the drug release (average 6 units) in Apparatus 2 (USP) at 100 rpm using 900 ml of acetate buffer containing 0.05% sodium dodecyl sulfate and having a pH of 4.5 at 37°C is greater than about 60% at 90 minutes, preferably greater than about 60% at 60 minutes, and more preferably greater than about 70% at 60 minutes.

28. 28. The solid dosage form of any one of claims 1 to 27, wherein after storage at 40°C and 75% HR for 6 months, greater than about 50% of Compound A is present as Form B, preferably greater than 80% is present as Form B, and more preferably greater than 90% is present as Form B, wherein Form B is identified by the presence of a peak (2θ) 12.2 in an X-ray diffraction pattern and Form A is identified by the presence of peaks (2θ) 5.6 and 17.1 in an X-ray diffraction pattern.

29. Stored at 40°C and 75% HR for 6 months, then stored at 25°C and 65% HR for 18 months 29. The solid dosage form of any one of claims 1 to 28, wherein the solid dosage form yields less than about 10% degradants, more preferably less than about 5% degradants, and even more preferably less than about 3% degradants after heating and after storage at 70°C and 85% HR for 21 days.

30. Ingredients: -Compound A: 1-50% - First diluent: 20-98% - Second diluent: 0-40% - Lubricant: 0.1 to 15% - Binder: 0-30% Disintegrant: 0-30% - Glidant: 0-10% 30. The solid dosage form of any one of claims 1 to 29, comprising:

31. A method for producing a solid dosage form according to any one of claims 1 to 30, comprising the steps of: a) mixing a predetermined amount of Compound A and at least one of a first diluent, a second diluent, a lubricant, a glidant, a disintegrant, and a binder in a mixer; b) optionally granulating the resulting mixture to obtain granules; and c) compressing the mixture obtained in a) or the granules of b) to form tablets or filling the mixture obtained in a) or the granules of b) into capsules. A method comprising:

32. a) mixing a predetermined amount of Compound A and at least one of a first diluent and / or binder, a lubricant, a glidant, a disintegrant, a second diluent, and a binder in a mixer; and i) wetting the mixture obtained in step a) with a solvent such as ethanol or acetone to obtain wet granules, drying the obtained granules, and subsequently roller compacting the obtained mixture to obtain granules; ii) compressing the mixture of step a) to form tablets; and iii) filling the mixture obtained from step a) or step i) into capsules.

32. The method of claim 31 for producing the solid dosage form of any one of claims 1 to 30, comprising:

33. 33. The method of claim 31 or 32, wherein the method comprises directly compressing the mixture obtained in step a).

34. 34. The method of any one of claims 31 to 33, wherein the method further comprises adding a further excipient to the mixer after step a).

35. 35. The method of any one of claims 31 to 34, wherein the method further comprises coating the resulting solid dosage form.

36. 36. The method of any one of claims 31 to 35, wherein the method further comprises micronizing the particles of Compound A to obtain a suitable particle size.

37. The predetermined amount of compound A is a micronized compound A, preferably having a particle size of: a. D50 is 1 μm to 60 μm, preferably 2 μm to 50 μm, or more preferably is 5 μm to 30 μm, b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm The method according to any one of claims 31 to 36, wherein

38. The method further comprises micronizing the particles of Compound A to obtain a suitable particle size, preferably the particle size is: a. D50 is from 1 μm to 60 μm, preferably from 2 μm to 50 μm, or more preferably from 5 μm to 30 μm; b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm The method according to any one of claims 31 to 37, wherein

39. A solid dosage form obtainable by the method of any one of claims 31 to 38.

40. 40. The solid dosage form of any one of claims 1 to 30 and 39 for use in treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease, disease with Lewy bodies, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

41. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having a particle size defined below. a. D50 is from 1 μm to 60 μm, preferably from 2 μm to 50 μm, or more preferably from 5 μm to 30 μm; b. D10 is ≥ 0.3 μm, preferably ≥ 0.5 μm, or more preferably ≥ 1 μm, and / or c. D90 is ≦100 μm, preferably ≦80 μm, or more preferably ≦60 μm

42. A crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide having particle sizes of D10: ≧0.3 μm, D50: 1 μm to 60 μm, and D90: ≦100 μm, preferably D10: ≧0.5 μm, D50: 2 μm to 50 μm, and D90: ≦80 μm, and even more preferably D10: ≧1 μm, D50: 5 μm to 30 μm, and D90: ≦60 μm.

43. The crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to claim 41 or 42, obtained by micronizing crystalline particles of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

44. 44. The 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidinium salt of claim 41, wherein the micronization is achieved by jet milling, mechanical milling, fluid milling, crushing, or grinding. Crystalline forms of din-3-carboxamide.

45. The crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of claims 41 to 44, wherein the crystalline form is Form A or Form B.

46. 46. ​​A pharmaceutical composition comprising the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide of any one of claims 41 to 45 and at least one pharmaceutically acceptable carrier or excipient.

47. 46. ​​A pharmaceutical composition obtainable by a process comprising the step of mixing a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide according to any one of claims 41 to 45 with at least one pharmaceutically acceptable carrier or excipient.

48. 48. The pharmaceutical composition of claim 46 or 47, wherein the composition is in a solid dosage form.

49. 46. ​​A method for preparing a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, comprising mixing the crystalline form of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide of any one of claims 41 to 45 with at least one pharmaceutically acceptable carrier or excipient.

50. 49. The solid dosage form of any one of claims 1 to 30 and 39, the crystalline form of any one of claims 41 to 45, or the pharmaceutical composition of any one of claims 46 to 48, for use in treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease, disease with Lewy bodies, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

51. 51. The solid dosage form, crystalline form, or pharmaceutical composition for use according to claim 50, wherein the disease is Parkinson's disease, e.g., GBA-PD.

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