WO2024181881A1

WO2024181881A1 - Formulation

Info

Publication number: WO2024181881A1
Application number: PCT/PT2024/050010
Authority: WO
Inventors: Hugo Miguel FERREIRA ALMEIDA; Teófilo CARDOSO DE VASCONCELOS; Pedro Miguel DA COSTA BARROCAS; Raquel de Queiroz PORTELA MENDES DE FIGUEIREDO; Cristina MESQUITA OLIVEIRA; Maria João TEIXEIRA ARAÚJO DOS SANTOS
Original assignee: Bial R&d Investments SA; Bial R&D Investments SA
Current assignee: Bial R&d Investments SA; Bial R&D Investments SA
Priority date: 2023-03-01
Filing date: 2024-03-01
Publication date: 2024-09-06
Anticipated expiration: 2025-09-01
Also published as: MX2025010378A; AR132044A1; KR20250170050A; CN121038783A; TW202502353A; AU2024229856A1; IL323027A

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); and at least one of a first diluent and/or binder; and a lubricant. A method for making the same and the use of said solid dosage form in the treatment of disease.

Description

Formulation

Field of the Invention

The present invention relates to a solid dosage form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolol[l,5-a]pyrimidine-3-carboxamide.

Background to the Invention

5,7-dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolol[l,5-a]pyrimidine-3- carboxamide (herein also referred to as "compound A") is an allosteric activator of the enzyme beta-glucocerebrosidase (GCase) being developed as a potential treatment for Parkinson's disease for patients with a mutation in the GBA1 gene (GBA-PD).

Compound A is present in four polymorphic forms: Form A (used in previous phase I clinical trials), Form B (thermodynamically most stable form at room temperature), Form C (metastable form) and Form D (hydrated form). In previous clinical trials of compound A an oral dosage form comprising polymorph Form A was used.

Whilst the polymorph Form B is the most thermodynamically stable, its solid state is still sensitive to hydrolysis and thermal degradation, including thermal degradation to other polymorphic forms, for example, Form A. It is therefore sensitive to the processing conditions commonly used during the preparation of an oral dosage form.

Additionally, compound A presents poor technological properties for formulation and industrial processing. For example, it has a small particle size, low bulk density (0.25g/mL), poor Hausner ratio (1.45), compressibility index (31) and no flow through a 010 mm orifice. Additionally, it presents low solubility. This makes it difficult to process into a clinical or commercial dosage form such as a tablet or capsule, and to solubilise.

Due to these difficulties, initial clinical studies used a drug in capsule dosage form that consists in manually or non-scalable equipment fill of capsules with the exact amount of compound. This process is extremely slow, variable and not scalable for larger clinical studies or commercial purposes. There is therefore a need to provide a robust and reproducible stable solid dosage form of compound A and a manufacturing process for manufacturing the same.

Summary of the Invention

In a first aspect of the invention, there is provided a solid dosage form comprising: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide; and at least one of i) a first diluent and/or binder; and ii) a lubricant, wherein the 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide is in the crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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 of those, 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 or wherein the solid dosage form is characterised by an X-ray powder diffraction pattern comprising peaks at the following diffraction angle (20): 12.2 ± 0.2.

In a second aspect of the invention, there is provided a solid dosage form comprising : a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine- 3-carboxamide; and at least one of i) a first diluent and/or binder; and ii) a lubricant, wherein the 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide is in the crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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 wherein the solid dosage form is characterised by an X-ray powder diffraction pattern comprising peaks (20) at 5.6± 0.2 and 17.1 ± 0.2.

The preferable process for forming an oral dosage form is to use powder direct compression, also known as direct compaction. Less equipment is required for a direct compression than for granulation processes. To provide a direct compression/ filling formulation, it is necessary to pre-blend the raw materials to provide a uniform tablet and to reduce segregation potential. However, compounds with poor technological properties, such as bulk density, particle size or flow rate are difficult to process into direct compression/ filling. Moreover, direct compression/ filling is also challenging to ensure a uniformity of content of compound in the final matrix. The crystal Forms A and B of compound A present very poor technological properties to be used in a direct compression/ filling process. In order to obtain a flowable powder that is capable of compression, it is necessary to include a first diluent and/or binder and/or a lubricant.

The solid dosage form of the first aspect of the invention can be formulated purely using compression without the need for the application of heat or moisture to the composition. The compound A in such a solid dosage form will therefore not undergo extensive polymorphic changes into a less stable form.

In a further embodiment of the first aspect of the invention, the solid dosage form is characterised by an X-ray diffraction pattern which does not comprise peaks at the following diffraction angles (20): 5.6 ± 0.2 and 17.1 ± 0.2.

The peaks at angles (20) 5.6 ± 0.2 and 17.1 ± 0.2 are indicative of the presence of Form A polymorphic form of Compound A in the solid dosage form. If the presence of the Form B identification peak at 12.2° ± 0.2 is confirmed, and the presence of both form A identification peaks is simultaneously also confirmed, the solid dosage form comprises a mixture of both Form A and Form B.

In a further embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide. This means that the crystalline Compound A that is used in the preparation of the solid dosage form has been micronized to reduce its particle size.

The particle size (distribution) of the micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide can be measured using any method known to the skilled person. For example, a laser light scattering method can be used, for example, using dry measurement with an air pressure of 1.0 bar and a feed rate of 35%. The particle size can be defined using the parameters D10, D50, and/or D90 or using any combination. The parameter D90 signifies the point in the size distribution, up to and including which, 90% of the total volume of material in the sample is ’contained'. For example, if the D90 is 60 pm, this means that 90% of the sample has a particle size of 60 pm or smaller, The definition for D50 is then the size point below which 50% of the material is contained. Similarly, the D10 is that size below which 10% of the material is contained. Possible values for D10, D50 and D90 are defined below, These may be used in isolation or in combination.

In view of the above, in the following description, the use of the expression ’micronized 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide having a particle size of D90' refers to the size which 90% of the total volume of material in the sample is below or equal to. For example, the expression 'micronized 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D90: < 100 pm' means that at least 90% of the total volume of material in the sample has a particle size which is less than or equal to 100 pm. Similarly, the expression 'micronized 5,7-Dimethyl-/V- ((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm' means that 50% of the total volume of material in the sample has a particle size which is more than or equal to 1pm and less than or equal to 60pm. Further, the expression 'micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm' means that less than 10% of the total volume of material in the sample has a particle size which is less than 0.3 pm.

Preferably, the particle size of the micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide is the particle size of the material that is used in the preparation of the solid dosage form. Preferably, this is the particle size of the material prior to the preparation of the solid dosage form.

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm, preferably 3pm - 50 pm, or more preferably 5pm - 30pm.

In another embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm, preferably > 0.5 pm, or more preferably > 1 pm. In a further embodiment of the first or second aspect, the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D90: < 100 pm, preferably < 80 pm, or more preferably < 60 pm.

In a further embodiment of the first or second aspect, the solid dosage form comprises 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm. Preferably the 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm; or even more preferably D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm.

If the particle size of the active compound is too large, the pharmacological characteristics of the active may be impaired. For example, the compound may have poor oral bioavailability as the large particles can take too long to dissolve in the intestinal fluids in the gastrointestinal tract of a patient. Additionally, the homogeneity of dosage (e.g. homogeneity of compound A in a tablet or within tablets) may be compromised. If the particle size of the compound A is too small, it can be difficult to prepare tablets. For example, small particles can exhibit poor flow characteristics or poor compression properties which may make it difficult to generate tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have poor hardness, exhibit poor homogeneity of content and/or exhibit poor uniformity of mass. This is particularly important if the manufacturing process is a direct compression or capsule filling.

In a further embodiment of the first or second aspect, the solid dosage form comprises: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide; b) a first diluent and/or binder; and c) a lubricant.

Surprisingly, the inclusion of a diluent and/or a binder and a lubricant ensure that the mixture has improved flowability, uniformity of content and dissolution. Good flowability is necessary to ensure good filing of a compression die for tabletting. Poor filing of the die results in uneven filing and non-uniformity of the resultant solid dosage form.

In a further embodiment 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.

A disintegrant improves the dissolution of Compound A in the digestive tract of a patient and improves the dissolution of the active ingredient in the dosage form. A glidant further improves the flowability of a mixture before compression enabling uniform filling of the die and ease of processing.

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

Inclusion of a second diluent improves the stability of the composition at high temperatures and high humidity.

The percentage range of components can be important for stability of the resultant composition.

In a further embodiment of the first or second aspect, the solid dosage form comprises: the 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (Compound A) in an amount from about 1% to about 60% by weight; preferably from about 1% to about 50% by weight; more preferably about 2% to about 40% by weight; even more preferably from about 3% to about 30% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount from about 1% to about 20% by weight, preferably from about 1% to about 10% by weight, or more preferably from about 1% to about 5% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount from about 3% to about 5% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount from about 10% to about 40% by weight, preferably from about 15% to about 35% by weight, or more preferably from about 20% to about 30% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount from about 23% to about 27% by weight. In some embodiments, the solid dosage form comprises Compound A in an amount from about 30% to about 60% by weight, preferably from about 35% to about 55% by weight, or more preferably from about 40% to about 50% by weight.

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

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

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

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

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

The amount of second diluent present in the solid dosage form affects the compression characteristics, namely hardness, disintegration and friability. If the amount of second diluent is too high, the solid dosage form is difficult to compress. If the second diluent is not present in a high enough concentration, the stability of the solid dosage form is reduced.

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

In a further embodiment of the first or second aspect, the solid dosage form comprises a glidant, the glidant being present in an amount from 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 from about 0.1% to about 10% by weight, preferably from about 0.1% to about 8% by weight, more preferably from about 0.25% to about 7% by weight or even more preferably from about 0.2% to about 6% by weight. In some embodiments, the glidant is present in an amount 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.

The amount of glidant used in the solid dosage form may be important. Excessive amounts could negatively impact the flow properties of the powder mixture by inhibiting its flowability, a lower amount may induce punch adherence.

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

The concentration of disintegrant impacts the technological properties of the tablets, namely the hardness and disintegration, this is important for controlling the dissolution rate of the COMPOUND A in a patient.

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

The amount of lubricant affects the flowability of the blend of ingredients. Many failures in pharmaceutical manufacturing operations are caused by issues related to lubrication. For example, if the concentration of the lubricant is too high, the stability of the compound A is adversely affected, dosage form hardness can be reduced, compression is impacted, and the rate of disintegration and dissolution of the dosage form is increased. If the concentration of the lubricant is too low, there is poor mixing of the ingredients resulting in uneven distribution of the compound A in the solid dosage forms.

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

The inclusion of a coating on the solid dosage form protects the compound A from moisture in the environment and provide aesthetical improvement. Additionally, a coating improves the colouring of the resultant solid dosage form. Examples of suitable coatings used in an embodiment of the invention include a capsule and/or a film coating.

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

In a further embodiment of the first or second aspect, the first and/or second diluent independently has a particle size D50 of below 500 pm, preferably below 300 pm, and more preferably below 200 pm.

The particle size of the diluent affects the flowability characteristics of the blend prior to compression. D50 is the corresponding particle size when the cumulative percentage reaches 50%. D50 is sometimes referred to as the median particle diameter or median particle size. For example, for a powder sample with D50 = 250 pm 50% of particles are larger than 250 pm and 50% of particles are smaller than 250 pm. The D50 particle size may be measured by any suitable means known in the art. For example, dynamic light scattering (DLS), laser diffraction, sieve analysis, dynamic image analysis (DIA), and static image analysis (SIA).

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

Compound A is sensitive to degradation and/or polymorphic change by hydration. It is therefore important to control the moisture content in any solid dosage form.

In a further embodiment of the first or second aspect, the first and/or second diluent is independently selected from the group consisting of sugars such as, sugar, sucrose, powdered sucrose, fructose, lactose, powdered hydrogenated maltose starch syrup, and maltose; sugar alcohols such as D-mannitol, D-sorbitol, xylitol, erythritol, maltitol; starch such as maize starch, wheat starch, corn starch, and potato starch; starch derivatives such as dextrin, beta-cyclodextrin (for example, a starch in which some of the d-glucopyranosyl units in the molecule have been modified, including pre-gelatinized starch), a cellulose or a derivative thereof such as microcrystalline cellulose, powdered cellulose, ethyl cellulose, a phosphate derivative (for example, calcium, sodium, potassium, magnesium, and ammonium phosphate (mono-, di-, and tri-basic)), cellulose, or a mixture thereof. Co-processed diluents combining one or more diluents, such as Prosovol®, cellacotse®, combilac®, Disintequik®, CompactCel® or others. In some embodiments, the first and/or second diluent is 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 diluent is independently selected from microcrystalline cellulose, pre-gelatinized starch, maize starch, lactose and a phosphate derivative (e.g. calcium phosphate). Preferably, the first and second diluents 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 pre-gelatinized starch.

It has surprisingly been found that microcrystalline cellulose and pregelatinized starch are particularly good at stabilising the dosage forms of the present invention.

In a further embodiment of the first and second aspect, 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, wherein the glidant is colloidal silicon dioxide.

Compound A is sensitive to degradation by hydration. It is therefore important to control the moisture content in any solid dosage form. The inclusion of an anhydrous glidant limits the moisture in the solid dosage form.

In a further embodiment of the first and second aspect, the glidant has a surface area (measured using the Branauer-Emmett-Teller (BET) method) above about 10 m²/g and more preferably above about 100 m²/g.

It has been suggested that a glidant improves the flowability of an API by occupying the spaces between the powder particles reducing contact between individual particles of the API. The BET method for measuring surface area of a substance forms part of the common general knowledge of the skilled person. Briefly, the surface area of a substance is determined by the physical adsorption of a gas (typically nitrogen, krypton, or argon) onto the surface of a sample at cryogenic temperatures).

In a further embodiment of the first or second aspect of the invention, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, magnesium silicate, polyethylene glycol (e.g. PEG6000, PEG 10,000, etc.), PEG derivate or mixtures thereof. In some embodiments, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, magnesium silicate, PEG derivate or mixtures thereof. Preferably, the glidant is polyethylene glycol (e.g. PEG6000, 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.

In a further embodiment of the first or second aspect of the invention, the particle size of the disintegrant is below a D90 of about 500 pm, preferably below a D90 of about 300 pm and more preferably below a D90 of about 150 pm. D90 is the corresponding particle size when the cumulative percentage reaches 90%. For example, for a powder sample with D90 = 500 pm, 90% of particles are smaller than 500 pm and 10% of particles are larger than 500 pm. The D90 particle size may be measured by any suitable means known in the art. For example, dynamic light scattering (DLS), laser diffraction, sieve analysis, dynamic image analysis (DIA), and static image analysis (SIA).

The particle size of the disintegrant impacts the disintegration time of the solid dosage form, it also affects the flowability of the blend prior to compression. For example, a larger particle size may improve the flow of the blend prior to compression but decrease the disintegration time of the resultant solid dosage form.

In a further embodiment of the first or second aspect of the invention, the disintegrant is selected from the group consisting include starch or a derivative thereof such as wheat starch, potato starch, corn starch partially pregelatinized starch, sodium carboxymethyl starch, and hydroxypropyl starch; cellulose or a derivative thereof such as microcrystalline cellulose, carboxymethyl cellulose (carmellose), calcium carboxymethyl cellulose (carmellose calcium), croscarmellose sodium, and low-substituted hydroxypropyl cellulose; crospovidone; alginic acid; and bentonite or mixtures 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.

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, aluminium stearate, calcium stearate, sodium stearyl fumarate, carnauba wax; glycerol ester of fatty acid; hydrogenated oil; yellow beeswax; white beeswax; talc; and polyethylene glycol (macrogols such as 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.

The inclusion of magnesium stearate improves the flow of the blend in the compression machine.

In a further embodiment of the first or second aspect of the 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, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, ethyl-cellulose, pregelatinized maize starch, partially pregelatinized starch; gelatine, acrylic acid based polymer 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 mixtures 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, and more preferably povidone. In some embodiments, the solid dosage forms according to the invention may comprise the following ingredients, the ranges being expressed in percentages by weight of the overall composition:

Al) - 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%

Cl) - 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%

DI) - 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% El) - 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: 1-10% - first diluent: 75-98%

- lubricant: 1-10%

Z) - compound A: 1-10%

- first diluent: 50-75%

- second diluent: 15-30%

- lubricant: 0.1-10%

In some embodiments for the solid dosage forms A) to Z) above, the first and second diluents (where present) may be selected from microcrystalline cellulose, starch, pregelatinized starch, lactose and calcium phosphate. The binder (where present) may be selected from povidone and hypromellose. The lubricant may be selected from magnesium stearate, sodium stearyl fumarate and stearic acid.

In addition, in some embodiments for the solid dosage forms A) to Z) above, the solid dosage form may comprise a disintegrant, for example, selected from crospovidone, sodium croscarmellose and sodium starch glycolate.

In addition, in some embodiments for the solid dosage forms A) to Z) above, the solid dosage form may comprise a glidant, for example, selected from colloidal silicon dioxide, polyethylene glycol (e.g. PEG 10 000) and talc.

The solid dosage forms A) to Z) above are exemplary embodiments, but the other description of the solid dosage forms is equally applicable to solid dosage forms A) to Z) above. For example, for the selection of possible ingredients falling within each excipient type (first diluent, second diluent, binder, lubricant), the other parts of the description equally apply. In addition, where alternative ranges are given for each ingredient (compound A, first diluent, second diluent, binder, lubricant) elsewhere in the description, these can be interchanged with the ranges given in the solid dosage forms A) to Z) above.

In particular embodiments, the solid dosage forms according to the invention may comprise the following ingredients, the ranges being expressed in percentages by weight of the overall composition:

- compound A: 1-50% - first diluent: 20-98%

- second diluent: 0-40%

- lubricant: 0.1-15%

- binder: 0 to 30%

- disintegrant: 0 to 30%

- glidant: 0 to 10%

For the particular embodiments above, alternative ranges for each ingredient found elsewhere in the description can be interchanged with the ranges given in the particular embodiments.

In some embodiment, the excipient blend in the solid dosage form does not consist of only calcium phosphate at about 86%-87%, maize starch at about 2.5%-3.5% and magnesium stearate at about 6%-7% as it can give the solid dosage form unusual dissolution characteristics. In a particular embodiment, the excipient blend in the solid dosage form does not consist of calcium phosphate at about 86.36%, maize starch at about 3% and magnesium stearate at about 6.38%.

In a further embodiment the present invention may comprise other components. Examples of other components include, surfactants, pH adjusters, preservatives, taste enhancers, antioxidants, buffers, chelating agents, solvents, hardening agents, sweeteners, brightening agents, and flavors.

In an embodiment of the first or second aspect of the invention, a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer at a pH of 4.5 at 37 ±0.5 °C with 0.05% of sodium dodecyl sulphate and 100 rpm for the solid dosage form is more than about 60% in 90 minutes, preferably more than about 60% in 60 minutes and even more preferably more than about 70% in 60 minutes.

The USP dissolution test is a standard dissolution test.

In an embodiment of the first or second aspect of the invention, more than about 50% of the compound A is present as Form B after 6 months stored at 40°C and 75% relative humidity, preferably more than about 80% as Form B and even more preferably more than about 90% as Form B; wherein Form B is identified as the presence of peak (20) 12.2 ± 0.2 in an X-ray diffraction pattern and Form A is identified as the presence of peaks (20) at 5.6± 0.2 and 17.1 ± 0.2 in an X-ray diffraction pattern.

In an embodiment of the first or second aspect of the invention, less than about 10 % of degradation products of compound A are found after 6 months stored at 40°C and about 75% relative humidity, after 18 months stored at 25°C and about 65% relative humidity and or after 21 days stored at 70°C and 85% relative humidity, more preferably less than about 5% of degradation products and even preferably less than about 3% of degradation products.

A third aspect of the invention provides a method for preparing a solid dosage form, for example the solid dosage form of the first or second aspect of the invention comprising: a) mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; and either: i. wet the mixture obtained with a solvent, such as ethanol or acetone to obtain wet granules and dry the resulting granules; roller compact the mixture obtained to obtain granules; ii. compress the mixture to form tablets; or iii. fill a capsule with the mixture obtained in a) or step i).

Alternatively, there is provided a method for preparing a solid dosage form, for example the solid dosage form of the first or second aspect of the invention comprising: a) mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; b) optionally, granulating the mixture obtained to obtain granules; and c) compressing the mixture obtained in a) or the granules in b) to form tablets; or filling a capsule with the mixture obtained in a) or the granules in b).

The granulation step in the method above can comprise wet granulation with a granulation liquid such as water, ethanol or acetone. Following wet granulation with the granulation liquid, the granules may be dried. The granulation step in the method above can comprise dry granulation. This involves compressing the mixture to obtain granules. This can be by roller compaction or compression.

The use of a wet granulation process as described above (e.g. in step i)) produces largely spherical granules which have better flow properties than a powder. Without wishing to be bound by theory, spherical particles flow better and compress easier meaning that lower pressure can be used during compression into a solid dosage form. In addition, a wet granulation process prevents segregation of components of a homogenous powder mix during processing, transferring, handling and/or storage, leading to reduced intra- and inter- batch variability.

The use of a direct compression method as described above (e.g. in step ii)) as opposed to a granulation or other method requires less equipment and fewer production stages. This reduces the associated labour costs, processing time and energy consumption. Another important advantage of the direct compression process is that it is a dry procedure with no need for a drying stage hence no heat and moisture related concerns. It is important to pre-coat the mixer with the excipients before the addition of the API to reduce the loss of active ingredient adhered to the sides of the mixer.

The formation of capsules as described in step iii) is a simple process requiring no need for complex equipment. The use of capsules also protects compound A from moisture or pressure since there is no need for the application of liquid or heat.

In a further embodiment of the third aspect of the invention, the method comprises direct compression of the mixture produced in step a).

In a particular embodiment of the method for preparing a solid dosage form, the method comprises: mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; wetting the mixture obtained 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. In another embodiment of the method for preparing a solid dosage form, the method comprises: mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; roller compacting the mixture obtained to obtain granules; and compressing the mixture to form tablets.

In a further embodiment of the method for preparing a solid dosage form, the method comprises: mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; dry granulating the mixture obtained to obtain granules; and compressing the mixture to form tablets.

In another embodiment of the method for preparing a solid dosage form, the method comprises: mixing a predetermined amount of Compound A with a composition as described in any one of the first or second aspect described above in a mixer; and compressing the mixture to form tablets.

In a further embodiment of the third aspect of the invention, the method further comprises: i) addition of further excipients to the mixer after step a).

In the case where excipients have a high moisture content or are chemically incompatible with the Compound A, it can be useful to add them to the mixer after the Compound A has been blended with other excipients.

In a further embodiment of the third aspect of the invention, the mixing time for each individual step is between about 1 and about 60 minutes, preferably between about 1 and about 30 minutes. Each individual step may have the same or different mixing time. In a further embodiment of the third aspect of the invention, the mixing speed for each individual step is between about 1 rpm and about 60 rpm, preferably between about 5 rpm and about 25 rpm. Each individual step may have the same or different mixing speed.

In a further embodiment of the third aspect of the invention, the method further comprises: ii) coating the obtained solid dosage form.

In a further embodiment 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 micronized Compound A is as described above. Preferably, the micronization is carried out prior to the mixing step.

Processing of the crystalline compound to the defined particle size may be done by any suitable method known to the skilled person. For example, the crystalline compound may be micronized. This may be by jet milling, mechanical milling, fluid milling, crushing or grinding. In a particular embodiment, jet milling is used.

As discussed above in relation to the first and second aspects, the particle size of compound A can impact the properties of the resultant formulation.

Also provided by the invention is a solid dosage form obtainable by the method (s) as described above. In particular, the solid dosage form is obtainable by any of the methods described for the third aspect of the invention.

In a fourth aspect of the invention, there is provided a solid dosage form as described in the first or second aspect of the invention for use in 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma. In a fifth aspect of the 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma. The method comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form as described in the first or second aspect of the invention. In one embodiment, the disorder is Parkinson's disease.

In a sixth aspect of the invention, there is provided a crystalline form of 5,7-dimethyl- /V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-ca rboxamide having a particle size as defined below: a) D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b) D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c) D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

In certain embodiments, the crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm, preferably D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm.

D10, D50 and D90 are as defined above for the expression micronized 5,7-Dimethyl- /V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-ca rboxamide having a particle size of...' on pages 3-4. The particle size of the micronized 5,7- Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide can be measured using any method known to the skilled person. For example, a laser light scattering method using dry measurement with an air pressure of 1.0 bar and a feed rate of 35%. As discussed above in relation to the first and second aspect, the particle size of the crystalline form of 5,7-dimethyl-/V-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide can impact the properties of any resultant pharmaceutical composition. If the particle size of the active compound is too large, the pharmacological characteristics of the active may be impaired. For example, the compound may have poor oral bioavailability as the large particles can take too long to dissolve in the intestinal fluids in the gastrointestinal tract of a patient. Additionally, the homogeneity of dosage (e.g. homogeneity of compound A in a tablet or within tablets) may be compromised. If the particle size of the compound A is too small, it can be difficult to prepare tablets. For example, small particles can exhibit poor characteristics or poor compression properties which may make it difficult to generate tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have poor hardness, exhibit poor homogeneity of content and/or exhibit poor uniformity of mass. This is particularly important if the manufacturing process is a direct compression or capsule filling.

In a further embodiment of the sixth aspect of the invention, the crystalline form of 5,7-dimethyl-/V-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide is prepared by micronizing a crystalline particle of 5,7-dimethyl-/V- ((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

In a further embodiment of the sixth aspect of the invention, micronization is performed by jet milling, mechanical milling, fluid milling, crushing or grinding. Preferably, jet milling is used.

FURTHER PHARMACEUTICAL COMPOSITIONS

In a separate aspect, albeit related to the various aspects and embodiments described above, there is provided a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide and at least one pharmaceutically acceptable carrier or excipient. The crystalline form of 5,7-dimethyl-/V-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size (prior to preparation of the pharmaceutical composition) as defined below: a) D50 is l|jm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b) DIO is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c) D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

In addition, there is provided a pharmaceutical composition obtainable by a process comprising a step in which a crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide is mixed with at least one pharmaceutically acceptable carrier or excipient, wherein the crystalline form of 5,7-dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide has a particle size as defined below: a) D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b) D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c) D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

Furthermore, there is provided a process for manufacturing a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, the process comprising mixing a crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide with at least one pharmaceutically acceptable carrier or excipient, wherein the crystalline form of 5,7- dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide has a particle size as defined below: a) D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b) D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c) D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

Preferably, the crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide is Form A or Form B. More preferably, the crystalline form is Form B. Form B is identified as the presence of peak (20) 12.2 ± 0.2 in an X-ray diffraction pattern and Form A is identified as the presence of peaks (20) at 5.6± 0.2 and 17.1 ± 0.2 in an X-ray diffraction pattern.

As described below, the pharmaceutical composition may be specially formulated for administration in liquid or solid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intra rectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

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

Pharmaceutical compositions include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.

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. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these compositions include the step of bringing into association the crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,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 the crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

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

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers by any methods well known in the art of pharmacy and/or those described herein.

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, for example, 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 (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetra hydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 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.

Suspensions, in addition to the active compound, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Pharmaceutical compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Pharmaceutical compositions which are 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.

Dosage forms for the 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 with any preservatives, buffers, or propellants which may be required.

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

Powders and sprays can contain, in addition to an active compound, 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. Transdermal patches have the added advantage of providing controlled delivery of an active compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

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

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

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

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 inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

Brief description of the figures

Figure 1 - is an X-ray powder diffractogram of crystalline polymorphic Form A of 5,7-dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide.

Figure 2 - is an X-ray powder diffractogram of crystalline polymorphic Form B of 5,7-dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide.

Figure 3 - is an X-ray diffractogram of a coated solid dosage form comprising lOmg crystalline polymorphic Form B of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide and starch 1500.

Figure 4 - is an X-ray diffractogram of a solid dosage form comprising 60 mg crystalline polymorphic Form B of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

Detailed Description The practice of the present invention employs, unless otherwise indicated, conventional techniques of formulation chemistry, organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques are explained in the literature, such as in Raymond C Rowe, Paul J Sheskey, Marian E Quinn. Handbook of Pharmaceutical Excipients, 6^th Edition (2009). Pharmaceutical Press. 1 Lambert High Street, London SEI I 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" (B.M. Trost & 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 herein incorporated by reference in its entirety.

Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

Definitions

To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

The terms "a" and "an" as used herein mean "one or more" and include the plural unless the context is inappropriate.

The invention also embraces isotopically labelled versions of Compound A which are identical to those recited 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 usually found in nature. Examples of isotopes that can be incorporated include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively.

As used herein, the term "solid dosage form" refers to the combination of an active agent with at least one carrier or excipient, inert or active (i.e., having a pharmacological effect), making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. 5,7-dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (Compound A) has the following structure:

The foregoing compound in crystalline form may be further characterized according to a particular crystalline form. In certain embodiments, the compound is crystalline polymorphic Form A. In certain other embodiments, the compound is crystalline polymorphic Form B.

A summary of the physicochemical properties of Compound A is presented in Table 1.

Table 1 - Physicochemical properties of Compound A

Crystalline Form A may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 5.7 ± 0.2, 11.5 ± 0.2, 11.8 ± 0.2, and 12.8 ± 0.2. In certain embodiments, such a compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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.

In certain embodiments, the compound in crystalline polymorphic Form A is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 2. TABLE 2 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM A.

The relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern. The compound in crystalline polymorphic Form A may be characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1. In certain embodiments, the compound in crystalline polymorphic Form A is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20 and optionally relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 3. TABLE 3 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM A.

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The compound in crystalline polymorphic Form A may exist in a monoclinic crystal system and have a P2i/c space group. The compound in crystalline polymorphic Form A may be characterized by the crystallographic unit cell parameters as set forth in Table 4.

TABLE 4 - UNIT CELL PARAMETERS OF CRYSTALLINE POLYMORPHIC FORM A.

In other embodiments, the compound in crystalline polymorphic Form A is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1.

Crystalline form B may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.0 ± 0.2, 10.9 ± 0.2, 12.3 ± 0.2, and 16.2 ± 0.2. In certain embodiments, the compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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.

In certain embodiments, the compound in crystalline polymorphic Form B is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 5.

TABLE 5 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM B.

The relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern. The compound in crystalline polymorphic Form B may be characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 2. The compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.2 ± 0.2, 10.9 ± 0.2, 11.5 ± 0.2, and 12.4 ± 0.2. In certain embodiments, the compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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 in crystalline polymorphic Form B may be characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20 and optionally relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 6. TABLE 6 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM B.

The compound in crystalline polymorphic Form B may exist in a monoclinic crystal system and have a P2i/c space group. The compound in crystalline polymorphic Form B may be characterized by the crystallographic unit cell parameters as set forth in Table 7.

TABLE 7 - UNIT CELL PARAMETERS OF CRYSTALLINE POLYMORPHIC FORM B.

Compound A can be made according to the methods described in WO 2019/126776. The content of which is incorporated herein by reference. Briefly, the method comprises:

1. admixing a compound of Formula (I), a base, and a solvent to produce a reaction mixture; wherein Formula (I) is represented by:

2. adding a n-pentyl alkylating agent to the reaction mixture to produce a compound of Formula (II):

3. exposing the compound of Formula (II) to acid HX to provide a compound of Formula (III):

wherein X is an anion; and

4. exposing the compound of Formula (III) to hydrogenation conditions, to provide a compound of Formula (IV):

wherein X is an anion;

5. admixing 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 by:

6. admixing 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 thereafter adding a compound of Formula (IV) to the amide-coupling reaction mixture, to provide a mixture containing a compound of Formula (VIII), wherein the compound of Formula (IV) is represented by:

, wherein X is an anion, the compound of

Formula (VII) is represented by

, and the compound of

Formula (VIII) is represented by:

The crystalline forms A and B of Compound A can be produced by a variety of methods.

In one approach for making a crystalline form of a compound of Formula (VIII) the method comprises adding water to the mixture containing a compound of Formula (VIII), to provide the compound of Formula (VIII) in the form of a crystalline solid. The volume of water added is in the range of about 0.5 to about 3 times the volume of the mixture containing a compound of Formula (VIII). In certain examples, the volume of water added is approximately equal to the volume of the mixture containing a compound of Formula (VIII).

The method further comprises the steps of:

(i) isolating the compound of Formula (VIII) in the form of a crystalline solid, to thereby provide 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) comprising water and dimethylformamide where the ratio of volume of water to dimethylformamide in solvent (S2) is in the range of 3: 1 to 5: 1, to provide a purified isolated crystalline compound of Formula (VIII).

Crystalline Polymorphic Form A

The following protocol can be used to create crystalline polymorphic Form A. The method comprises the steps of: (i) isolating the compound of Formula (VIII) in the form of a solid, to thereby provide an isolated compound of Formula (VIII);

(ii) admixing the isolated compound of Formula (VIII) with C5-8 alkane and (Ci-4 alkyl)-CO2-(Ci-4 alkyl) to form a mixture, and then heating the mixture to a temperature of at least 65 degrees Celsius to provide a heated mixture;

(iii) cooling the heated mixture of step (ii) so that the temperature of the heated mixture is less than 55 degrees Celsius to provide a cooled mixture;

(iv) aging the cooled mixture of step (iii) to provide a compound of Formula (VIII) in the form of a crystalline solid; and

(v) isolating the compound of Formula (VIII) in the form of a crystalline solid to provide an isolated crystalline compound of Formula (VIII).

The C5-8 alkane may be heptane. The (Ci-4 alkyl)-CO2-(Ci-4 alkyl) may be ethyl acetate.

Crystalline Polymorphic Form B

The following protocol can be used to create crystalline polymorphic Form B. The method comprises the steps of: a. isolating the compound of Formula (VIII), produced in section C, in the form of a solid, to thereby provide an isolated compound of Formula (VIII); b. dissolving the isolated compound of Formula (VIII) in (Ci-4 alkyl)-CO2-(Ci-4 alkyl) ester, or saturated aliphatic alcohol, or (Ci-4 alkyl)-C0-(Ci-4 alkyl) ketone solvent at a temperature in the range of about 20 degrees Celsius to about 50 degrees Celsius, thereby forming a mixture; c. adding an alkane solvent to the mixture of step (ii) and allowing the mixture to cool to a temperature of from about 0 degrees Celsius to about 25 degrees Celsius; d. aging the cooled mixture of step (iii) to provide a compound of Formula (VIII) in the form of a crystalline solid; and e. isolating the compound of Formula (VIII) in the form of a first crystalline solid to provide a first isolated crystalline compound of Formula (VIII), namely Form B. The Cs-s alkane may be heptane. The C5-8 alkane may be methylcyclohexane. The (Ci-4 alkyl)-CO2-(Ci-4 alkyl) may be ethyl acetate. The (Ci-4 alkyl)-CO2-(Ci-4 alkyl) may be butyl acetate. The saturated alcohol may be 1-pentanol. The saturated alcohol may be isopentanol. The (Ci-4 alkyl)-C0-(Ci-4 alkyl) may be methyl ethyl ketone. The (Ci-4 alkyl)-C0-(Ci-4 alkyl) may be methyl isobutyl ketone (MIBK).

Further processing of Compound A

The crystalline polymorphic forms of compound A are preferably in a predefined particle size distribution. If the compound A particles resulting from its synthesis are not of an appropriate particle size, the crystalline polymorphic forms of compound A may further be processed to a predefined particle size. Processing of the crystalline compound to the defined particle size may be done by any suitable method known to the skilled person. For example, the crystalline compound may be micronized. This may be by jet milling, mechanical milling, fluid milling, crushing or grinding.

One method of micronizing the crystalline particles of compound A is to use a jet mill. A jet mill grinds materials by using a high-speed jet of compressed air or inert gas to impact particles into each other. Optionally, Compound A may be sieved prior to micronizing using, for example, a 20-mesh sieve.

Diluent

The term 'filler' and the term 'diluent' are herein used interchangeably. It is known that, in general, the term 'filler' is used in the context of capsular formulations and the term 'diluent' in tablet formulations. Diluents act as fillers in pharmaceutical tablets to increase weight and improve content uniformity. Diluents provide better tablet properties such as improved cohesion or to promote flow. Diluents must be non-toxic, commercially available in acceptable grade, physiologically inert, and physically and chemically stable by themselves as well as in combination with active pharmaceutical ingredients (APIs).

Alternative names for diluents include carriers, extenders and volumizing agents. Not every solid dosage form requires a diluent. 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 A-N™, Emcompress Anhydrous™, Fujicalin™), calcium phosphate, dibasic dihydrate (Cafos™, Calipharm™, Calstar™, Di-Cafos™, Emcompress™), calcium phosphate tribasic (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium sulphate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™, USG Terra Alba™), cellulose powdered (Arbocel™, Elcema™, Sanacel™, Solka-Floc™), silicified microcrystalline cellulose (ProSolv™), cellulose acetate, compressible sugar (Di-Pac™), confectioner's sugar, dextranes (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™, Sim 90™), lactitol (Finlac ACX™, Finlac DC™, Finlac MCX™), lactose (Lactose® 80, Aero Flo 20™, Aero Flo 65™, Anhydrox™, CapsuLac™, Fast-Flo™, FlowLac™, GranuLac™, InhaLac™, Lactochem™, Lactohale™, Lactopress™, Microfine™, Microtose™, Pharmatose™, Prisma Lac™, Respitose™, SacheLac™, SorboLac™, Super-Tab™, Tablettose™, Wyndale™, Zeparox™), magnesium carbonate, magnesium oxide (MagGran MO™), maltodextrin (C*Dry MD™, Glucidex™, Glucodry™, Lycatab DSH™, Maldex™, Maltagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star-Dri™), maltose (Advantose 100™), mannitol (Mannogem™, Pearlitol™), microcrystalline cellulose (Avicel PH™, Celex™, Celphere™, Ceolus KG™, Emcocel™, Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™), simethicone (Dow Corning Q7-2243 LVA™, Cow Corning Q7-2587™, Sentry Simethicone™), sodium alginate (Kelcosol™, Keltone™, Protanal™), sodium chloride (Alberger™), sorbitol (Liponec 70-NC™, Liponic 76-NCv, Meritol™, Neosorb™, Sorbifin™, Sorbitol Instant™, Sorbogem™), starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™), pregelatinized starch (Instastarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™, Unipure WG220™), sucrose, trehalose, isomalt (GaleniQ) and xylitol (Klinit™, Xylifm™, Xylitab™, Xylisorb™, Xylitolo™), or mixtures thereof.

Preferred diluents include lactose, starch, a starch derivative (for example, pregelatinized starch), a phosphate derivative, cellulose, or a mixture thereof.

More preferably, the first and second diluents 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 pre-gelatinized starch. A particularly preferred diluent is microcrystalline cellulose. Examples include Avicel® pHlOl and Avicel® pH102. In some embodiments, Avicel® pH102 is preferred.

Binder

Binder excipients hold the ingredients of a formulation together, for example in a tablet. Binders ensure that tablets, powders, granules and others can be formed with the required mechanical strength. Moreover, they give volume to low active dose tablets. Examples of binders may be in the dry or liquid form.

Suitable binders for inclusion in the composition of the invention include acacia, alginic acid (Kelacid™, Protacid™, Satialgine H8™), carbomer (Acritamer™, Carbopol™, Pemulen™, Ultrez™), carboxymethylcellulose sodium (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel™, Tylose™), ceratonia (Meyprofleur™), cottonseed oil, dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofm™, Lycedex PF™, Roferose™, Tabfme D-IOO™), gelatin (Cryogel™, Instagel™, Solugel™), guar gum (Galactosol™, Meprogat™, Meyprodor™, Meyprofm™, Meyproguar™), hydrogenated vegetable oil type I (Akofine™, Lubritab™, Sterotex™, Dynasan P[omicron]O™, Softisan 154™, Hydrocote™, Lipovol™, HS-K™, Sterotex HM™), hydroxyethyl cellulose (Alcoramnosan™, Cellosize™, Idroramnosan™, Liporamnosan™, Natrosol™, Tylose PHA™), hydroxyethyl methyl cellulose (Culminal™, Tylopur MH™, Tylopur MHB™, Tylose MB™, Tylose MH™, Tylose MHB™), hydroxypropyl cellulose (Klucel™, Methocel™, Nisso HPC™), low substituted hydroxypropyl cellulose, hypromellose (Benecel MHPC™, Methocel™, Metolose™, Pharmacoat™, Spectracel 6™, Spectracel 15™, Tylopur™), magnesium aluminium silicate (Carrisorb™, Gelsorb™, Magnabite™, Neusilin™, Pharmsorb™, Veegum™), maltodextrin (C*Dry MD™, Glucidex™, Glucodry™, Lycatab DSH™, Maldex™, Maltagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star-Dri™) maltose (Advantose 100™), methylcellulose (Benecel™, Culminal MC™, Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, Celex™, Celphere™, Ceolus KG™, Emcocel™, Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™), polyethylene oxide (Polyox™), polymethacrylates (Eastacryl 30D™, Eudragit™, Kollicoat MAE 30D™, Kollicoat MAE 30DP™), povidone (Kollidon™, Plasdone™), sodium alginate (Kelcosol™, Keltone™, Protanal™), starch (Aytex P™, Fluftex W™, Instant Pure- Cote™, Melojel™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure- Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™), pregelatinised starch (Instastarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™, Unipure WG 220™), stearic acid (Crodacid™, Emersol Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), sucrose and zein, or mixtures thereof.

Glidant

Glidants are usually fine powders that enhance the movement of powders or granules within the manufacturing machinery (for example, the hopper) prior to compaction, compression, or encapsulation. By enhancing flow rates of powders or granules, there is less weight variability of the tablets manufactured, resulting in more consistent dosing of the drug substance(s).

It has been suggested that the ability of glidants to enhance the movement of the powder or granules within the hopper and into the tablet die in the tablet press is due to the ability of particles of the glidants to locate within the spaces between the powder particles/ granules and thus decreasing the overall surface charge present on the blend decreasing friction between particles of the blend and filling in the gaps on the surface, thus further enhancing the rate of movement and flow.

Glidants are typically hydrophobic and therefore care should be taken to ensure that the concentration of glidants used in the formulation does not adversely affect tablet disintegration and drug dissolution.

The concentration of glidant to be added in the dry powder blend of excipient and active ingredient can be important as above a certain concentration the glidant may itself inhibit good flow.

Suitable glidants include tribasic calcium phosphate (Tri-Cafos™, TRI-CAL™, TRITAB™), calcium silicate, cellulose, powdered (Arbocel™, Elcema™, Sanacel™, Solka- Floc™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Sil M-5P™, Wacker HDK™, Syloid™), magnesium silicate, magnesium trisilicate, starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™. Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™), PEG6000, PEG10000 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.

Disintegrant

Disintegrants or disintegrating agents are raw materials that appear in some solid dosage forms. They are added to formulations to overcome the cohesive strength imparted during compression, thus facilitating the breakdown of the tablet into granules for ready drug availability once they come into contact with moisture in a patient. There is still a lack of understanding with respect to the mechanisms by which disintegrants elicit their functions.

Disintegrants may enable tablet disintegration by increasing the porosity and wettability of the compressed tablet matrix or facilitate tablet disintegration due to the increase in the internal pressure within the tablet matrix.

The concentration of disintegrant may have a direct relationship with the rate of disintegration until it gets to maximum after which disintegration rate decreases with increase in concentration of disintegrants.

Suitable disintegrants include alginic acid (Kelacid™, Protacid™, Satialgine H8™), calcium phosphate, tribasic (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), carboxymethylcellulose calcium (ECG 505™, Nymcel ZSC™), carboxymethylcellulose sodium (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™), silicified microcrystalline cellulose (ProSolv™), starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure- Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™) or pregelatinized starch (Instanstarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™ and Unipure WG220™), or mixtures thereof.

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

Lubricant

Lubricants, as the name suggest, reduce friction between the powder mix and the die walls during compression and ejection. They also prevent the mixed powders/ granules from sticking to the processing zone of the tablet press especially the punches and die. In some cases, lubricants reduce inter-particulate friction and thus, improve flow rates of powders or granules. The best lubricants are those with low shear strength but strong cohesive tendencies perpendicular to the line of shear.

Powder flow can be important during tableting as it must flow easily and uniformly into the tablet dies to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties. Smaller particles such as particles of COMPOUND A with low densities and an irregular surface and shape exhibit decreased flow compared to large, smooth, and spherical particles with high densities. Particle shape and surface morphology affect particle-particle contact and therefore can increase friction if contact area is increased which then reduces flowability. As boundary layer lubricants form a film around particles, these lubricants can affect friction through modified particle-particle contact, thereby also affecting powder flow.

Inadequate lubrication during tablet manufacture results in the production of tablets with a pitted surface. Conversely, excessive use of lubricants may yield tablets with reduced rates of disintegration and dissolution. Preferably lubricants for use in the 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.

Coating

Pharmaceutical film coating is considered a key part in the production of solid pharmaceutical dosage forms since it improves the physical and chemical stability of dosage forms and modify 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.

Methods of treatment

The solid dosage forms described herein may be useful in 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

Described herein is 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma, said method comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form described herein.

The amount or dose of the solid dosage form that is administered should be sufficient to alleviate the disease in vivo. The dose will be determined by the efficacy of the particular formulation, as well as the body weight of the subject to be treated.

The dose of the solid dosage form will also be determined by the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular formulation. Typically, a physician will decide the dosage of the composition with which to treat each individual subject, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound/formulation to be administered, route of administration, and the severity of the condition being treated. The appropriate dosage can be determined by one skilled in the art. By way of non-limiting example, the total dose of COMPOUND A in the solid dosage form of the present invention can be about 2 to about 500 mg, from about 5 to about 300 mg, from about 10 mg about 200 mg, and from about 20 mg to about 100 mg. In a preferred embodiment the total amount of COMPOUND A in the solid dosage form of the present invention is about 10, about 30 or about 60 mg.

Examples

The following examples are not to be considered limiting.

Example 1

Bulk and tapped density, Carr index, compressibility index, Hausner ratio, real density, porosity, relative solid content, and flow rate were obtained for micronized Compound A. The results are summarized in Table 8.

Compound A was micronized using a jet-mill PM6 with the following process parameters: feed rate - 20%, control feeding 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 a laser light scattering method.

Table 8 - Pharmacotechnical characterization of Compound A

Solid dosage forms - characterization

Unless indicated otherwise the following methods were used to characterize the solid dosage forms prepared:

Example 2 - Creation of a solid dosage form containing no active ingredient

A solid dosage form with the components according to Table 9 was prepared according to the following protocol:

The particle size of the microcrystalline cellulose and crospovidone were calibrated using a 500 pm sieve. The particles that passed through the sieve were placed into a biconic mixer for 15 minutes at 21 rpm. Magnesium stearate particle size was calibrated using a 250 pm sieve. The particles that passed through the sieve were placed into the biconic mixer and mixed for a further five minutes at 21 rpm. The bulk density of the resulting blend was measured to be 0.37 g/mL. The resultant blend was passed into an eccentric tableting machine using an oblong concave punch with 11x5.7 mm dimensions and compressed.

Table 9 - Batch 210113-L composition (Placebo)

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties.

The resultant tablets had the following properties:

• Appearance: white oblong biconvex tablets with a single break line on both sides

• Hardness: 119 N

• Disintegration: < 2 minutes

Example 3 - Batch 210115-L containing 60 mg of COMPOUND A

Tablets with the composition described in Table 10 below were prepared according to the following method. COMPOUND A, Avicel pH102 and Crospovidone were separately calibrated by passing through a 500 pm sieve. 50% of Avice °pH102 was placed into a biconic mixer and mixed for 5 minutes at 21 rpm. The COMPOUND A and the remaining 50% of Avicel'pH102 were placed into the mixer and mixed for 15 minutes at 21 rpm. The Crospovidone was added, and the blend mixed for 15 minutes at 21 rpm. Finally, magnesium stearate which had been calibrated by passing 250 pm sieve was added and mixed for 5 minutes at 21 rpm. The resultant blend has a bulk density of 0.33 g/mL. The blend was compress in an eccentric tableting machine using an oblong concave punch with 11x5.7 mm dimensions. Table 10 - Batch 210115-L composition (60 mg)

Example 4 - Batch 210117-L with 60 mg COMPOUND A

A solid dosage form was prepared with the components of Table 11 below. The solid dosage form was prepared using the same method as in Example 3. The bulk density of the blend is 0.38 g/mL.

Table 11 - Batch 210117-L composition (60 mg)

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties. The solid dosage forms had the following properties: • Appearance: white oblong biconvex tablets with a single break line on both sides

• Hardness: 189 N

• Disintegration: < 1 minute

• Compression: regular filling of the die, with adequate uniformity of mass (RSD < 2%)

Example 5 - Batch 210124-L - 10 mg COMPOUND A

A solid dosage form with a composition as described in Table 12 below was prepared according to the method of Example 3 and 4 with the following minor changes. The duration of the first and second mixture (addition of COMPOUND A) was increased to 30 minutes and mixer speed was increased to 25 rpm in all mixtures to assure optimized blend uniformity. The resultant blend had a bulk density of 0.38 g/mL.

Table 12 - Batch 210124-L composition (10 mg)

The solid dosage forms had the following properties:

• Hardness: 234 N

• Disintegration: < 2 minutes

• Friability: < 0.2% • Compression: regular filling of the die, with adequate uniformity of mass

(RSD < 2%)

• Dosage uniformity:

Tablets with adequate technological properties and uniformity of mass were obtained. Considering hydrolysis one of the main degradation pathways for COMPOUND A, pregelatinized starch (Starch® 1500) was added to the formulation. This being hygroscopic, captures moisture reducing the risk of degradation by humidity.

Example 6 - Batch 210142-L -10 mg COMPOUND A

A solid dosage form with a composition according to Table 13 was prepared according to the following method. The size of the COMPOUND A, A Avicel"pH102, Aerosil® 200, Starch® 1500 and Crospovidone particles were calibrated using a 500 pm sieve. Part of the Avicel®pH102 and 50% of Aerosil® 200 were mixed in a biconic mixer for 30 minutes at 25 rpm. The COMPOUND A and remaining Avicel®pH102, Starch® 1500, 50% of Aerosil® 200, Crospovidone were added to the blend and mixed for 30 minutes at 25 rpm.

Magnesium stearate was calibrated using a 250 pm sieve and added to the mixer before mixing for 5 minutes at 25 rpm. The resultant blend had a density of 0.39 g/mL The blend was compressed in an eccentric tableting machine using an oblong concave punch with 11x5.7 mm dimensions.

Table 13 - Batch 210142-L composition (10 mg)

The resultant tablets had the following properties:

• Hardness: 182 N

• Disintegration: < 1 minute

• Friability: < 0.2 %

• Compression: regular filling of the die, with excellent uniformity of mass (RSD < 2%)

• Dosage uniformity:

Tablets with adequate technological properties and uniformity of mass were obtained.

Batches 210124-L and 210142-L were produced by a robust and reproducible manufacturing process tablets that meet all critical quality attributes previously defined.

Example 7 - Batch 230012-L

A solid dosage form with the composition detailed in the table below was obtained by simple mixing of the excipients, followed by direct compression.

The resultant blend had the following properties:

• Bulk density: 0.42 g/mL

• Tapped density: 0.54 g/mL

• Flowability (s/100 g): 13.6 (15 mm)

The blend was compressed in an eccentric tableting machine using an oblong concave punch with 11x5.7 mm dimensions.

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.21%

• Hardness: 118 N

• Disintegration: < 30 minutes

• Dissolution at 60 min: 63%

Example 8 - Batch 230013-L

The resultant blend had the following properties:

• Bulk density: 0.37 g/mL

• Tapped density: 0.53 g/mL

• Flowability (s/100 g): 11.8 (15 mm)

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.65%

• Hardness: 319 N

• Disintegration: > 120 minutes

• Dissolution at 60 min: 89.1%

Example 9 - Batch 230014-L

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties. The resultant blend had the following properties:

• Bulk density: 0.58 g/mL

• Tapped density: 0.79 g/mL

• Flowability (s/100 g): 5.6 (15 mm)

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.04%

• Hardness: 55 N

• Disintegration: < 2 minutes

• Dissolution at 60 min: 88%

Example 10 - Batch 230015-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.89%

• Disintegration: < 3 minutes

• Dissolution at 60 min: 88% Example 11 - Batch 230016-L

The resultant tablets had the following properties: • Uniformity of weight (RSD): 1.5% Disintegration: < 2 minutes

• Dissolution at 60 min: 98%

Example 12 - Batch 230017-L

The resultant blend had the following properties:

• Bulk density: 0.33 g/mL

• Tapped density: 0.44 g/mL

• Flowability (s/100 g): 15.6 (15 mm)

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.95%

• Hardness: 148 N

• Disintegration: < 1 minute

• Dissolution at 60 min: 96%

Example 13 - Batch 230018-L

The resultant blend had the following properties:

• Bulk density: 0.36 g/mL

• Tapped density: 0.52 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.34%

• Hardness: 132 N

• Disintegration: < 1 minute

• Dissolution at 60 min: 53%

Example 14 - Batch 230019-L

The resultant blend had the following properties:

• Bulk density: 0.74 g/mL Tapped density: 1.01 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.05%

• Disintegration: < 1 minute

• Dissolution at 60 min: 95%

Example 15 - Batch 230020-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.50%

• Hardness: 223 N

• Disintegration: < 30 minutes

• Dissolution at 60 min: 82% Example 16 - Batch 230021-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.96%

• Hardness: 102 N

• Disintegration: < 5 minutes

• Dissolution at 60 min: 97 %

Example 17 - Batch 230022-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.72%

• Hardness: 307 N • Disintegration: < 5 minutes

• Dissolution at 60 min: 89%

Example 18 - Batch 230023-L

The resultant blend had the following properties:

• Bulk density: 0.46 g/mL

• Tapped density: 0.60 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.96%

• Hardness: 124 N

• Disintegration: < 50 minutes

• Dissolution at 60 min: 95%

Example 19 - Batch 230024-L

The resultant blend had the following properties:

• Bulk density: 0.4 g/mL Tapped density: 0.5 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.78%

• Hardness: 124 N

• Disintegration: < 1 minute

• Dissolution at 60 min: 104%

Example 20 - Batch 230025-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.08%

• Hardness: 30 N

• Disintegration: < 5 minutes

• Dissolution at 60 min: 106%

Example 21 - Batch 230026-L

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.59%

• Disintegration: < 1 minute

• Dissolution at 60 min: 92%

Example 22 - Batch 230027-L

The resultant blend had the following properties:

• Flowability (s/100 g): 4.6 (15 mm)

16.6 (10 mm) The blend was compressed in an eccentric tableting machine using an oblong concave punch with 11x5.7 mm dimensions.

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 0.46%

• Hardness: 50 N

• Disintegration: < 2 minutes

• Dissolution at 60 min: 13%

The dissolution result above was felt to be artificially low because of visible nondisintegration of the tablet in the dissolution vessel (however, in the disintegration test, values were less than 2 minutes and tablet hardness was relatively low) due to poor wettability of the tablet resulting from an overblending of the magnesium stearate. This result did not accurately reflect the properties of this solid dosage form. The dissolution was found to be much higher using a slightly lower magnesium stearate content.

Example 23 - Batch 240022-L

The resultant tablets had the following properties:

• Hardness: 30 N

• Disintegration: < 2 minutes • Dissolution at 60 min: 88.6%

Example 24 - Batch 240006-L

A solid dosage form with the composition detailed in the table below was obtained by wet granulation, using purified water as granulation liquid.

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties. ‘ Purified water is an auxiliar on the manufacturing process, being removed during drying.

The resultant blend had the following properties:

• Bulk density: 0.4 g/mL

• Tapped density: 0.5 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.44%

• Hardness: 115 N

• Disintegration: < 2 minutes

• Dissolution at 60 min: 92%

Example 25 - Batch 240014-L

A solid dosage form with the composition detailed in the table below was obtained by dry granulation.

The resultant blend had the following properties:

• Bulk density: 0.56 g/mL

• Tapped density: 0.70 g/mL

The resultant tablets had the following properties:

• Uniformity of weight (RSD): 1.00%

• Hardness: 89 N

• Disintegration: < 2 minutes

• Dissolution at 60 min: 98%

Example 26 - Stability testing

To assess drug product stability, batches formulations (with the compositions shown in Tables 14, 15, 16 and 17) were manufactured and submitted to a stress study. For the formulations with pregelatinized starch (Starch® 1500), it was decided to reduce its percentage to 10% in the active formulations to compensate the reduction in the quantity of microcrystalline cellulose due to the introduction of COMPOUND A and therefore improve the compression characteristics of the final blend. For the placebo the 20% percentage of pregelatinized starch (Starch® 1500) was kept. As blinding between strengths was a major concern, film-coated tablets were also produced and tested for stability. Formulations were packaged in HDPE bottles and stored at 70°C and 70°C/80% RH for 21 days.

Table 14 - Uncoated formulations without Starch® 1500

5

Table 15 - Uncoated formulations with Starch® 1500

itr

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties. Table 16 - Film-coated formulations without Starch® 1500

Table 17 - Film-coated formulations with Starch® 1500

*Microcrystalline cellulose's primary role is as a diluent although it also has low binder properties. The results are shown below in Table 18.

Table 18 - Technological results at TO (stress study)

All batches produced by a robust and reproducible manufacturing process tablets that meet all critical quality attributes previously defined.

A matrixing design was established to assess formulations stability at TO, Til days and T21 days. Formulations were tested for appearance, assay and purity. • TO days

Appearance: white oblong biconvex tablets with a single break line on both sides for 5 all formulations tested

Table 19 - Assay results for different formulations

The results were obtained using HPLC. All the tablets showed good assay results with values between 95 and 105.

Table 20 - Purity results (% a/a) measured by HPLC at 220 nm, using a C18 column and gradient of mobile phase composed bv eluent A (acidified water) and 5 eluent B (acidified ACN) :

The purity of the solid dosage forms is shown below.

Til days Appearance: white oblong biconvex tablets with a single break line on both sides for film-coated formulations tested (FADU and FADY) stored at 70°C and 70°C/80% RH. Yellowish oblong tablets with a single break line on both sides for uncoated formulations tested (FADZ and FAEC) stored at 70°C and 70°C/80% RH

Table 21 - Assay (w/w%) results

Table 22 - Purity (% a/a):

• T21 days

Appearance: white oblong biconvex tablets with a single break line on both sides for film-coated formulations tested (FADU and FADY) stored at 70°C and 70°C/80% RH. Yellowish oblong tablets with a single break line on both sides for uncoated formulations tested (FADZ and FAEC) stored at 70°C and 70°C/80% RH.

Table 23 - Assay (w/w%):

Table 24 - Purity (% a/a):

5

Example 27 - X-rav diffraction of polymorphic forms of Compound A (Form A and Form B)

Crystalline Polymorphic Form A and Crystalline Polymorphic Form B can be prepared using the methods described herein or, for example, in WO2019/126776.

10

A Rigaku MiniFlex benchtop X-ray diffractometer was set up with the following instrumental parameters.

Table 25 - instrumental conditions for XRPD analysis of polymorphic forms

15 of Compound A (Form A and Form B)

2. Spread the powder samples evenly in the sample holder.

3. Place a glass plate on the top of the sample and press with fingertips to compress.

4. Place the sample inside the equipment autosampler

5. Run the XRPD analysis

6. Evaluate the obtained diffractogram.

Example 28 - X-rav diffraction of solid dosage form tablets

The following tablets were prepared using the methods described above.

• Film-coated tablets containing 10 mg of Compound A, FADX (results in Figure 3)

• Tablets containing 60 mg of Compound A, FAEA (results in Figure 4)

Table 26 - instrumental conditions for XRPD analysis of solid dosage form tablets

Tablet samples were prepared and analysed using the following method :

1. Grind 10 tablets of the sample to obtain a fine and homogenous powder.

2. Set up the XRPD instrument parameters as described in Table 25.

3. Spread the powder samples evenly in the sample holder.

4. Place a glass plate on the top of the sample and press with fingertips to compress.

5. Place the sample inside the equipment autosampler

6. Run the XRPD analysis

7. Evaluate the obtained diffractogram.

The results are shown in Figures 3 and 4.

Qualitative visual evaluation of the sample diffractograms obtained after analysis to confirm the presence of Form B identification peak around 12.2° 20 and the absence of Form A identification peaks around 5.6° 20 and 17.1° 20 simultaneously.

If the presence of the Form B identification peak around 12.2° 20 is confirmed, and simultaneously the absence of both Form A identification peaks around 5.6 °20 and 17.1 20 is also confirmed, the identification of Compound A Form B is confirmed with no Form A.

If the presence of the Form B identification peak around 12.2 20 is confirmed, and the presence of both Form A identification peaks around 5.6 and 17.1 20 simultaneously is also confirmed, the compound A is present in both the Form A and Form B form.

If the presence of the Form B identification peaks is not confirmed, and the presence of the Form A identification peaks is confirmed, the compound A is present only in the Form B form.

Conclusion

The solid dosage forms of the invention therefore exhibit high stability and high polymorphic purity. The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Embodiments of the invention:

In addition to the various aspects and embodiments of the invention described above, the invention is further defined by the following embodiments:

1. A solid dosage form comprising: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide (Compound A); and at least one of i) a first diluent and/or binder; and ii) a lubricant, wherein the solid dosage form is characterised by an X-ray powder diffraction pattern comprising peaks at the following diffraction angle (20): 12.2 ± 0.2.

2. A solid dosage form comprising: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide (COMPOUND A); and at least one of i) a first diluent and/or binder; and ii) a lubricant, wherein the 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide is in the crystalline form characterized by an X- ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 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. The solid dosage form according to embodiment 1 or embodiment 2, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

4. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm.

5. The solid dosage form according to embodiment 4, wherein D50 is 3|jm - 50 pm. 6. The solid dosage form according to embodiment 4, wherein D50 is 5|jm - 30|jm.

7. The solid dosage form of any preceding embodiment, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of DIO: > 0.3 pm.

8. The solid dosage form of embodiment 7, wherein DIO is > 0.5 pm.

9. The solid dosage form embodiment 7, wherein D10 is > 1 pm.

10. The solid dosage form of any previous embodiment, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D90: < 100 pm.

11. The solid dosage form of embodiment 10, wherein D90 is < 80 pm.

12. The solid dosage form of embodiment 10, wherein D90 is < 60 pm.

13. The solid dosage form any preceding embodiment, wherein the solid dosage form comprises 5,7-Dimethyl-/V-((l/?,4/?)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm.

14. The solid dosage form of embodiment 13, wherein the 5,7-Dimethyl-/V- ((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm.

15. The solid dosage form of embodiment 13, wherein the 5,7-Dimethyl-/V- ((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm.

16. The solid dosage form according to any previous embodiment, wherein the solid dosage form comprises: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide; b) a first diluent and/or binder; and c) a lubricant.

17. The solid dosage form according to any preceding embodiment, wherein the solid dosage form further comprises: i) a disintegrant and a glidant; and/or ii) a second diluent.

18. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises:

5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide in an amount from about 1% to about 60% by weight.

19. The solid dosage form according to embodiment 18, wherein the solid dosage form comprises:

5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide in an amount about 2% to about 40% by weight.

20. The solid dosage form according to embodiment 18, wherein the solid dosage form comprises:

5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide in an amount from about 3% to about 30% by weight.

21. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a first diluent and/or binder, the first diluent and/or binder being present in an amount of about 20% to about 98% by weight.

22. The solid dosage form according to embodiment 21, 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 30% to about 80% by weight. 23. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount from about 1% to about 40% by weight.

24. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount from about 2% to about 40% by weight.

25. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount from about 3% to about 30% by weight.

26. The solid dosage form according to embodiment 25, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount from less than about 10% by weight.

27. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a glidant, the glidant being present in an amount from about 0.25% to about 7% by weight.

28. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a glidant, the glidant being present in an amount from about 0.3% to about 5% by weight.

29. The solid dosage form according to embodiment 27, wherein the solid dosage form comprises a glidant, the glidant being present in an amount from about 0.5% to about 2% by weight.

30. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant, the disintegrant being present in an amount of from about 0.5% to about 25% by weight.

31. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant, the disintegrant being present in an amount of from about 1% to about 20% by weight. 32. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant, the disintegrant being present in an amount of from about 2% to about 10% by weight.

33. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant, the disintegrant being present in an amount of from about 3% to about 7% by weight.

34. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a lubricant, the lubricant being present in an amount of about 0.1% to about 15% by weight.

35. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a lubricant, the lubricant being present in an amount of about 0.1% to about 12% by weight.

36. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a lubricant, the lubricant being present in an amount of about 5% to about 10% by weight.

37. The solid dosage form according to embodiment 36, wherein the solid dosage form comprises a lubricant, the lubricant being present in an amount of from about 1% to about 5% by weight.

38. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a binder, the binder being present in an amount of from about 0.5% to about 30% by weight.

39. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a binder, the binder being present in an amount of from about 1% to about 20% by weight.

40. The solid dosage form according to embodiment 39, wherein the solid dosage form comprises a binder, the binder being present in an amount of from about 2% to about 10% by weight. 41. The solid dosage form according to embodiment 39, wherein the solid dosage form comprises a binder, the binder being present in an amount of from about 3% to about 7% by weight.

42. The solid dosage form according to any preceding embodiment, wherein the solid dosage form further comprises a coating.

43. The solid dosage form according to embodiment 42, wherein the coating comprises a capsule or a film coating.

44. The solid dosage form according to embodiment 42, wherein the coating comprises a film coating.

45. The solid dosage form according to any preceding embodiment, wherein the first and/or second diluent independently has a particle size D50 of below 500 pm.

46. The solid dosage form according to embodiment 45, wherein the first and/or second diluent independently has a particle size D50 of below 300 pm.

47. The solid dosage form according to embodiment 45, wherein the first and/or second diluent independently has a particle size D50 of below 200 pm.

48. The solid dosage form according to any preceding embodiment, wherein the first and/or second diluent independently has a moisture content of less than about 15%.

49. The solid dosage form according to embodiment 48, wherein the first and/or second diluent independently has a moisture content of less than about 7%.

50. The solid dosage form according to any preceding embodiment, wherein the first and/or second diluent is independently selected from the group consisting of lactose, starch, a starch derivative, cellulose, calcium phosphate or a mixture thereof. 51. The solid dosage form according to any preceding embodiment, wherein the first and/or second diluent is independently selected from the group consisting of lactose, starch, a starch derivative, cellulose, or a mixture thereof.

52. The solid dosage form according to embodiment 51, wherein the first and second diluents are independently polymeric diluents.

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

54. The solid dosage form of embodiment 51, wherein the second diluent is pregelatinized starch.

55. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a glidant and wherein the glidant is an anhydrous glidant.

56. The solid dosage form according to embodiment 55, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, PEG6000 or mixtures thereof.

57. The solid dosage form according to embodiment 55, wherein the glidant is talc or colloidal silicon dioxide.

58. The solid dosage form according to embodiment 55, wherein the glidant is colloidal silicon dioxide.

59. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a glidant and wherein the glidant has a surface area measured using the BET method above about 10 m²/g.

60. The solid dosage form according to embodiment 59, wherein the solid dosage form comprises a glidant and wherein the glidant has a surface area measured using the BET method above about 100 m²/g. 61. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is below 500 pm.

62. The solid dosage form according to embodiment 61, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is below 300 pm.

63. The solid dosage form according to embodiment 61, wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is below 150 pm.

64. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a disintegrant and wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, or mixtures thereof.

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

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

67. The solid dosage form according to any preceding embodiment, wherein the solid dosage form comprises a lubricant and wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate or mixtures thereof.

68. The solid dosage form according to embodiment 67, wherein the lubricant is magnesium stearate.

69. The solid dosage form according to any preceding embodiment, wherein the solid dosage form further comprises a binder and the binder is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, ethyl-cellulose, pregelatinized maize starch, gelatine, or mixtures thereof. 70. The solid dosage form according to any preceding embodiment, wherein the solid dosage form further comprises a binder and the binder is selected from the group consisting of povidone, hypromellose, pregelatinized maize starch, or mixtures thereof.

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

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

73. The solid dosage form according to any preceding embodiment, wherein a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer with a pH of 4.5 at 37 °C with 0.05% of sodium dodecyl sulphate and 100 rpm is more than about 60% in 90 minutes.

74. The solid dosage form according to embodiment 73, wherein a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer with a pH of 4.5 at 37 °C with 0.05% of sodium dodecyl sulphate and 100 rpm is more than about 50% in 60 minutes.

75. The solid dosage form according to embodiment 73, wherein a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer with a pH of 4.5 at 37 °C with 0.05% of sodium dodecyl sulphate and 100 rpm is more than about 60% in 60 minutes.

76. The solid dosage form according to embodiment 73, wherein a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer with a pH of 4.5 at 37 °C with 0.05% of sodium dodecyl sulphate and 100 rpm is more than about 70% in 60 minutes.

77. The solid dosage form according to any preceding embodiment, wherein more than about 50% of the compound A is present as Form B after 6 months stored at 40°C and 75%HR, wherein Form B is identified as the presence of peak (2theta) 12.2 in an X-ray diffracton pattern and Form A is identified as the presence of peaks (2theta) at 5.6 and 17.1 in an X-ray diffraction pattern. 78. The solid dosage form according to embodiment 77, wherein more than about 80% of the compound A is present as Form B after 6 months stored at 40°C and 75%HR; wherein Form B is identified as the presence of peak (2theta) 12.2 in an X-ray diffracton pattern and Form A is identified as the presence of peaks (2theta) at 5.6 and 17.1 in an X-ray diffraction pattern.

79. The solid dosage form according to embodiment 77, wherein more than about 90% of the compound A is present as Form B after 6 months stored at 40°C and 75%HR; wherein Form B is identified as the presence of peak (2theta) 12.2 in an X-ray diffracton pattern and Form A is identified as the presence of peaks (2theta) at 5.6 and 17.1 in an X-ray diffraction pattern.

80. The solid dosage form according to any preceding embodiment, wherein less than about 10 % of degradation products are found after 6 months stored at 40°C and 75%HR, 18 months stored at 25°C, and 65% HR and 21 days stored at 70°C and 85% HR.

81. The solid dosage form according to embodiment 80, wherein less than about 5 % of degradation products are found after 6 months stored at 40°C and 75%HR, 18 months stored at 25°C, and 65% HR and 21 days stored at 70°C and 85% HR.

82. The solid dosage form according to any preceding embodiment, wherein less than about 3 % of degradation products are found after 6 months stored at 40°C and 75%HR, 18 months stored at 25°C, and 65% HR and 21 days stored at 70°C and 85% HR.

83. A method for preparing 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, second diluent, lubricant, glidant, disintegrant and binder in a mixer; b) optionally, granulating the mixture obtained to obtain granules; and

C) compressing the mixture obtained in a) or the granules in b) to form tablets; Or filling a capsule with the mixture obtained in a) or the granules in b).

84. A method according to claim 83 for preparing 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 and or binder, lubricant, glidant, disintegrant, second diluent and binder in a mixer and either: i) wet the mixture obtained in step a) with a solvent, such as ethanol or acetone to obtain wet granules and dry the resulting granules and subsequently roller compact the mixture obtained to obtain granules; ii) compress the mixture from step a) to form tablets; or iii) fill a capsule with the mixture obtained from step a) or step i).

85. The method according to embodiment 83 or 84, wherein the method comprises direct compression of the mixture obtained in step a).

86. The method according to any one of embodiments 83 to 85, wherein the method further comprises addition of further excipients to the mixer after step a).

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

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

89. The method according to any one of embodiments 83-87, wherein the method further comprises micronizing the particles of compound A to obtain a suitable particle size, wherein preferably the particle size is as defined below: a. D50 is l|jm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm

- 30pm; b. DIO is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c. D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

90. A solid dosage form obtainable by the method of any one of embodiments 83 to 89.

91. A solid dosage form as described any one of embodiments 1 to 82 for use in 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

92. A crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size as defined below: a. D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm

- 30pm; b. D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c. D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

93. The crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm, preferably a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm.

94. The crystalline form of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to embodiment 92 or 93, wherein the crystalline form is prepared by micronizing a crystalline particle of 5,7-dimethyl-/V-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

95. The crystalline form of 5,7-dimethyl-/V-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 94, wherein micronization is performed by jet milling, mechanical milling, fluid milling, crushing or grinding.

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

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

98. A pharmaceutical composition obtainable by a process comprising a step in which a crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to any one of embodiments 92 to 96 is mixed with at least one pharmaceutically acceptable carrier or excipient.

99. A pharmaceutical composition according to embodiment 97 or 98, wherein the composition is a solid dosage form.

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

101. A solid dosage form as described in any one of embodiments 1 to 82 and 90, a crystalline form as described in any one of embodiments 92 to 96, or a pharmaceutical composition as described in any one of embodiments 97 to 99 for use in 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma. . The solid dosage form, crystalline form or pharmaceutical composition for use according to embodiment 101, wherein the disorder is Parkinson's disease, for example GBA-PD.

Claims

3. The solid dosage form according to claim 1 or claim 2, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

4. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises micronized 5,7-Dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm, preferably 3pm - 50 pm, or more preferably 5pm - 30pm; and/or having a particle size of D10: > 0.3 pm, preferably > 0.5 pm, or more preferably > 1 pm; and/or having a particle size of D90: < 100 pm, preferably < 80 pm, or more preferably < 60 pm.

5. The solid dosage form any preceding claim, wherein the solid dosage form comprises 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of DIO: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm, preferably D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm.

6. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises: a) 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide; b) a first diluent and/or binder; and c) a lubricant.

7. The solid dosage form according to any preceding claim, wherein the solid dosage form further comprises: i) a disintegrant and a glidant; and/or ii) a second diluent.

8. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises: 5,7-Dimethyl-/V-((l/?,4/?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide in an amount from about 1% to about 60% by weight; preferably about 2% to about 40% by weight, more preferably from about 3% to about 30% by weight.

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

10. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a second diluent, the second diluent being present in an amount from about 3% to about 30% by weight, preferably less than about 10% by weight.

11. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a glidant, the glidant being present in an amount from about 0.3% to about 5% by weight, preferably about 0.5% to about 2% by weight.

12. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a disintegrant, the disintegrant being present in an amount of from about 1% to about 20% by weight, preferably about 2% to about 10% by weight, more preferably from about 3% to about 7% by weight.

13. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a lubricant, the lubricant being present in an amount of about 5% to about 10% by weight and more preferably from about 1% to about 5% by weight.

14. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a binder, the binder being present in an amount of from about 1% to about 20% by weight, preferably about 2% to about 10% by weight, more preferably from about 3% to about 7% by weight.

15. The solid dosage form according to any preceding claim, wherein the solid dosage form further comprises a coating, preferably wherein the coating comprises a capsule or a film coating.

16. The solid dosage form according to any preceding claim, wherein the solid dosage form further comprises a film coating.

17. The solid dosage form according to any preceding claim, wherein the first and/or second diluent independently has a particle size D50 of below 500 pm, preferably below 300 pm, and more preferably below 200 pm; and/or

18. The solid dosage form according to any preceding claim, wherein the first and/or second diluent independently has a moisture content of less than about 15%, preferably less than about 7%.

19. The solid dosage form according to any preceding claim, wherein the first and/or second diluent is independently selected from the group consisting of lactose, starch, a starch derivative, cellulose, or a mixture thereof, preferably, wherein the first and second diluents are independently polymeric diluents, more preferably, where the first diluent is microcrystalline cellulose and/or the second diluent is a starch derivative; most preferably, the second diluent is pre-gelatinized starch.

20. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a glidant and wherein the glidant is preferably an anhydrous glidant.

21. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a glidant and wherein 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, wherein the glidant is colloidal silicon dioxide.

22. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a glidant and wherein the glidant has a surface area measured using the BET method above about 10 m2/g and more preferably above about 100 m2/g.

23. The solid dosage form according to any preceding claim wherein the solid dosage form comprises a disintegrant, and wherein the particle size D90 of the disintegrant is below 500 pm, preferably below 300 pm and more preferably below 150 pm.

24. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a disintegrant and wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, or mixtures thereof; preferably, the disintegrant is crospovidone or sodium starch glycolate, more preferably, the disintegrant is crospovidone.

25. The solid dosage form according to any preceding claim, wherein the solid dosage form comprises a lubricant and wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate or mixtures thereof, preferably magnesium stearate.

26. The solid dosage form according to any preceding claim, wherein the solid dosage form further comprises a binder and the binder is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, ethyl-cellulose, pregelatinized maize starch, gelatine, or mixtures thereof, preferably, the bind is povidone, or methylcellulose, more preferably povidone.

27. The solid dosage form according to any preceding claim, wherein a drug release (average of 6 units) in apparatus 2 (USP) with 900 ml of acetate buffer with a pH of 4.5 at 37 °C with 0.05% of sodium dodecyl sulphate and 100 rpm is more than about 60% in 90 minutes, preferably more than about 60% in 60 minutes and even more preferably more than about 70% in 60 minutes.

28. The solid dosage form according to any preceding claim, wherein more than about 50% of the compound A is present as Form B after 6 months stored at 40°C and 75%HR, preferably more than 80% as from B and even more preferably more that 90% as form B; wherein Form B is identified as the presence of peak (2theta)12.2 in an X-ray diffraction pattern and Form A is identified as the presence of peaks (2theta) at 5.6 and 17.1 in an X-ray diffraction pattern.

29. The solid dosage form according to any preceding claim, wherein less than about 10 % of degradation products are found after 6 months stored at 40°C and 75%HR, 18 months stored at 25°C, and 65% HR and 21 days stored at 70°C and 85% HR: more preferably less than about 5% of degradation products and even preferably less than about 3% of degradation products.

30. The solid dosage form according to any preceding claim, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition:

- compound A: 1-50%

- first diluent: 20-98%

- second diluent: 0-40% - lubricant: 0.1-15%

- binder: 0 to 30%

- disintegrant: 0 to 30%

- glidant: 0 to 10%

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

32. A method according to claim 31 for preparing a solid dosage form according to any one of claims 1 to 30, comprising: a) mixing a predetermined amount of Compound A and at least one of a first diluent and or binder, lubricant, glidant, disintegrant, second diluent and binder in a mixer and either: i) wet the mixture obtained in step a) with a solvent, such as ethanol or acetone to obtain wet granules and dry the resulting granules and subsequently roller compact the mixture obtained to obtain granules; ii) compress the mixture from step a) to form tablets; or iii) fill a capsule with the mixture obtained from step a) or step i).

33. The method according to claim 31 or 32, wherein the method comprises direct compression of the mixture obtained in step a).

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

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

36. The method according to 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 method according to any one of claims 31 to 36, wherein the predetermined amount of Compound A is micronized Compound A, wherein preferably the particle size is as defined below:

1. D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm

- 30pm;

2. D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or

3. D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

38. The method according to any one of claims 31 to 37, wherein the method further comprises micronizing the particles of compound A to obtain a suitable particle size, wherein preferably the particle size is as defined below: a. D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm

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

40. A solid dosage form according to any one of claims 1 to 30 and 39 for use in 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, an 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-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size as defined below: a. D50 is l|jm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b. DIO is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and/or c. D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

42. The crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm, preferably a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm.

43. The crystalline form of 5,7-dimethyl-N-((lR,4R)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to claim 41 or 42, wherein the crystalline form is prepared by micronizing a crystalline particle of 5,7-dimethyl-N-((lR,4R)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

44. The crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to any one of claims 41 to 43, wherein micronization is performed by jet milling, mechanical milling, fluid milling, crushing or grinding.

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

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

48. A pharmaceutical composition according to claim 46 or 47, wherein the composition is a solid dosage form.

49. A process for manufacturing a pharmaceutical composition comprising a crystalline form of 5,7-dimethyl-N-((lR,4R)-4-

(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, the process comprising mixing a crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide according to any one of claims 41 to 45 with at least one pharmaceutically acceptable carrier or excipient.

50. A solid dosage form according to any one of claims 1 to 30 and 39, a crystalline form according to any one of claims 41 to 45, or a pharmaceutical composition according to any one of claims 46 to 48 for use in 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, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma.

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