Pharmaceutical compositions of ENT1 inhibitors

Abstract

Disclosed herein are pharmaceutical compositions comprising an ENT1 inhibitor a pharmaceutically acceptable excipient. In some embodiments, the ENT1 inhibitor is selected from Compound 1 or a hydrate or solvate thereof or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutically acceptable excipient is a diluent. Compound 1

Description

Attorney Docket No: 01330-0113-00PCT PHARMACEUTICAL COMPOSITIONS OF ENT1 INHIBITORS FIELD OF THE INVENTION

[0001] The present disclosure relates to pharmaceutical compositions comprising an ENT1 inhibitor and a pharmaceutically acceptable excipient. In some embodiments, the ENT1 inhibitor selected from Compound 1 or a hydrate or solvate thereof, and pharmaceutically acceptable salts thereof. In some embodiments, the excipient is a diluent.Compound 1 BACKGROUND AND SUMMARY

[0002] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasmalemmal transport proteins which transport nucleoside substrates into cells. There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4. Inhibitors of ENT have been found to be useful in treatment of a variety of conditions, such as cancer. See, e.g., WO 2021 / 204896, the entire contents of which is incorporated herein by reference.

[0003] Novel macrocyclic diamine selective ENT inhibitors have recently been disclosed. See, e.g., WO 2021 / 204896, the entire contents of which is incorporated herein by reference. For example, (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (Compound 10 in WO 2021 / 204896) has been shown to effectively inhibit ENT1. See id. at p. 197 (showing Compound 10 exhibits an IC50 between 0.001 and 0.02 µM in a human ENT1 binding assay). However, that compound (called “Compound 1” or “Compound 1 (free base)” herein and with the formula shown below)Attorney Docket No: 01330-0113-00PCTCompound 1 as prepared in WO 2021 / 204896 was an amorphous free base. Amorphous free base solids tend to be less stable than crystalline and / or salt forms. Indeed, amorphous Compound 1 (free base) was found to be hygroscopic and have a propensity to absorb at least moderate amounts of water. As such, Compound 1 (free base) was found to be difficult to process and manufacture into pharmaceutical compositions, such as solid dosage forms (e.g., tablets and capsules).

[0004] Further, even crystalline and / or salt forms of pharmaceutical compositions are not always easy to process and manufacture. For example, Compound 1 was prepared as a variety of different salts. One crystalline salt form was identified as being particularly stable - crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. However, even this crystalline salt was challenging to process and manufacture into pharmaceutical compositions such as solid dosage forms, including tablets and capsules. Accordingly, there is a need for a suitable pharmaceutical composition of Compound 1 and hydrates, solvates, and salts thereof, including compositions in a solid dosage form, such as a tablet or capsule.

[0005] In addition, in the context of pharmaceutical development, the choice between tablets and capsules can be important, particularly when considering patient acceptability and adherence. For example, tablets, such as film-coated tablets, are generally smaller than capsules for the same dosage strength due to the compression process. This size difference can be an important consideration in terms of patient acceptability, as smaller tablets tend to be easier to swallow, especially for populations such as the elderly or those with dysphagia. Further, film-coated tablets offer additional functional benefits. For example, the coating can mask unpleasant tastes or odors, and protect the active ingredient from environmental factors.

[0006] However, the complexity in manufacturing film-coated tablets, which involves multiple steps such as blending, optional granulation, tableting, and coating, is greater compared to capsules. Tableting involves compressing a powder blend or granules into tablets. It requires control over compression force and tablet weight. Variations in theseAttorney Docket No: 01330-0113-00PCT parameters can affect the tablet’s hardness, disintegration time, and overall quality of the final drug product.

[0007] The film coating process is also challenging. It involves applying a uniform layer of coating material to each tablet, which can be difficult to achieve consistently. The coating must be uniform to ensure proper drug release and protection of the API from environmental factors.

[0008] Thus, in one aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof, and (b) two pharmaceutically acceptable excipients.

[0009] In another aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof andAttorney Docket No: 01330-0113-00PCT (b) a pharmaceutically acceptable excipient, wherein the composition is in the form of a tablet.

[0010] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline.

[0011] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a di(hydrogen sulfate) or hydrate or solvate thereof. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0012] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 1 µm to about 20 µm, an average d50 particle size of from about 10 µm to about 50 µm, and / or an average d90 particle size of from about 40 µm to about 180 µm.

[0013] In some embodiments, one or more excipients are diluents. In some embodiments, two or more excipients are diluents.

[0014] In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is present in an amount of from about 5% to about 14% w / w of the composition.

[0015] In some embodiments, the composition comprises a dose of from about 1 mg and about 50 mg of Compound 1 (free base).

[0016] In some embodiments, when the composition is in the form of a tablet, the tablet size is from about 100 mg to about 600 mg.

[0017] In another aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) Compound 1 or a hydrate or solvate thereof:Attorney Docket No: 01330-0113-00PCT Compound 1 or a pharmaceutical salt thereof, and (b) a diluent.

[0018] In some embodiments, Compound 1 is a hydrate or solvate. In some embodiments, the pharmaceutical salt is a hydrate or solvate of Compound 1.

[0019] In some embodiments, the composition comprises a second diluent. In some embodiments, the second diluent is the same as the first diluent. In some embodiments, the second diluent is different than the first diluent.

[0020] In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition. In some embodiments, the Compound 1 or salt or hydrate or solvate thereof is present in an amount of from about 5% to about 14% w / w of the composition. In some embodiments, the Compound 1 or salt or hydrate or solvate thereof is present in an amount of from about 6% to about 7% w / w of the composition

[0021] In some embodiments, the composition comprises a dose of from about 1 mg and about 50 mg of Compound 1.

[0022] In some embodiments, the composition is in the form of a tablet. In some embodiments, the tablet size is from about 100 mg to about 600 mg.

[0023] In another aspect, the present disclosure relates to a method of inhibiting ENT1 comprising administering a pharmaceutical composition as disclosed here. In one aspect, the present disclosure relates to a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for inhibiting ENT1.

[0024] In another aspect, the present disclosure relates to a method of treating cancer comprising administering to a patient in need thereof a pharmaceutical composition as disclosed here. In one aspect, the present disclosure relates to a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cancer.

[0025] In another aspect, the present disclosure relates to a process of preparing a pharmaceutical composition as described herein.

[0026] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.Attorney Docket No: 01330-0113-00PCT

[0027] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1A shows an XRPD pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0029] FIG. 1B shows a peak picked XRPD pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0030] FIG. 2 shows XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate as prepared in Example 1 – damp and dried samples – compared to an exemplary pattern for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0031] FIG. 3 shows TG / DSC results of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0032] FIG. 4 shows a DSC thermogram of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0033] FIG. 5 shows a1H-NMR spectrum of dissolved crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1, compared to an exemplary spectrum of dissolved Compound 1 (free base).

[0034] FIG. 6 shows a DVS isothermal plot for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0035] FIG. 7 shows a DVS kinetic plot for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0036] FIG. 8 shows an XRPD pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 2, compared to an exemplary pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0037] FIG. 9 shows a Raman Spectrum of a sample of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 2.

[0038] FIG. 10 shows XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3 - damp, dried, and after moisture equilibration samples - compared to an exemplary XRPD pattern and an exemplary simulated single crystal XRPD of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.Attorney Docket No: 01330-0113-00PCT

[0039] FIG. 11 shows PLM images of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate samples prepared according to Example 3 - damp, dried, and after moisture equilibration.

[0040] FIG. 12 shows an overlay of Particle Size Distributions of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3 at 4.33% and 6.07% water contents.

[0041] FIG. 13 shows TG / DSC data of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0042] FIG. 14 shows a DSC thermogram of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0043] FIG. 15 shows a1H-NMR spectrum of dissolved crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0044] FIG. 16 shows an FT-Infrared spectrum of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0045] FIG. 17 shows a Single Crystal Structure Drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K – orientation 1.

[0046] FIG. 18 shows Single Crystal Structure Drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K – orientation 2 .

[0047] FIG. 19 shows simulated XRPD patterns for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate from crystallographic data obtained at 100 K and 295 K.

[0048] FIG. 20 shows stacked plots of simulated XRPD patterns from crystallographic data obtained at 100 K and 295 K (bottom two patterns) along with the experimental XRPD for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 298 K (top pattern).

[0049] FIG. 21 shows XRPD patterns taken during the experiments relating to crystalline Compound 1 as described in Example 5, compared to exemplary patterns of Compound 1 Form 1 and Compound 1 Form 2.

[0050] FIG. 22 shows an XRPD pattern of crystalline Form 1 Compound 1, as prepared in Example 5.

[0051] FIG. 23 shows an XRPD pattern of crystalline Form 2 Compound 1, as prepared in Example 5.

[0052] FIG. 24 shows XRPD patterns of the results of the DVS experiment described in Example 5 on crystalline Form 1 Compound 1 compared to the input material.

[0053] FIG. 25 is an XRPD pattern of amorphous Compound 1 di(hydrogen sulfate) prepared according to Example 6(B).Attorney Docket No: 01330-0113-00PCT

[0054] FIG. 26 shows compression profile of four compositions, as discussed in Example 8.

[0055] FIG. 27 shows results of a strain rate sensitivity study discussed in Example 8.

[0056] FIG. 28 shows compression profile of four compositions, as discussed in Example 8.

[0057] FIG. 29 shows compression profile of six compositions, as discussed in Example 8.

[0058] FIG. 30 shows dissolution rates of two compositions, as discussed in Example 9.

[0059] FIG. 31 shows compression profile of five compositions, as discussed in Example 10.

[0060] FIG. 32 shows compression profile of four compositions, as discussed in Example 12.

[0061] FIG. 33 shows compression profile of five compositions, as discussed in Example 12.

[0062] FIG. 34 shows the dissolution rate of a composition, as discussed in Example 12.

[0063] FIG. 35 shows the dissolution rate of a composition, as discussed in Example 12.

[0064] FIG. 36 shows the dissolution rate of a composition, as discussed in Example 12.

[0065] FIG. 37 shows the dissolution rate of a composition, as discussed in Example 12.

[0066] FIG. 38 shows the dissolution rate of a composition, as discussed in Example 12.

[0067] FIG. 39 shows dissolution rates of two compositions, as discussed in Example 12. DETAILED DESCRIPTION Definitions

[0068] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for preparation and analysis of solid forms. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0069] At various places in the present disclosure, variables or parameters are disclosed in groups or ranges. It is specifically intended that the description include each and every individual sub-combination of the members of such groups and ranges. For example, an integer in the range of 0 to 10 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.Attorney Docket No: 01330-0113-00PCT

[0070] The use of any and all examples, or exemplary language herein, for example “such as” or “including” is intended to merely illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure.

[0071] Unless otherwise indicated, the following terms have the following meanings:

[0072] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0073] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0074] As used herein, the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise.

[0075] The expression “pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0076] The term “excipient” means any substance other than active pharmaceutical ingredient or prodrug thereof that is included in the manufacturing process of or is contained in a pharmaceutical composition, such as a solid dosage form. Examples of excipients in pharmaceutical compositions, such as solid dosage form, include one or more of binders, diluents, lubricants, disintegrating agents, and plasticizers. A tablet is an example of a solid dosage form.

[0077] The term “and / or” as used herein is to be taken to mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0078] The term “or” as used herein is used in the inclusive sense (equivalent to “and / or”) unless the context requires otherwise.

[0079] The term “diluent” or “diluents” as used herein refers to a type of excipient used to increase the volume or weight of a pharmaceutical composition, for example a solid dosageAttorney Docket No: 01330-0113-00PCT form, such as a tablet or capsule. In some embodiments, these substances are added when the active ingredient alone is not sufficient to create a product of the desired size or weight. In some embodiments, these substances are added to ensure uniformity and improve flowability and compressibility of the blend.

[0080] The term “disintegrant” as used herein refers to agents added to composition to promote the break-up of a solid dosage form, such as a table, into smaller fragments in an liquid environment, thereby increasing the available surface area and promoting a more rapid release of the drug substance.

[0081] The term “glidant” as used herein refers to an additive substance that is used to enhance the flowability of a composition by reducing the interparticle friction, surface charge, and cohesion, which in turn decreases the angle of repose.

[0082] The term “lubricant” as used herein refers to an additive to reduce friction.

[0083] The term “screen”, “screened”, or “screening” as used herein refers to passing a substance through a sieve or other device, with or without using a sieve brush. In some embodiments, an excipient(s) is screened through a 1 mm sieve without using a sieve brush. In some embodiments, the ENT1 inhibitor is screened through a 250 µm sieve using a sieve brush. Compositions, Dosage Forms, and Kits

[0084] Disclosed herein are compositions, dosage forms, and kits comprising an ENT1 inhibitor.

[0085] In one aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof, andAttorney Docket No: 01330-0113-00PCT (b) two pharmaceutically acceptable excipients.

[0086] In another aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof and (b) a pharmaceutically acceptable excipient, wherein the composition is in the form of a tablet.

[0087] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a di(hydrogen sulfate) or hydrate or solvate thereof.

[0088] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a hydrate.

[0089] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a trihydrate.

[0090] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline.

[0091] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0092] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks atAttorney Docket No: 01330-0113-00PCT about 4.9° 2θ and about 11.7° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.0° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.7° 2θ, and about 15.0° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ about 10.2° 2θ, about 11.7° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.0° 2θ, about 15.7° 2θ, about 19.0° 2θ, and about 19.6° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.2° 2θ and about 15.0° 2θ.

[0093] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as that of FIG. 1A.

[0094] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate can be prepared in a number of different ways. The XRPD diffraction patterns of FIGs. 1A and 1B are, as with the other XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate disclosed herein, exemplary patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0095] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an FT-IR spectrum substantially the same as that of FIG. 16.

[0096] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a melting onset as measured by DSC in a sealed aluminum pan with a pierced lid of about 144°C.

[0097] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a DSC thermogram substantially the same as that of FIG. 4.

[0098] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate)Attorney Docket No: 01330-0113-00PCT trihydrate, exhibiting a mass loss of between about 5% wt and about 9% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibits a weight loss of about 6% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibits a weight loss of about 7% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a TGA thermogram substantially the same as in FIG. 3.

[0099] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibiting a moisture uptake of between about 5% and about 7% between about 0% RH and about 10% RH. In some embodiments, the moisture uptake is between about 6% and about 6.5% between about 0% RH and about 10% RH. In some embodiments, the moisture uptake is about 6% between about 0 % RH and about 10% RH. In some embodiments, the moisture uptake is about 7% between about 0 % RH and about 10% RH. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an isotherm plot substantially the same as in FIG. 6.

[0100] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having a water content of between about 4% and about 7%. In some embodiments, the water content is between about 6% and about 7%. In some embodiments, the water content is about 4%. In some embodiments, the water content is about 6%. In some embodiments, the water content is about 7%.

[0101] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having a chemical purity of about 95%. In some embodiments, the chemical purity is about 97%. In some embodiments, the chemical purity is 99%. In some embodiments, the chemical purity is greater than 99%.

[0102] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one or more peaks chosen from the peak list in Table A below (all peaks that can be or have beenAttorney Docket No: 01330-0113-00PCT chosen from Table A are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table A below (all peaks that can be or have been chosen from Table A are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table A below (all peaks that can be or have been chosen from Table A are rounded to the nearest 0.1° 2θ). Table A: Peak list for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 3.2145 27.4858 144.12 16.34 2 4.8584 18.18883 503.65 57.11 3 9.8661 8.96524 282.03 31.98 4 10.2164 8.65865 784.06 88.9 5 11.6994 7.56419 119.98 13.6 6 12.6578 6.99355 140.57 15.94 7 14.3558 6.16994 159.37 18.07 8 15.0008 5.90607 803.41 91.1 9 15.6918 5.64753 424.18 48.1 10 16.2234 5.46363 127.56 14.46 11 18.0641 4.91085 105.13 11.92 12 19.0052 4.66973 225.18 25.53 13 19.5999 4.52935 237.59 26.94 14 20.019 4.43548 142.38 16.14 15 20.3701 4.35981 881.93 100 16 21.4304 4.14645 352.47 39.97 17 21.7663 4.08321 585.79 66.42 18 22.0553 4.03035 135.37 15.35 19 22.6211 3.93081 160.73 18.23 20 23.3558 3.8088 120.51 13.66 21 23.7449 3.74726 454.73 51.56 22 24.2988 3.66308 159.23 18.05Attorney Docket No: 01330-0113-00PCT 23 25.0687 3.55229 188.58 21.38 24 25.3332 3.51581 306.82 34.79 25 25.5499 3.48647 253.82 28.78 26 26.2676 3.39282 56.63 6.42 27 26.5834 3.35323 95.33 10.81 28 27.4053 3.2545 94.49 10.71 29 29.7707 3.00109 50.92 5.77 30 33.0781 2.70819 33 3.74

[0103] Below is the peak list and parameters used for a simulated XRPD diffractogram that was calculated for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate from the crystallographic analysis conducted at 295 K. Accordingly, in some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.8° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.1° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.8° 2θ, and about 15.1° 2θ.

[0104] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ, about 10.3° 2θ, about 11.8° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.1° 2θ, about 15.7° 2θ, about 19.1° 2θ, and about 19.7° 2θ.Attorney Docket No: 01330-0113-00PCT

[0105] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.3° 2θ and about 15.1° 2θ.

[0106] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern substantially the same as the bottom pattern of FIG. 19 (Simulated at 295 K).

[0107] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one or more peaks chosen from the peak list in Table C or D below (all peaks that can be or have been chosen from Table C or D are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table C or D below (all peaks that can be or have been chosen from Table C or D are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table C or D below (all peaks that can be or have been chosen from Table C or D are rounded to the nearest 0.1° 2θ). Table B. Crystallographic parameters and refinement indicators of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) C33H55N3O19S2 Empirical *the calculated formula differs from the reported formula by two formula hydrogen atoms and one oxygen atom that were not located Formula weight 858.89 g / mol Temperature / K 295 Crystal system Triclinic Space group P1 a / Å 9.669(2) b / Å 12.439(3) c / Å 18.717(4) α / ° 102.143(13) β / ° 94.505(14)Attorney Docket No: 01330-0113-00PCT γ / ° 110.746(12) Volume / Å32029.0(8) Z , Z` 2, 2 ρcalcg / cm31.406 μ / mm-11.896 F(000) 910.0 Crystal size / mm30.26 × 0.18 × 0.1 Radiation CuKα (λ = 1.54184) 2Θ range for 4.898 to 133.718 data collection / ° Index ranges -11 ≤ h ≤ 11, -14 ≤ k ≤ 14, -22 ≤ l ≤ 22 Reflections 59429 collected Independent 13898 [Rint = 0.0790, Rsigma = 0.0782] reflections Data / restraints / 13898 / 9 / 1037 parameters S 1.141 Final R indexes 2 R1 = 0.0835, wR2 = 0.2430 [F > 2σ (F2)] Final R indexes R1 = 0.1304, wR2 = 0.2767 [all data] Δρmax , Δρmin / -30.75 / -0.72 e Å Flack parameter 0.016(16) R1= (Σ |Fo| – |Fc| ) / Σ |Fo|) ; wR2= {Σ [w(Fo2– Fc2)2] / Σ [w(Fo2)2]}½; S = {Σ [w(Fo2– Fc2)2] / (n-p)}½.Table C. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) (to 35° 2θ) No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 4.8946 18.03960 6042.30 59.50Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 2 7.8547 11.24670 556.77 5.48 3 8.1269 10.87055 210.73 2.08 4 9.9142 8.91452 3372.58 33.21 5 10.2843 8.59445 8325.80 81.99 6 11.0213 8.02136 246.99 2.43 7 11.3260 7.80626 124.83 1.23 8 11.7769 7.50836 1449.36 14.27 9 12.7288 6.94891 946.25 9.32 10 13.7978 6.41286 208.45 2.05 11 14.0557 6.29576 175.68 1.73 12 14.4212 6.13703 1381.48 13.60 13 14.8161 5.97431 798.24 7.86 14 15.0866 5.86780 8503.98 83.74 15 15.7472 5.62311 4635.76 45.65 16 16.3067 5.43141 950.60 9.36 17 16.5804 5.34236 396.22 3.90 18 16.7518 5.28810 732.42 7.21 19 17.6648 5.01677 1162.56 11.45 20 18.1455 4.88495 977.39 9.63 21 18.7007 4.74114 895.86 8.82 22 19.1179 4.63861 2593.46 25.54 23 19.3951 4.57295 1135.31 11.18 24 19.6844 4.50638 3525.96 34.72 25 20.1541 4.40241 1482.37 14.60 26 20.5087 4.32709 10154.64 100.00 27 20.6883 4.28991 3063.49 30.17 28 21.5353 4.12307 4158.59 40.95 29 21.8691 4.06089 5594.20 55.09 30 22.1724 4.00602 2019.79 19.89 31 22.7572 3.90438 1932.14 19.03 32 23.2319 3.82567 774.16 7.62Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 33 23.4414 3.79193 1503.00 14.80 34 23.8808 3.72316 4836.63 47.63 35 24.0983 3.69005 976.79 9.62 36 24.4603 3.63624 1794.58 17.67 37 25.1790 3.53406 2515.82 24.78 38 25.4667 3.49479 3482.27 34.29 39 25.6807 3.46614 2622.15 25.82 40 25.8405 3.44507 1042.79 10.27 41 26.0935 3.41223 282.03 2.78 42 26.4560 3.36630 534.53 5.26 43 26.7225 3.33333 988.58 9.74 44 26.8890 3.31307 537.29 5.29 45 27.5852 3.23101 1124.78 11.08 46 27.8048 3.20599 721.02 7.10 47 28.0213 3.18171 737.19 7.26 48 28.1626 3.16606 700.32 6.90 49 28.3719 3.14318 450.70 4.44 50 28.7104 3.10689 799.44 7.87 51 28.9146 3.08541 359.05 3.54 52 29.0906 3.06714 581.41 5.73 53 29.4930 3.02620 888.83 8.75 54 29.6586 3.00969 595.93 5.87 55 29.9076 2.98519 897.31 8.84 56 30.1441 2.96231 360.12 3.55 57 30.5331 2.92544 448.44 4.42 58 30.9066 2.89094 637.94 6.28 59 31.2138 2.86318 500.03 4.92 60 31.7259 2.81813 403.18 3.97 61 31.9896 2.79550 180.41 1.78 62 32.3740 2.76318 292.01 2.88 63 32.7117 2.73542 173.43 1.71Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 64 32.9971 2.71240 310.93 3.06 65 33.3364 2.68557 441.08 4.34 66 33.9267 2.64018 201.06 1.98 67 34.1530 2.62320 165.81 1.63 68 34.6331 2.58793 175.24 1.73 Table D. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) (20 most intense peaks). No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 20.5087 4.32709 10154.64 100.00 2 15.0866 5.86780 8503.98 83.74 3 10.2843 8.59445 8325.80 81.99 4 4.8946 18.03960 6042.30 59.50 5 21.8691 4.06089 5594.20 55.09 6 23.8808 3.72316 4836.63 47.63 7 15.7472 5.62311 4635.76 45.65 8 21.5353 4.12307 4158.59 40.95 9 19.6844 4.50638 3525.96 34.72 10 25.4667 3.49479 3482.27 34.29 11 9.9142 8.91452 3372.58 33.21 12 20.6883 4.28991 3063.49 30.17 13 25.6807 3.46614 2622.15 25.82 14 19.1179 4.63861 2593.46 25.54 15 25.1790 3.53406 2515.82 24.78 16 22.1724 4.00602 2019.79 19.89 17 22.7572 3.90438 1932.14 19.03 18 24.4603 3.63624 1794.58 17.67 19 23.4414 3.79193 1503.00 14.80 20 20.1541 4.40241 1482.37 14.60Attorney Docket No: 01330-0113-00PCT

[0108] Below is the peak list and parameters used for a simulated XRPD diffractogram that was calculated for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K. Accordingly, in some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one or more peaks chosen from the peak list in Table F or G below (all peaks that can be or have been chosen from Table F or G are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table F or G below (all peaks that can be or have been chosen from Table F or G are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table F or G below (all peaks that can be or have been chosen from Table F or G are rounded to the nearest 0.1° 2θ). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as the top pattern of FIG. 19 (Simulated at 100 K). Table E. Crystallographic parameters and refinement indicators of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) Empirical formula C33H57N3O20S2 Formula weight 879.93 g / mol Temperature / K 100 Crystal system Triclinic Space group P1 a / Å 9.6794(2) b / Å 12.3886(2) c / Å 18.4016(4) α / ° 101.6708(8) β / ° 94.7448(8) γ / ° 110.7514(8) Volume / Å31991.88(7) Z , Z` 2, 2 ρcalcg / cm31.467 μ / mm-11.962Attorney Docket No: 01330-0113-00PCT F(000) 936.0 Crystal size / mm30.38 × 0.24 × 0.12 Radiation CuKα (λ = 1.54178) 2Θ range for data collection / ° 4.974 to 144.29 Index ranges -10 ≤ h ≤ 11, -15 ≤ k ≤ 15, -22 ≤ l ≤ 2 Reflections collected 97841 Independent reflections 15198 [Rint = 0.0299, Rsigma = 0.0202] Data / restraints / parameters 15198 / 33 / 1139 S 1.029 Final R indexes [F2> 2σ (F2)] R1= 0.0586, wR2 = 0.1588 Final R indexes [all data] R1 = 0.0592, wR2 = 0.1597 Δρmax , Δρmin / e Å-30.63 / -1.17 Flack parameter -0.008(5) R1= (Σ |Fo| – |Fc| ) / Σ |Fo|) ; wR2= {Σ [w(Fo2– Fc2)2] / Σ [w(Fo2)2]}½; S = {Σ [w(Fo2– Fc2)2] / (n-p)}½.Table F. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) (to 35° 2θ) No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 4.9708 17.76340 5692.39 57.05 2 7.8721 11.22177 192.87 1.93 3 8.2012 10.77221 118.89 1.19 4 9.9051 8.92269 2513.16 25.19 5 10.3093 8.57375 6074.58 60.88 6 11.0697 7.98639 381.20 3.82 7 11.8171 7.48292 506.02 5.07 8 12.8134 6.90323 597.90 5.99 9 13.9479 6.34418 211.75 2.12 10 14.1586 6.25023 346.39 3.47 11 14.4510 6.12442 967.78 9.70 12 15.2031 5.82311 7129.03 71.45 13 15.7809 5.61116 4079.65 40.89Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 14 16.4745 5.37646 794.87 7.97 15 16.7852 5.27763 453.42 4.54 16 17.7061 5.00516 847.97 8.50 17 18.3200 4.83881 709.84 7.11 18 18.6841 4.74533 393.29 3.94 19 19.3213 4.59023 3032.46 30.39 20 19.6644 4.51092 3526.60 35.34 21 19.8463 4.46998 1072.98 10.75 22 20.1614 4.40082 1610.14 16.14 23 20.7696 4.27331 9978.21 100.00 24 21.5995 4.11096 759.84 7.61 25 21.8102 4.07171 3594.54 36.02 26 22.2082 3.99964 5614.95 56.27 27 22.3481 3.97491 1892.70 18.97 28 22.7901 3.89882 1412.77 14.16 29 23.2451 3.82351 1120.21 11.23 30 23.4845 3.78508 1365.48 13.68 31 23.7730 3.73979 884.41 8.86 32 24.0898 3.69132 1251.47 12.54 33 24.3072 3.65880 5161.43 51.73 34 24.5353 3.62530 1465.70 14.69 35 24.7824 3.58971 996.51 9.99 36 25.4465 3.49751 2461.31 24.67 37 25.8398 3.44517 3425.07 34.33 38 26.1214 3.40866 2704.76 27.11 39 26.7881 3.32531 828.92 8.31 40 26.9212 3.30917 1036.14 10.38 41 27.3278 3.26086 516.98 5.18 42 27.5109 3.23957 527.00 5.28 43 27.7881 3.20787 1169.38 11.72 44 28.1012 3.17284 937.34 9.39Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 45 28.3241 3.14838 1081.95 10.84 46 28.5401 3.12505 773.11 7.75 47 28.7454 3.10318 1024.38 10.27 48 29.1078 3.06537 964.03 9.66 49 29.4874 3.02676 857.33 8.59 50 29.9255 2.98345 806.76 8.09 51 30.1457 2.96215 1038.18 10.40 52 30.4145 2.93659 577.92 5.79 53 30.7961 2.90106 714.10 7.16 54 30.9877 2.88356 724.52 7.26 55 31.2722 2.85797 663.29 6.65 56 31.7460 2.81639 339.03 3.40 57 32.0668 2.78894 523.95 5.25 58 32.3819 2.76252 429.15 4.30 59 32.6774 2.73821 209.40 2.10 60 33.3433 2.68503 859.27 8.61 61 33.9170 2.64091 408.11 4.09 62 34.1856 2.62078 272.79 2.73 63 34.6088 2.58969 110.44 1.11 64 34.8394 2.57308 228.50 2.29 Table G. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) (20 most intense peaks) No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 20.7696 4.27331 9978.21 100.00 2 15.2031 5.82311 7129.03 71.45 3 10.3093 8.57375 6074.58 60.88 4 4.9708 17.76340 5692.39 57.05 5 22.2082 3.99964 5614.95 56.27 6 24.3072 3.65880 5161.43 51.73 7 15.7809 5.61116 4079.65 40.89Attorney Docket No: 01330-0113-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 8 21.8102 4.07171 3594.54 36.02 9 19.6644 4.51092 3526.60 35.34 10 25.8398 3.44517 3425.07 34.33 11 19.3213 4.59023 3032.46 30.39 12 26.1214 3.40866 2704.76 27.11 13 9.9051 8.92269 2513.16 25.19 14 25.4465 3.49751 2461.31 24.67 15 22.3481 3.97491 1892.70 18.97 16 20.1614 4.40082 1610.14 16.14 17 24.5353 3.62530 1465.70 14.69 18 22.7901 3.89882 1412.77 14.16 19 23.4845 3.78508 1365.48 13.68 20 24.0898 3.69132 1251.47 12.54

[0109] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate contains one stereogenic center and is a single enantiomer with the R- configuration, as shown in Table H. It contains three molecules of water, as shown in Table H, and thus is a trihydrate. Table H Chemical Structure x 2 H2SO4x 3 H2O Molecular formula C33H47N3O9, 2 H2SO4, 3 H2O (C33H51N3O17S2, 3 H2O)Attorney Docket No: 01330-0113-00PCT Relative molecular 629.75 (free base); 879.94 (salt: di(hydrogen sulfate) mass (MW) trihydrate)

[0110] Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has a single Compound 1 cation and at least one hydrogen sulfate anion and where the other sulfate moiety may be in the form of a second hydrogen sulfate anion or sulfuric acid (which would be neutral).

[0111] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average X10 particle size of from about 1 µm to about 20 µm, an average X50 particle size of from about 10 µm to about 50 µm, and / or an average X90 particle size of from about 40 µm to about 180 µm.

[0112] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average X10particle size of from about 2 µm to about 10 µm, an average X50particle size of from about 15 µm to about 45 µm, and / or an average X90particle size of from about 50 µm to about 170 µm.

[0113] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average X10 particle size of from about 2 µm to about 5 µm, an average X50 particle size of from about 15 µm to about 20 µm, and / or an average X90 particle size of from about 50 µm to about 75 µm.

[0114] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average X10particle size of from about 2 µm to about 4 µm, an average X50particle size of from about 15 µm to about 17 µm, and / or an average X90 particle size of from about 55 µm to about 75 µm.

[0115] In some embodiments, in compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof and a pharmaceutically acceptable excipient wherein the composition is in the form of a tablet, the excipient is selected from diluents, disintegrants, glidants, and lubricants. In some embodiments, the excipient is a diluent.Attorney Docket No: 01330-0113-00PCT

[0116] In some embodiments, in compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof and a pharmaceutically acceptable excipient wherein the composition is in the form of a tablet, the composition comprises two excipients. In some embodiments, at least one of the two excipients is a diluent. In some embodiments, both excipients are diluents. In some embodiments, one excipient is a diluent and one excipient is a disintegrant. In some embodiments, one excipient is a diluent and one excipient is a glidant. In some embodiments, one excipient is a diluent and one excipient is a lubricant. In some embodiments, one excipient is a disintegrant and one excipient is a glidant. In some embodiments, one excipient is a disintegrant and one excipient a lubricant. In some embodiments, one excipient is a glidant and one excipient is a lubricant.

[0117] In some embodiments, in compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof and two pharmaceutically acceptable excipients, at least one of the two excipients is a diluent. In some embodiments, both of the two excipients are diluents. In some embodiments, one excipient is a diluent and one excipient is a disintegrant. In some embodiments, one excipient is a diluent and one excipient is a glidant. In some embodiments, one excipient is a diluent and one excipient is a lubricant. In some embodiments, one excipient is a disintegrant and one excipient is a glidant. In some embodiments, one excipient is a disintegrant and one excipient a lubricant. In some embodiments, one excipient is a glidant and one excipient is a lubricant.

[0118] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the composition comprises three excipients. In some embodiments, at least one of the three excipients are diluents. In some embodiments, one excipient is a diluent, one excipient is a disintegrant, and one excipient is a glidant. In some embodiments, one excipient is a diluent, one excipient is a lubricant, and one excipient is a glidant. In some embodiments, at least two of the three excipients are diluents. In some embodiments, two of the excipients are diluents, and one excipient is a disintegrant. In some embodiments, two of the excipients are diluents, and one excipient is a glidant. In some embodiments, two of the excipients are diluents, and one excipient is a lubricant.

[0119] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the composition comprises four excipients. In some embodiments, at least one of the four excipients are diluents. In some embodiments, one excipient is a diluent, one excipient is a disintegrant, one excipient is a glidant, and one excipient is a lubricant. In some embodiments, at least two of the four excipients are diluents. In some embodiments, two of the excipients are diluents, one excipient is a disintegrant, andAttorney Docket No: 01330-0113-00PCT one excipient is a glidant. In some embodiments, two of the excipients are diluents, one excipient is a disintegrant, and one excipient is a lubricant. In some embodiments, two of the excipients are diluents, one excipient is a lubricant, and one excipient is a glidant.

[0120] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the diluent or diluents are chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate. In some embodiments, the diluent or diluents are microcrystalline cellulose. In some embodiments, the diluent or diluents are lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the lactose monohydrate is spray-dried. In some embodiments, the diluent or diluents are starch, such as a pregelatinized starch. In some embodiments, the diluent or diluents are mannitol. In some embodiments, the mannitol has a mean particle size of about 100 µm. In some embodiments, the mannitol has a mean particle size of about 170 µm. In some embodiments, the diluent or diluents are dicalcium phosphate, such as dicalcium phosphate anhydrous.

[0121] In some embodiments, the diluents are microcrystalline cellulose and lactose. In some embodiments, the diluents are microcrystalline cellulose and starch. In some embodiments, the diluents are microcrystalline cellulose and mannitol. In some embodiments, the diluents are microcrystalline cellulose and dicalcium phosphate. In some embodiments, the diluents are lactose and starch.

[0122] In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL, or an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL, or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0123] In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL. In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL. In some embodiments, the microcrystalline cellulose has an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0124] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the total weight of the diluent or diluents in the composition is from about 20% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 90% ofAttorney Docket No: 01330-0113-00PCT the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 70% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 80% to about 90% of the composition.

[0125] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 90% to about 95% of the composition.

[0126] In some embodiments, the total weight of the diluent or diluents in the composition is from about 70% to about 95% of the composition.

[0127] In some embodiments, the total weight of the diluent or diluents in the composition is from about 80% to about 90% w / w of the composition.

[0128] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the composition further comprises a disintegrant. In some embodiments, the disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate. In some embodiments, the disintegrant is crospovidone. In some embodiments, the crospovidone has an average particle size of from about 30 µm to about 150 µm. In some embodiments, the crospovidone has an average particle size of about 30 µm. In some embodiments, the crospovidone has an average particle size of about 150 µm.

[0129] In some embodiments, the disintegrant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 2% to about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 2% to about 4% w / w of the composition.Attorney Docket No: 01330-0113-00PCT

[0130] In some embodiments, the disintegrant is present in an amount of about 2% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 4% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 5% w / w of the composition.

[0131] In some embodiments, the disintegrant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 1% to about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 1% to about 4% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 1% to about 5% w / w of the composition.

[0132] In some embodiments, the disintegrant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 4% to about 5% w / w of the composition.

[0133] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the composition further comprises a glidant. In some embodiments, the glidant is a colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide has a BET surface area of from about 75 m2 / g to about 410 m2 / g. In some embodiments, the colloidal silicon dioxide has a BET surface area of from 175 m2 / g to about 225 m2 / g. In some embodiments, the glidant is selected from talc, glycerol monostearate, and precipitated silica.

[0134] In some embodiments, the glidant is present in an amount of about 1% w / w of the composition. In some embodiments, the glidant is present in an amount of about 1.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 2% w / w of the composition. In some embodiments, the glidant is present in an amount of about 2.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of about 3.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of about 4.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 5.5% w / w of the composition.Attorney Docket No: 01330-0113-00PCT

[0135] In some embodiments, the glidant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the glidant is present in an amount from about 1% to about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 1% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 1% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 4% to about 5% w / w of the composition.

[0136] In some embodiments, in any of the compositions comprising Compound 1 hydrogen sulfate or hydrate or solvate thereof, the composition further comprises a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is vegetable stearin or stearic acid. In some embodiments, the lubricant is a fat.

[0137] In some embodiments, the lubricant is present in an amount of about 1% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 1.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 2% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 2.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 3.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 4.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 5.5% w / w of the composition.

[0138] In some embodiments, the lubricant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of fromAttorney Docket No: 01330-0113-00PCT about 2% to about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 2% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 4% to about 5% w / w of the composition.

[0139] In one aspect, the present disclosure relates to a pharmaceutical composition comprising: (a) Compound 1 or a hydrate or solvate thereof:Compound 1 or a pharmaceutical salt thereof, and (b) a diluent.

[0140] In some embodiments, Compound 1 is a hydrate or solvate. In some embodiments, the pharmaceutical salt is a hydrate or solvate of Compound 1.

[0141] In some embodiments, the diluent is chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the lactose monohydrate is spray-dried. In some embodiments, the diluent is starch, such as a pregelatinized starch. In some embodiments, the diluent or diluents are mannitol. In some embodiments, the mannitol has a mean particle size of about 100 µm. In some embodiments, the mannitol has a mean particle size of about 170 µm. In some embodiments, the diluent or diluents are dicalcium phosphate, such as dicalcium phosphate anhydrous.

[0142] In some embodiments, the composition comprises a second diluent. In some embodiments, the second diluent is the same as the first diluent. In some embodiments, theAttorney Docket No: 01330-0113-00PCT first and second diluents are microcrystalline cellulose. In some embodiments, the first and second diluents are lactose. In some embodiments, the first and second diluents are starch.

[0143] In some embodiments, the second diluent is different than the first diluent. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is lactose. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is starch. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is mannitol. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is dicalcium phosphate. In some embodiments, the first diluent is lactose and the second diluent is starch.

[0144] In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL, or an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL, or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0145] In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL. In some embodiments, the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL. In some embodiments, the microcrystalline cellulose has an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0146] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 70% to about 90% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 80% to about 90% of the composition.

[0147] In some embodiments, the total weight of the diluent or diluents in the composition is from about 70% to about 95% of the composition.Attorney Docket No: 01330-0113-00PCT

[0148] In some embodiments, the total weight of the diluent or diluents in the composition is from about 80% to about 90% w / w of the composition.

[0149] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 95% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 90% to about 95% of the composition.

[0150] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 30% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 40% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 40% of the composition.

[0151] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 50% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 50% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 50% of the composition.

[0152] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 60% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 60% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 60% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 60% of the composition.

[0153] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 70% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 70% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 70% of the composition. In some embodiments, theAttorney Docket No: 01330-0113-00PCT total weight of the diluent or diluents in the composition is from about 50% to about 70% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 70% of the composition.

[0154] In some embodiments, the total weight of the diluent or diluents in the composition is from about 20% to about 80% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 30% to about 80% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 40% to about 80% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 50% to about 80% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 60% to about 80% of the composition. In some embodiments, the total weight of the diluent or diluents in the composition is from about 70% to about 80% of the composition.

[0155] In some embodiments, the composition further comprises a disintegrant.

[0156] In some embodiments, the disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate. In some embodiments, the disintegrant is crospovidone. In some embodiments, the crospovidone has an average particle size of from about 30 µm to about 150 µm. In some embodiments, the crospovidone has an average particle size of about 30 µm. In some embodiments, the crospovidone has an average particle size of about 150 µm.

[0157] In some embodiments, the disintegrant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 2% to about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 2% to about 4% w / w of the composition.

[0158] In some embodiments, the disintegrant is present in an amount of about 2% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 4% w / w of the composition. In some embodiments, the disintegrant is present in an amount of about 5% w / w of the composition.

[0159] In some embodiments, the disintegrant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 1% to about 3% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 1% to about 4% w / w of the composition.Attorney Docket No: 01330-0113-00PCT In some embodiments, the disintegrant is present in an amount of from about 1% to about 5% w / w of the composition.

[0160] In some embodiments, the disintegrant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the disintegrant is present in an amount of from about 4% to about 5% w / w of the composition.

[0161] In some embodiments, the composition further comprises a glidant.

[0162] In some embodiments, the glidant is a colloidal silicon dioxide. In some embodiments, the glidant is selected from talc, glycerol monostearate, and precipitated silica.

[0163] In some embodiments, the glidant is present in an amount of about 1% w / w of the composition. In some embodiments, the glidant is present in an amount of about 1.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 2% w / w of the composition. In some embodiments, the glidant is present in an amount of about 2.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of about 3.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of about 4.5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of about 5.5% w / w of the composition.

[0164] In some embodiments, the glidant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the glidant is present in an amount from about 1% to about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 1% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 1% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 3% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the glidant is present in an amount of from about 4% to about 5% w / w of the composition.

[0165] In some embodiments, the composition further comprises a lubricant.Attorney Docket No: 01330-0113-00PCT

[0166] In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is vegetable stearin or stearic acid. In some embodiments, the lubricant is a fat.

[0167] In some embodiments, the lubricant is present in an amount of about 1% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 1.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 2% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 2.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 3.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 4.5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of about 5.5% w / w of the composition.

[0168] In some embodiments, the lubricant is present in an amount of from about 1% to about 2% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 1% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 2% to about 3% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 2% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 2% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 3% to about 4% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 3% to about 5% w / w of the composition. In some embodiments, the lubricant is present in an amount of from about 4% to about 5% w / w of the composition.

[0169] In some embodiments, in any of the compositions herein, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or hydrate or solvate or salt thereof, is present in an amount of from about 5% to about 25% w / w of the composition. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or hydrate or solvate or salt thereof, is present in an amount of from about 5% to about 20% w / w of the composition. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or hydrate or solvate or salt thereof, is present in an amount of from about 5% to about 15% w / w of the composition.Attorney Docket No: 01330-0113-00PCT

[0170] In some embodiments, in any of the compositions herein, the composition comprises about 6% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 6.75% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 7% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 8% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 9% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, in any of the compositions herein, the composition comprises about 10% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 11% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 12% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 13% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 14% of Compound 1 hydrogen sulfate or hydrate or solvate thereof. In some embodiments, the composition comprises about 15% of Compound 1 hydrogen sulfate or hydrate or solvate thereof.

[0171] In some embodiments, in any of the compositions herein, the composition comprises about 1% of Compound 1 (free base). In some embodiments, the composition comprises about 2% of Compound 1. In some embodiments, the composition comprises about 3% of Compound 1. In some embodiments, the composition comprises about 4% of Compound 1. In some embodiments, the composition comprises about 5% of Compound 1. In some embodiments, the composition comprises about 6% of Compound 1. In some embodiments, the composition comprises about 7% of Compound 1. In some embodiments, the composition comprises about 8% of Compound 1. In some embodiments, the composition comprises about 9% of Compound 1. In some embodiments, the composition comprises about 10% of Compound 1. In some embodiments, the composition comprises about 11% of Compound 1. In some embodiments, the composition comprises about 12% of Compound 1. In some embodiments, the composition comprises about 13% of Compound 1. In some embodiments, the composition comprises about 14% of Compound 1. In some embodiments, the composition comprises about 15% of Compound 1.

[0172] In some embodiments, in any of the compositions herein, the composition comprises a dose of from about 1 mg and about 40 mg of Compound 1 (free base). In some embodiments, the composition comprises a dose of from about 1 mg and about 30 mg of Compound 1. InAttorney Docket No: 01330-0113-00PCT some embodiments, the composition comprises a dose of from about 1 mg and about 25 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 1 mg and about 20 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 1 mg and about 15 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 1 mg and about 10 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 1 mg and about 5 mg of Compound 1.

[0173] In some embodiments, the composition comprises a dose of from about 5 mg and about 40 mg of Compound 1 (free base). In some embodiments, the composition comprises a dose of from about 5 mg and about 35 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 5 mg to about 30 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 5 mg and about 25 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 5 mg and about 20 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 5 mg and about 15 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 5 mg and about 10 mg of Compound 1.

[0174] In some embodiments, the composition comprises a dose of from about 10 mg and about 40 mg of Compound 1 (free base). In some embodiments, the composition comprises a dose of from about 10 mg and about 30 mg of Compound 1. In some embodiments, the composition comprises a dose of from about 10 mg and about 20 mg of Compound 1.

[0175] In some embodiments, the composition comprises a dose of about 5 mg of Compound 1 (free base). In some embodiments, the composition comprises a dose of about 10 mg of Compound 1. In some embodiments, the composition comprises a dose of about 15 mg of Compound 1. In some embodiments, the composition comprises a dose of about 20 mg of the Compound 1. In some embodiments, the composition comprises a dose of about 25 mg of Compound 1. In some embodiments, the composition comprises a dose of about 30 mg of Compound 1. In some embodiments, the composition comprises a dose of about 35 mg of Compound 1. In some embodiments, the composition comprises a dose of about 40 mg of the Compound 1.

[0176] In some embodiments, in any of the compositions herein, the composition is in the form of an solid dosage form. In some embodiments, the solid dosage form is an oral dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet size is from about 100 mg to about 600 mg. In some embodiments, the tablet size isAttorney Docket No: 01330-0113-00PCT about 100 mg. In some embodiments, the tablet size is about 200 mg. In some embodiments, the tablet size is about 400 mg. In some embodiments, the tablet size is about 600 mg.

[0177] In some embodiments, the tablet has a diameter of less than about 10 mm. In some embodiments, the tablet has a diameter of from about 4 to about 10 mm. In some embodiments, the tablet has a diameter of from about 4.5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 5.5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 6 to about 10 mm. In some embodiments, the tablet has a diameter of from about 6.5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 7 to about 10 mm. In some embodiments, the tablet has a diameter of from about 7.5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 8 to about 10 mm. In some embodiments, the tablet has a diameter of from about 8.5 to about 10 mm. In some embodiments, the tablet has a diameter of from about 9 to about 10 mm. In some embodiments, the tablet has a diameter of from about 9.5 to about 10 mm.

[0178] In some embodiments, the tablet has a diameter of less than about 6.5 mm. In some embodiments, the tablet has a diameter of from about 4 to about 6.5 mm. In some embodiments, the tablet has a diameter of from about 4.5 to about 6.5 mm. In some embodiments, the tablet has a diameter of from about 5 to about 6.5 mm. In some embodiments, the tablet has a diameter of from about 5.5 to about 6.5 mm. In some embodiments, the tablet has a diameter of from about 6 to about 6.5 mm

[0179] In some embodiments, the tablet has a diameter of about 6 mm. In some embodiments, the tablet has a diameter of about 6.5 mm.

[0180] In some embodiments, the tablet is film-coated. In some embodiments, the film- coating does not contain titanium dioxide. For example, in some embodiments, the film- coating is Opadry titanium dioxide free (TF). In some embodiments, the tablet is not coated.

[0181] In some embodiments, the tablet is an immediate release tablet. In some embodiments, the tablet is an extended release tablet.

[0182] In some embodiments, the tablets are shelf stable. For example, in some embodiments, the tablets are stable up to three months, up to six months, up to nine months, up to 12 months, or up to 36 months when stored at about 15°C to about 25°C.

[0183] In some embodiments, the tablets are stable up to three months, up to six months, up to nine months, up to 12 months, or up to 36 months when stored at about 40°C and aboutAttorney Docket No: 01330-0113-00PCT 75% relative humidity (“40°C / 75%RH”) or at about 25°C and about 60%RH (“25°C / 60%RH”).

[0184] In one aspect, the present disclosure provides a kit of parts comprising a pharmaceutical composition, such as a solid dosage form, as described herein. In one aspect, the present disclosure provides a kit of parts comprising: (1) a pharmaceutical composition such as a solid dosage form as described herein; and (2) instructions for use. Methods, Uses, and Processes

[0185] Disclosed herein are methods and uses comprising a pharmaceutical composition, dosage form, and / or kit as described herein.

[0186] In one aspect, the present disclosure relates to a method of inhibiting ENT1 comprising administering a pharmaceutical composition as disclosed here. In one aspect, the present disclosure relates to a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for inhibiting ENT1.

[0187] In another aspect, the present disclosure relates to a method of treating cancer comprising administering to a patient in need thereof a pharmaceutical composition as disclosed herein. In one aspect, the present disclosure relates to a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cancer.

[0188] In some embodiments, in any of the methods described herein, the pharmaceutical composition is a solid dosage form, such as a tablet.

[0189] In another aspect, the present disclosure relates to a process of preparing a pharmaceutical composition as described herein.

[0190] In some embodiments, the present disclosure relates to a process of preparing a pharmaceutical composition comprising combining a diluent with a Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, to create a diluent mixture. In some embodiments, the process of preparing a pharmaceutical composition further comprises combining the diluent mixture with an additional diluent. In some embodiments, the additional diluent is the same as the first diluent. In some embodiments, the additional diluent is different that the first diluent. In some embodiment, the method further comprises adding a lubricant.

[0191] In some embodiments, present disclosure relates to a process of preparing a pharmaceutical composition comprising combining a diluent with a Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, followed by addition of a disintegrant. In some embodiment, the method further comprisesAttorney Docket No: 01330-0113-00PCT adding a glidant and / or an additional diluent. In some embodiments, the additional diluent is the same as the first diluent. In some embodiments, the additional diluent is different that the first diluent. In some embodiment, the method further comprises adding a lubricant.

[0192] some embodiments, present disclosure relates to a process of preparing a pharmaceutical composition comprising: (1) combining a diluent with a Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, to create a first mixture; (2) combining a disintegrant with the first mixture to create a second mixture; (3) combining a glidant with the second mixture to create a third mixture; (4) combining additional diluent to the third mixture to create a fourth mixture; and (5) adding a lubricant to the fourth mixture. In some embodiments, the additional diluent is the same as the first diluent. In some embodiments, the additional diluent is different that the first diluent.

[0193] In some embodiments, in any of the processes of preparing described herein, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is screened before combining with a diluent. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is screened through a 250 µm sieve. In some embodiments, the diluent, disintegrant, glidant, and / or lubricant is screened. In some embodiment, the diluent, disintegrant, glidant, and / or lubricant is screened through a 1 mm sieve.

[0194] In some embodiments, in any of the processes of preparing described herein, the process further comprises granulation. In some embodiments, in any of the processes of preparing described herein, the process does not comprise granulation.

[0195] In some embodiments, in any of the processes of preparing described herein, the process further comprises compressing the composition into a solid dosage form. In some embodiments, the dosage form is a tablet. In some embodiments, the process further comprises coating the solid dosage form, such as a tablet. ENUMERATED EMBODIMENTS

[0196] Embodiment 1. A pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Attorney Docket No: 01330-0113-00PCTCompound 1 or a hydrate or solvate thereof, and (b) two pharmaceutically acceptable excipients.

[0197] Embodiment 2. The pharmaceutical composition according to embodiment 1, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a di(hydrogen sulfate) or hydrate or solvate thereof.

[0198] Embodiment 3. The pharmaceutical composition according to embodiment 1 or 2, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a hydrate.

[0199] Embodiment 4. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a trihydrate.

[0200] Embodiment 5. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline.

[0201] Embodiment 6. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0202] Embodiment 7. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ.

[0203] Embodiment 8. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ.Attorney Docket No: 01330-0113-00PCT

[0204] Embodiment 9. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.7° 2θ.

[0205] Embodiment 10. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.0° 2θ.

[0206] Embodiment 11. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.7° 2θ, and about 15.0° 2θ.

[0207] Embodiment 12. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ about 10.2° 2θ, about 11.7° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.0° 2θ, about 15.7° 2θ, about 19.0° 2θ, and about 19.6° 2θ.

[0208] Embodiment 13. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.2° 2θ and about 15.0° 2θ.

[0209] Embodiment 14. The pharmaceutical composition according to any one of embodiments 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as that of FIG. 1A.

[0210] Embodiment 15. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an FT-IR spectrum substantially the same as that of FIG. 16.

[0211] Embodiment 16. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvateAttorney Docket No: 01330-0113-00PCT thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a melting onset as measured by DSC in a sealed aluminum pan with a pierced lid of about 144°C.

[0212] Embodiment 17. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a DSC thermogram substantially the same as that of FIG. 4.

[0213] Embodiment 18. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 1 µm to about 20 µm, an average d50 particle size of from about 10 µm to about 50 µm, and / or an average d90 particle size of from about 40 µm to about 180 µm.

[0214] Embodiment 19. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 2 µm to about 10 µm, an average d50 particle size of from about 15 µm to about 45 µm, and / or an average d90 particle size of from about 50 µm to about 170 µm.

[0215] Embodiment 20. The pharmaceutical composition according to any one of the preceding embodiments, wherein at least one of the two excipients is a diluent.

[0216] Embodiment 21. The pharmaceutical composition according to any one of the preceding embodiments, wherein both of the two excipients are diluents.

[0217] Embodiment 22. The pharmaceutical composition according to embodiment 20 or 21, wherein the diluent or diluents are chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate.

[0218] Embodiment 23. The pharmaceutical composition according to embodiment 22, wherein the diluent or diluents are microcrystalline cellulose.

[0219] Embodiment 24. The pharmaceutical composition according to embodiment 22, wherein the diluent or diluents are lactose.

[0220] Embodiment 25. The pharmaceutical composition according to embodiment 21, wherein the diluents are microcrystalline cellulose and lactose.

[0221] Embodiment 26. The pharmaceutical composition according to any one of embodiments 22, 24, and 25, wherein the lactose is lactose monohydrate.Attorney Docket No: 01330-0113-00PCT

[0222] Embodiment 27. The pharmaceutical composition according to any one of embodiments 22, 23, and 25, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL, or an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL, or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0223] Embodiment 28. The pharmaceutical composition according to embodiment 27, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0224] Embodiment 29. A pharmaceutical composition comprising: (a) Compound 1 or a hydrate or solvate thereof:Compound 1 or a pharmaceutical salt thereof, and (b) a diluent.

[0225] Embodiment 30. The pharmaceutical composition according to embodiment 30, wherein the diluent is chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate.

[0226] Embodiment 31. The pharmaceutical composition according to embodiment 31, wherein the diluent is microcrystalline cellulose.

[0227] Embodiment 32. The pharmaceutical composition according to embodiment 31, wherein the diluent is lactose.

[0228] Embodiment 33. The pharmaceutical composition according to any one of embodiments 30-33, wherein the composition comprises a second diluent.

[0229] Embodiment 34. The pharmaceutical composition according to embodiment 34, wherein the second diluent is the same as the first diluent.Attorney Docket No: 01330-0113-00PCT

[0230] Embodiment 35. The pharmaceutical composition according to embodiment 35, wherein the first and second diluents are microcrystalline cellulose.

[0231] Embodiment 36. The pharmaceutical composition according to embodiment 34, wherein the second diluent is different than the first diluent.

[0232] Embodiment 37. The pharmaceutical composition according to embodiment 35, wherein the first diluent is microcrystalline cellulose and the second diluent is lactose.

[0233] Embodiment 38. A pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof and (b) a pharmaceutically acceptable excipient, wherein the composition is in the form of a tablet.

[0234] Embodiment 39. The pharmaceutical composition according to embodiment 38, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a di(hydrogen sulfate) or hydrate or solvate thereof.

[0235] Embodiment 40. The pharmaceutical composition according to embodiment 38 or 39, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a hydrate.

[0236] Embodiment 41. The pharmaceutical composition according to any one of embodiments 38-40, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a trihydrate.

[0237] Embodiment 42. The pharmaceutical composition according to any one of embodiments 38-41, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline.

[0238] Embodiment 43. The pharmaceutical composition according to any one of embodiments 38-42, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.Attorney Docket No: 01330-0113-00PCT

[0239] Embodiment 44. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ.

[0240] Embodiment 45. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ.

[0241] Embodiment 46. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.7° 2θ.

[0242] Embodiment 47. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.0° 2θ.

[0243] Embodiment 48. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.7° 2θ, and about 15.0° 2θ.

[0244] Embodiment 49. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ about 10.2° 2θ, about 11.7° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.0° 2θ, about 15.7° 2θ, about 19.0° 2θ, and about 19.6° 2θ.

[0245] Embodiment 50. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.2° 2θ and about 15.0° 2θ.

[0246] Embodiment 51. The pharmaceutical composition according to any one of embodiments 38-43, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof,Attorney Docket No: 01330-0113-00PCT or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as that of FIG. 1A.

[0247] Embodiment 52. The pharmaceutical composition according to any one of embodiments 38-51, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an FT-IR spectrum substantially the same as that of FIG. 16.

[0248] Embodiment 53. The pharmaceutical composition according to any one of embodiments 38-52, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a melting onset as measured by DSC in a sealed aluminum pan with a pierced lid of about 144°C.

[0249] Embodiment 54. The pharmaceutical composition according to any one of embodiments 38-53, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a DSC thermogram substantially the same as that of FIG. 4.

[0250] Embodiment 55. The pharmaceutical composition according to any one of embodiments 38-54, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 1 µm to about 20 µm, an average d50 particle size of from about 10 µm to about 50 µm, and / or an average d90 particle size of from about 40 µm to about 180 µm.

[0251] Embodiment 56. The pharmaceutical composition according to any one of embodiments 38-55, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 2 µm to about 10 µm, an average d50 particle size of from about 15 µm to about 45 µm, and / or an average d90 particle size of from about 50 µm to about 170 µm.

[0252] Embodiment 57. The pharmaceutical composition according to any one of embodiments 38-56, wherein the excipient is a diluent.

[0253] Embodiment 58. The pharmaceutical composition according to any one of embodiments 38-57, wherein the composition comprises two excipients.

[0254] Embodiment 59. The pharmaceutical composition according to embodiment 58, wherein at least one of the two excipients is a diluent.

[0255] Embodiment 60. The pharmaceutical composition according to embodiment 58, wherein both excipients are diluents.Attorney Docket No: 01330-0113-00PCT

[0256] Embodiment 61. The pharmaceutical composition according to any one of embodiments 57-60, wherein the diluent or diluents are chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate.

[0257] Embodiment 62. The pharmaceutical composition according to embodiment 61, wherein the diluent or diluents are microcrystalline cellulose.

[0258] Embodiment 63. The pharmaceutical composition according to embodiment 61, wherein the diluent or diluents are lactose.

[0259] Embodiment 64. The pharmaceutical composition according to any one of embodiments 57-63, wherein the diluents are microcrystalline cellulose and lactose.

[0260] Embodiment 65. The pharmaceutical composition according to any one of embodiments 61, 63, or 64, wherein the lactose is lactose monohydrate.

[0261] Embodiment 66. The pharmaceutical composition according to any one of embodiments 61, 62, or 64, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL, or an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL, or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0262] Embodiment 67. The pharmaceutical composition according to embodiment 66, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

[0263] Embodiment 68. The pharmaceutical composition according to any one of embodiments 20-37, 57, or 59-67, wherein the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition.

[0264] Embodiment 69. The pharmaceutical composition according to embodiment 68, wherein the total weight of the diluent or diluents in the composition is from about 70% to about 95% of the composition.

[0265] Embodiment 70. The pharmaceutical composition according to embodiment 69, wherein the total weight of the diluent or diluents in the composition is from about 80% to about 90% w / w of the composition.

[0266] Embodiment 71. The pharmaceutical composition according to any one of the preceding embodiments, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of from about 5% to about 14% w / w of the composition.Attorney Docket No: 01330-0113-00PCT

[0267] Embodiment 72. The pharmaceutical composition according to embodiment 71, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of from about 6% to about 7% w / w of the composition.

[0268] Embodiment 73. The pharmaceutical composition according to embodiment 71, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of from about 7% w / w of the composition.

[0269] Embodiment 74. The pharmaceutical composition according to embodiment 71, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of about 6.75% w / w of the composition.

[0270] Embodiment 75. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition further comprises a disintegrant.

[0271] Embodiment 76. The pharmaceutical composition according to embodiment 75, wherein the disintegrant is crospovidone.

[0272] Embodiment 77. The pharmaceutical composition according to embodiment 75 or 76, wherein the disintegrant is present in an amount of from about 2% to about 5% w / w of the composition.

[0273] Embodiment 78. The pharmaceutical composition according to any one of embodiments 74-77, wherein the disintegrant is present in an amount of about 2% w / w of the composition.

[0274] Embodiment 79. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition further comprises a glidant.

[0275] Embodiment 80. The pharmaceutical composition according to embodiment 79, wherein the glidant is a colloidal silicon dioxide.

[0276] Embodiment 81. The pharmaceutical composition according to embodiment 79 or 80, wherein the glidant is present in an amount from about 1% to about 3% w / w of the composition.

[0277] Embodiment 82. The pharmaceutical composition according to embodiment 81, wherein the glidant is present in an amount of about 1% w / w of the composition.

[0278] Embodiment 83. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition further comprises a lubricant.Attorney Docket No: 01330-0113-00PCT

[0279] Embodiment 84. The pharmaceutical composition according to embodiment 83, wherein the lubricant is magnesium stearate.

[0280] Embodiment 85. The pharmaceutical composition according to embodiment 83 or 84, wherein the lubricant is present in an amount of about 1% w / w of the composition.

[0281] Embodiment 86. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition comprises a dose of from about 1 mg and about 50 mg of Compound 1.

[0282] Embodiment 87. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition comprises a dose of from about 5 mg to about 30 mg of Compound 1.

[0283] Embodiment 88. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition comprises a dose of about 5 mg of Compound 1.

[0284] Embodiment 89. The pharmaceutical composition according to any one of embodiments 1-87, wherein the composition comprises a dose of about 10 mg of Compound 1.

[0285] Embodiment 90. The pharmaceutical composition according to any one of embodiments 1-87, wherein the composition comprises a dose of about 20 mg of Compound 1.

[0286] Embodiment 91. The pharmaceutical composition according to any one of embodiments 1-87, wherein the composition comprises a dose of about 30 mg of Compound 1.

[0287] Embodiment 92. The pharmaceutical composition according to any one of embodiments 1-37 or 68-91, wherein the composition is in the form of a tablet.

[0288] Embodiment 93. The pharmaceutical composition according to any one of embodiments 38-67 or 92, wherein the tablet size is from about 100 mg to about 600 mg.

[0289] Embodiment 94. The pharmaceutical composition according to embodiment 93, wherein the tablet size is about 100 mg.

[0290] Embodiment 95. The pharmaceutical composition according to embodiment 93, wherein the tablet size is about 200 mg.

[0291] Embodiment 96. The pharmaceutical composition according to embodiment 93, wherein the tablet size is about 400 mg.

[0292] Embodiment 97. The pharmaceutical composition according to embodiment 93, wherein the tablet size is about 600 mg.Attorney Docket No: 01330-0113-00PCT EXAMPLES Abbreviations API-DS The active pharmaceutical ingredient salt used in the Examples, which is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. AV acceptance value BA bioavailability BU blend uniformity DSC differential scanning calorimetry DVS dynamic vapor sorption GC gas chromatography HPLC high-performance liquid chromatography HPMC hydroxypropyl methylcellulose IPA isopropyl alcohol IR immediate release FT-IR Fourier Transform infrared spectroscopy KF Karl Fischer LOQ limit of quantification MCC microcrystalline Cellulose NMR nuclear magnetic resonance PLM polarized light microscopy PSD particle size distribution RH relative humidity RPM revolutions per minute RRT Relative retention time SEM scanning electron microscopy tBME methyl tert-butyl etherAttorney Docket No: 01330-0113-00PCT USP United States Pharmacopeia XRPD X-ray powder diffraction Example 1. Preparation 1 of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0293] In this preparation method, a sample of Compound 1 (which is a free base) and 6 vol. of IPA / water (75:25% v / v) were added to a 20 mL scintillation vial. 2.05 mole equivalents of sulfuric acid were added as a solution in 2 vol. of IPA / water (75:35% v / v) . The solution was stirred for about one hour at 40°C. The temperature was then cycled between 40°C and 5°C with a 0.1 °C / min ramp and a one hour hold between each step. After about 48 hours of cycling, a clear solution was still observed. Up to 6 vol. of anti-solvent (tBME) was added to 40°C to facilitate precipitation. The experiment (now a slurry) was further temperature cycled for 24 hours. The solids were then isolated via vacuum filtration and dried under vacuum at about 40°C for 48 hours. The damp and dried solids were subsampled and analyzed by XRPD and shown to be crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate as shown in FIG. 2. TG / DSC data show a mass loss of 7.3% corresponding to an endothermic event with an onset of 67°C which is likely due to water loss (approximating 3.6 mole equivalents of water) (FIG. 3). DSC shows an endotherm at an onset of 144°C, which is consistent with a melting event (FIG. 4) whereas a small melting event was observed in the TG / DSC data with an onset of 130°C.

[0294] KF analysis shows a water content of 6.74%.1H-NMR is consistent with the Compound 1 (free base) structure with peak shifts indicating salt formation (FIG. 5). A DVS experiment (FIG. 6 and FIG. 7) shows a moisture uptake of about 6.3% between 0 and 10% RH with a more gradual uptake of 1.7% as RH is raised to 80% from 10%. Example 2. Preparation 2 of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0295] Approximately 1.5 g of Compound 1 was added to three 20 mL scintillation vials. 5 mL of 2-propanol:water (75:25 % v / v) was added to each vial, and the samples were stirred at 40°C. 2.05 mole equiv. of H2SO4 was added to each sample as solutions in 5 mL of propanol:water (75:25 % v / v). Clear solutions were observed in all samples. Stirring continued at 40°C for about 1.5 hours after addition of H2SO4. tBME was then added to each sample, also at 40°C, as an anti-solvent in 1 mL aliquots until the solutions turned cloudy.Attorney Docket No: 01330-0113-00PCT The samples were then temperature-cycled between 40°C and 5°C for about 20 hours with 0.1 °C / min ramp and a 1 hour hold between steps. The resultant slurries were subsampled, and solids isolated via centrifugation. The isolated solids were analyzed by XRPD. The remainder of the slurries were vacuum filtered as one sample using a Buchner funnel. The filter cake was dried under vacuum at 40°C for 48 hours. 4.87 g of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate was obtained; isolated yield = 81 %. An XRPD pattern was collected confirming crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (FIG. 8). A Raman spectrum was also collected (FIG. 9). Example 3. Preparation 3 of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0296] 253.75 g of a mixture of crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base) (see Example 5 below) was added to a 5 L temperature- controlled reactor. 1.10 L of 1-propanol:water (80:20 %v / v) was added to the reactor, followed by stirring at 50°C at 100 RPM. 2.5 equivalents of sulfuric acid (95 %wt.) were added to the reactor as a solution in 0.17 L of the solvent system, achieving a concentration of about 200 mg / mL. The experiment was equilibrated at 50°C, cooled to 40°C and seeded with 1% crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. The seed crystal can be prepared methods such as those disclosed herein. Post-seeding, equilibration of ca. 6 hr was applied. The stirring speed was increased to 120 RPM during the equilibration period. The experiment was cooled to 20°C at 0.2 °C / min and equilibrated at 20°C for 1 hour. At 20°C, anti-solvent addition with 1-propanol was carried out at 0.25 L / hr. 2.96 L of 1- propanol was added to reach a final ratio of 94:6 %v / v. The stirring speed was increased to 190 RPM during the addition. Equilibration at 20°C for about 1 hour was applied post- addition followed by cooling to 5°C at 0.2 °C / min and stirring at 5°C for about 20 hours. The resulting slurry was vacuum filtered, and the resulting isolated cake was washed with 0.5 L of the precooled resulting solvent system. The filter cake was dried under vacuum at 40°C for 4 days. The dried solids were exposed to ambient conditions for about 20 hours to allow time for moisture equilibration. The moisture content of the solids after about 20 hours of exposure to ambient condition was measured as 4.33 %w / w. The solids were then re-exposed to ambient conditions for 2 days to allow time for further moisture uptake and equilibration during which time the solids were manually mixed intermittently.Attorney Docket No: 01330-0113-00PCT

[0297] The resulting solids were shown to be crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate by XRPD. FIG. 10 shows the material before drying, after drying, and after drying and moisture equilibration. All diffractograms are those of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. An isolated yield of 80.4% was obtained, with the theoretical yield estimated as 80.3% (based on the concentrations of the extracted mother liquor and wash). The purity of the dried solids was determined as >99.99 % area by HPLC and GC indicated about 0.12% by weight residual 1-propanol.

[0298] PLM showed the particle to be birefringent after anti-solvent addition at 20°C, as damp solids, after drying, and after moisture equilibration (FIG. 11). According to KF measurements, a water content on average of 4.33% w / w was measured after about 21 hours of re-exposure to ambient conditions, which increased to 6.07% after another 48 hours. A water content of 6.14% is the theoretical content for a trihydrate.

[0299] Particle size-measurements were taken before and after complete equilibration (moisture content of 4.33% and then later 6.07%). FIG. 12 is an overlay of the two measurements showing the difference in particle size distributions. The data are summarized in Table 1 below: Table 1: Particle Size Measurements After Equilibration Before complete equilibration; After complete equilibration; 24 hr post-drying 3 days post-drying (moisture content = 4.33%) (moisture content = 6.07%) D1017.596 µm 6.32 µm D5046.785 µm 32.90 µm D90109.799 µm 84.73 µm

[0300] These data show that the average particle size decreased with longer equilibration times and higher water contents.

[0301] TG / DSC thermograms are presented in FIG. 13 of a fully equilibrated sample of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. The data reveal a mass loss of about 6.4% between about 20°C and 130°C, which corresponded with an endothermic event at about 61°C, both of which are likely due to solvent / water loss. A small endothermic event with a peak onset of about 150°C may be due to melting and the thermal events above 200°C are likely due to degradation. A DSC thermogram is provided in FIG. 14 showingAttorney Docket No: 01330-0113-00PCT thermal events at onsets of about 89°C and about 148°C. The lower one is likely dehydration whereas the higher one is a melting event.

[0302] 1H-NMR spectra were collected on crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate and the spectrum was consistent with the di(hydrogen sulfate) structure (FIG. 15).

[0303] An FT-IR spectrum of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate are shown in FIG. 16. Example 4. Single Crystal Study of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0304] A single crystal of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate was prepared in the following manner. Approximately 10 mg of amorphous Compound 1 di(hydrogen sulfate) (prepared as described in Example 6(B)). was added to a 2 mL vial, into which 100 µL of 2-ethoxyethanol was added. Complete dissolution was observed at ambient temperature (ca. 20°C). The solvent was then allowed to evaporate at ambient conditions for 3 days. Post-evaporation, the residual solid was observed to be clear block-like particles, which were analyzed by single crystal X-ray diffraction. FIGs. 17 and 18 show a single crystal structure drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100K in two different orientations. Simulated XRPD diffractograms were calculated for structures collected at 295 K and 100 K, respectively (FIG. 19), and compared to an experimental (room temperature) diffractogram (FIG. 20). The simulated diffractogram showed good correlation with the experimental diffractogram indicating that the structure presented in this data is representative of the bulk material. Example 5. Preparation of Crystalline Form 1 Compound 1 (free base) and Crystalline Form 2 Compound 1 (free base)

[0305] Approximately 100 mg of amorphous Compound 1 (free base) (see Example 6A) was weighed into a 1.5 mL screw-cap vial. Acetonitrile was added in 100 μL aliquots while stirring at 40°C until the material dissolved (500 μL). The solution was stirred at 40°C for 0.25 hr and then cooled to 5°C at 0.1°C / min. A thick slurry (poorly mixed) was obtained at ca. 30°C and so 200 μL of tBME was added as anti-solvent, but the slurry dissolved. After 11 hr at 5°C, a slurry was obtained. A portion of the slurry was isolated by centrifugation (0.22 μm nylon filter) and analyzed by XRPD. The isolated solids were consistent with a mixtureAttorney Docket No: 01330-0113-00PCT of crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base), which dried to crystalline Form 1 Compound 1 (free base).

[0306] Further aliquots of tBME were added to the remaining slurry (total of 600 μL), but dissolution was observed. Aliquots of heptane (3 × 100 μL) were added, but solution remained. Material was recovered by rotary evaporation and re-slurried in acetonitrile, then isolated by centrifugation (0.22 μm nylon filter) and analyzed by XRPD and found to be crystalline Form 1 Compound 1 (free base).

[0307] All liquors were evaporated to recover material. Solids were dried under vacuum at 35°C for ca. 21 hr and then re-analyzed by XRPD. The solids were found to be crystalline Form 2 Compound 1 (free base), which dried to crystalline Form 1 Compound 1 (free base) with some loss of crystallinity. FIG. 21 is a stackplot of XRPD patterns taken during this experiment including crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base) reference patterns. FIG. 22 is a separate XRPD pattern of crystalline Form 1 Compound 1 (free base) and FIG. 23 is a separate XRPD Pattern of crystalline Form 2 Compound 1 (free base) each prepared separately.

[0308] Hot stage microscopy showed that crystalline Form 1 Compound 1 (free base) started to melt at 65°C, with melting complete at 80°C. DVS analysis indicated that crystalline Form 1 Compound 1 (free base) was slightly hygroscopic with water uptake of 0.9% between 40- 80% RH in the first sorption cycle. A further uptake of 3.8% between 80-90% RH likely resulted in formation of amorphous material, which was then moderately hygroscopic (uptake of 3.3% at 80% RH) in the second sorption cycle. Post-DVS XRPD analysis indicated that predominantly amorphous material was recovered (traces of crystalline Form 1 Compound 1 (free base)) as shown in FIG. 24. Example 6. Preparation of Amorphous Compound 1 (free base) and Amorphous Compound 1 di(hydrogen sulfate)

[0309] (A) Amorphous Compound 1 (free base) was used to prepare different crystalline forms. Compound 1 (free base) can be prepared as described by, for example, WO 2021 / 204896 or as described by WO 2023 / 056910, for example, as well.

[0310] (B) Amorphous Compound 1 di(hydrogen sulfate) was used to prepare the single crystal that was used in the Single Crystal Study (see Example 4 above). The amorphous Compound 1 di(hydrogen sulfate) was prepared as follows. Approximately 2.5 g of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (see, e.g., Example 4) wasAttorney Docket No: 01330-0113-00PCT added to a 250 mL conical flask. 100 mL of methanol was added to the flask to dissolve the solid at ambient temperature. When complete dissolution was observed, the solvent was removed under vacuum via rotary evaporation. An amorphous solid resulted as determined by XRPD (FIG. 25).1H-NMR analysis of a solution of the compound prepared from the solid material was consistent with the1H-NMR spectrum of Compound 1. Example 7. Analytical Methods for the Characterization of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate tablets. All materials used are detailed in Table 2. All USP testing was performed according to USP2023 Issue 3 released on 01 June 2023. Table 2: Materials Used in Tablet Development Material Type Crystalline Form 2 Compound 1 API-DS Di(hydrogen Sulfate) Trihydrate* Starch (StarTab®) Diluent Crospovidone (Vivapharm PVPP XL-10) Disintegrant Colloidal Silicone Dioxide (Aerosil 200) Glidant Microcrystalline Cellulose (Vivapur PH102) Diluent Mannitol (Pearlitol 200SD) Diluent Di-calcium Phosphate anhydrous (A-Tab®) Diluent Microcrystalline Cellulose (Vivapur PH302) Diluent Microcrystalline Cellulose (Vivapur PH200) Diluent Lactose Monohydrate (SuperTab® 11SD) Diluent Magnesium Stearate (Parteck Lub MST) Lubricant *The API-DS can be prepared as shown in, for example, Examples 1-4 Particle Size Analysis of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0311] Particle size distribution (PSD) analysis was carried out using a Sympatec HELOS laser diffraction particle size analyzer on two batches of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate – Batch A and Batch B. In addition, samples of Batch A andAttorney Docket No: 01330-0113-00PCT Batch B were screened through a 125μm sieve and then analyzed. The analysis was carried out with the following settings, in triplicate: Dispersing pressure: 2 bar; Vacuum pressure: ~105 mbar; Lens: R5 (0.5-875.0 μm). Approximately 50 mg of the API-DS (i.e., crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate) was placed into small Aspiros tubes (small glass vials) and actuated by the instrument for each measurement. Blend Characterization

[0312] Bulk and Tapped Density - The bulk and tapped density of the blends was measured using a Copley JV1000 Tapped Density Tester, with a method according to USP <616> Bulk Density and Tapped Density of Powders. Each blend was carefully poured into a 25 mL graduated cylinder. The powder weight and unsettled volume were recorded. The cylinder was tapped 500 times, then a further 750 times, then in increments of 1250 taps until there was no further measurable decrease in tapped volume. Bulk density, tapped density, Carr’s Index, and the Hausner ratio were calculated for each sample. Carr’s Index formula: (ρtapped-ρbulk) / ρtapped*100, with ρtapped: the tapped bulk density of the material (kg / m3); ρbulk: the loose bulk density of the material (kg / m3). Hausner ratio formula: H = ρtapped / ρbulk, with ρtapped: the tapped bulk density of the material (kg / m3); ρbulk: the loose bulk density of the material (kg / m3). Assay, Related Substances, Blend, and Content Uniformity Testing

[0313] The HPLC method was developed based on the conditions detailed in Table 3. Table 3. HPLC Chromatographic Conditions Chromatographic conditions ColumnWaters XSelect CSH Fluoro-Phenyl 150 x 4.6mm, 2.5µm Guard: N / A Column Temperature 30°C Wavelength of Detection 266 nm Data Collection Rate (Peak > 0.1 min (2 s resp. time) (3.43 Hz) width) Method Length 30 mins Flow Rate 1.0 mL / min Autosampler 5°CAttorney Docket No: 01330-0113-00PCT Mobile Phase A 0.1% TFA in Water Mobile Phase B 0.1% TFA in Acetonitrile Injection Volume 25 µL Target Standard / Sample 0.1 mg / mL Concentration Blank Injection Diluent 30:70 MeOH: H2O Needle Wash 100% MeOH Time%MPA %MPB0.0 95 5 5.0 75 25 18.0 65 35 Gradient 20.0 50 50 22.0 5 95 25.0 5 95 25.1 95 5 30.0 95 5 Tablet Characterization

[0314] Tablet Compression and Compressibility Assessment - The compressibility assessment has been performed using 8mm flat faced round tooling aiming for 200mg tablet size. The die is manually filled with the required quantity of powder as per the tablet weight and then it is compressed on single-station laboratory tablet press. A set of compression forces were established based on previous experience / expected instrument tolerances. Forces used: 0.26, 0.52, 0.78, 1.04, 1.30, 1.56 metric tonnes.

[0315] This is equivalent to 50-300 MPa for 8mm round tooling. N=3 tablets were compressed for each set of forces.

[0316] Hardness Testing - Tablet breaking force was measured using a Copley Hardness Tester (TH3 / 500) in accordance with USP <1217> Tablet Breaking Force. Any caplet shaped tablets were tested lengthways.

[0317] Friability Testing - Friability testing of tablets was performed according to USP <1216> Tablet Friability using a Copley Friability Tester (FRV 1000). The tester was used toAttorney Docket No: 01330-0113-00PCT rotate the tablets 100 times at a speed of 25 RPM for 4 minutes. Results were evaluated according to the USP so that post-rotation, no tablets should be obviously cracked, cleaved, or broken and the maximum mean weight loss was calculated based on tablet weight pre- and post-rotation, and be less than 1.0% w / w.

[0318] Disintegration Testing - Disintegration time of tablets was tested using a Copley DTG 2000, containing DI water at 37 °C according to USP <701> Disintegration. Tablets were agitated until no palpable mass was remaining in the baskets. Time recorded for each of the tablets tested and average calculated and reported.

[0319] Dissolution Testing - The dissolution parameters are presented in Table 4. Table 4: Dissolution Method Parameters Parameter Specification Apparatus Paddles / USP II Speed 75 rpm Media and Volume 500mL of 0.1 M HCl Media Temperature 37.0 ± 0.5 °C Timepoints 15, 20, 30, 45, and 60 mins Cannula filters None 0.45 µm Nylon syringe filter or Sample Preparation centrifuge Sinkers Not required* Sampling Method 5 mL Manual, no replacement *Tablets sink in the vessel, sinkers not required. Heckel test

[0320] In these studies, a known weight of a blend was compacted to theoretical zero porosity using 10 mm diameter faced punches at low and fast punch speed (0.1 mm / s to 300 mm / s). During compression, the locations of the punch tips were accurately determined and the compression force was recorded. Data were processed by the compaction analysis software to generate values for yield pressure (Py) using Heckel equation: ln(1 / 1-D)=kP+A (with D relative density of the compact, P pressure, K gradient of the line in the linear region).” Strain rate sensitivity (SSR) was defined as the potency of some materials toAttorney Docket No: 01330-0113-00PCT exhibit different deformation characteristics in function of the force applied. The SSR was determined as = 100 x (Py fast - Py Slow) / Py slow. Example 8. Process for Manufacturing and Testing of Initial Blend Formulations of Crystalline Form 2 Compound 1 Di(hydrogen Sulfate) Trihydrate Characterization of Crystalline Form 2 Compound 1 Di(hydrogen Sulfate) Trihydrate (“API- DS”)

[0321] PSD methods are described in Example 7 and PSD results are presented in Table 5. Table 5: PSD Results for Crystalline Form 2 Compound 1 Di(hydrogen Sulfate) Trihydrate API-DS X10(µm) X50(µm) X90(µm) VMD (µm) Batch A9.04 41.51 160.01 64.54Batch A 6.84 29.89 86.20 39.15 (125µm screened) Batch B3.26 16.85 71.91 29.44Batch B 2.98 15.56 59.72 25.02 (125µm screened)

[0322] The data shows that the implementation of the screening step (as described in Example 7) aids the uniformity of the particle size distribution. Compound 1 (free base) loading was set to 5% and the screen size used in the screening step was set to 250 µm. Lactose Compatibility Assessment

[0323] The compatibility between the API-DS, which can be prepared according to Examples 1-4 for example, and lactose was tested. A binary mix of API-DS, Batch A and lactose was prepared as 1 part Compound 1 and 3 parts lactose by weight. Because Compound 1 was prepared as a di(hydrogen sulfate) trihydrate salt, it has a higher molecular weight (879.94 g / mol) as compared with Compound 1, which is a free base (629.75 g / mol). Thus, to have a 1:4 weight ratio of Compound 1 (free base) to lactose, the amount of API-DS used was multiplied by 1.4 to account for the differences in molecular weight. Thus, a 1:4 by weight mixture of Compound 1 to lactose contains about 35% by weight of the API-DS to about 65% lactose (corrected for salt in that the salt used is 40% heavier than the free base.) UnlessAttorney Docket No: 01330-0113-00PCT stated otherwise, all tablets and blends made in the Examples herein were made with the API- DS and not the free base.

[0324] In this study, the mixtures of API-DS and lactose were prepared in a scintillation vial that was placed loosely capped in the oven at 40°C for 14 days. A T=0 of the same binary sample mix and placebo (lactose only) was prepared on the day of the analysis; all samples were tested together in duplicate. Results presented in Table 6. Table 6: Lactose Compatibility Results Sample T=0 T=2 weeks Binary mix RRT 1.13 = 0.06% RRT 1.13 = 0.06% Lactose: API-DS RRT 1.39 = 0.12% RRT 1.39 = 0.12% Initial blend formulations using API-DS, Batch A

[0325] Four initial blends were prepared using API-DS, Batch A at 50g scale. Excipients were screened through a 1 mm sieve without using a sieve brush. API-DS, Batch A was screened through a 250 µm sieve using a sieve brush. The appropriate amount of API-DS and excipients for the blend were weighed. For each blend, using an appropriate size amber jar, the materials were added in the following order:

[0326] Composition A1: ½ Diluent → API-DS → ½ Diluent

[0327] Composition A2-A4: ½ Diluent → API-DS →Disintegrant → Glidant → ½ Diluent

[0328] Each blend was then further mixed on the Turbula T2F blender for 20 minutes at 32 RPM. Magnesium stearate was added, and the powder was blended for a further 2 minutes at 32 RPM.

[0329] Formulations of exemplary initial blend formulations are shown in Table 7 below. Table 7. Formulations of Exemplary Initial Blend Formulations Using API-DS, Batch A Composition Formulation A1 7.00% API-DS, Batch A 92.00% StarTab®1.00% Magnesium Stearate A2 7.00% API-DS, Batch A 86.00% StarTab®5.00% CrospovidoneAttorney Docket No: 01330-0113-00PCT 1.00% Aerosil 1.00% Magnesium Stearate A3 7.00% API-DS, Batch A 89.00% MCC PH102 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A4 7.00% API-DS, Batch A 44.50% MCC PH102 44.50% SuperTab®11SD 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate

[0330] All exemplary formulations described herein can be made into tablets of different strengths. For example, for a tablet corresponding to Formulation A4 and containing a dose of 5 mg Compound I (free base), total amounts could be: 7.0 mg Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, 44.5 mg of microcrystalline cellulose such as MCC PH102, 44.5 mg of lactose such as SuperTab®11SD, 2.0 mg Crospovidone, 1.0 mg colloidal silicon dioxide such as Aerosil®, and 1.0 mg Magnesium Stearate. Similarly, to prepare a tablet corresponding to Formulation A4 and containing a dose of 15 mg Compound 1 (free base), total amounts could be: 21.0 mg Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, 133.5 mg of microcrystalline cellulose such as MCC PH102, 133.5 mg of lactose such as SuperTab®11SD, 6.0 mg Crospovidone, 3.0 mg of colloidal silicon dioxide such as Aerosil®, and 3.0 mg Magnesium Stearate. Such tablets may be coated, for example, using Opadry TF.

[0331] StarTab® is a directly compressible starch made by Colorcon. As the free base of Compound 1 is only about 71.3% of the API-DS, a salt correction factor of 1.40 was applied based on a target drug loading of 5% w / w Compound 1 (free base). The 71.3% value also takes impurities and residual solvents and the like into account. However, with the correction factor calculated to be 7% w / w for the API-DS, the diluent % w / w were adjusted accordingly as reflected in Table 7.Attorney Docket No: 01330-0113-00PCT

[0332] Blends were characterized for bulk and tapped density to evaluate the resulting flow. Bulk and tapped density results are presented in Table 8. Table 8: Bulk and Tapped Density Results Average Average Hausner Resulting Composition Bulk Tapped Carr’s Ratio Flow Density Density Index A1 0.5575 0.6585 1.18 15.3 Good A2 0.5350 0.6155 1.15 13.0 Good A3 0.3460 0.4795 1.39 27.9 Poor A4 0.4465 0.5570 1.25 19.8 Fair

[0333] The results detailed in Table 8 show that Compositions A1 and A2 presented a good flow, Composition A4 presented a fair flow, and Composition A3 presented a poor flow. Compositions A1 and A2 offered the best flowability performance. Without being bound by theory, it is believed that this difference in performance was due to the difference in excipients, StarTab® grade starch versus microcrystalline cellulose.

[0334] Next, the compositions were tested for blend uniformity. The results are presented in Table 9. A total of 10 aliquots were collected from the top (N=3), middle (N=4), and bottom (N=3) of the composition for testing. Table 9: Composition Uniformity Results Mean Recovery AV* Composition (90.0-110.0% Target) (<15 Target) A1 99.8% 7.6 A2 100.5% 6.3 A3 101.0% 3.4 A4 99.4% 5.8 *Acceptance Value as per Ph. Eur. 2.9.40

[0335] Overall, all the compositions presented a good recovery and low AV, suggesting that the screening and blending techniques adopted were useful in preparing the compositions.Attorney Docket No: 01330-0113-00PCT

[0336] The four compositions (A1-A4) were progressed for compressibility. Tablets (N=3) were compressed from each composition for each set of forces. The actual compression pressure applied and the tablet tensile strength averages (both expressed as MPa) from the 3 replicates have been plotted to create the compression profiles as presented in FIG. 26.

[0337] From the compression profile assessment, Compositions A3 and A4 were the most compressible formulations, requiring a lower force (~100MPa) to achieve 2MPa tensile strength. On the other hand, Compositions A1 and A2 were less compressible as they required a high compression force. In addition, Compositions A1 and A2 couldn’t be compressed at the lowest compression force (0.26 mT equivalent to ~50MPa) as the resulting tablets couldn’t hold the shape, crumbling into powder.

[0338] Compressed tablets of Compositions A1, A3, and A4 with varying amounts of API- DS were prepared. Specially, tablets were prepared using API-DS as follows: (1) 100 mg tablet size containing a dose of 5 mg Compound 1 (free base); (2) 200 mg tablet size containing a dose of 10 mg Compound 1 (free base); (3) 400 mg tablet size containing a dose of 20 mg Compound 1 (free base); and (4) 600 mg tablet size containing a dose of 30 mg Compound 1 (free base). Tablet sizes 100 mg and 600 mg were studied for hardness, thickness, friability, and disintegration. Results are presented in Table 10 for the 100 mg tablet and Table 11 for the 600 mg tablet (reported results are calculated as average of 3 tablets). Table 10: Thickness, Hardness, Friability, and Disintegration Time for 100 mg Tablets Composition A1 Composition A3 Composition A4 Compression Force: 1.5 mT Compression Force: 0.4 mT Compression Force: 0.9 mT Thickness: 3.03mm Thickness: 3.20mm Thickness: 2.90mm Hardness: 1.8kg Hardness: 8.3kg Hardness: 8.2kg Friability: 0.1% Friability: 0.01% Friability: 0.02% Disintegration: 1min 30sec Disintegration: 6 min Disintegration: 8min

[0339] For Composition A1, previous findings of poor compressibility were again confirmed by the high compression force used versus the hardness achieved. Higher compression force was also tested but hardness reached a plateau.Attorney Docket No: 01330-0113-00PCT Table 11: Thickness, Hardness, Friability, and Disintegration Time for 600 mg Tablets Composition A1 Composition A3 Composition A4 Compression Force: 2.0 mT Compression Force: 0.7 mT Compression Force: 1.5 mT Thickness: 5.23mm Thickness: 5.74mm Thickness: 5.90mm Hardness: 7.08 kg Hardness: 15.29kg Hardness: 18.16kg Friability: 0.5% Friability: 0.1% Friability: 0.1% Disintegration: 1min and Disintegration: 1min and Disintegration: 54 sec 30sec 30sec

[0340] Although the friability result for Composition A1 is <1.0%, the tablets visually failed the test presenting chipped edges. Initial Blends Formulations Using API-DS, Batch B

[0341] The compositions with the same ingredients as in Compositions A1, A3, and A4 were prepared at 100 g scale using API-DS, Batch B. Excipients were screened through a 1 mm sieve without using a sieve brush. API-DS, Batch B was screened through 250µm sieve using a sieve brush. The appropriate amount of API-DS and excipients for the blend were weighed. For each composition, using an appropriate size amber jar, the materials were added in the following order:

[0342] Composition B1: ½ Diluent → API-DS → ½ Diluent (refer to Table 12)

[0343] Composition B3 and B4: ½ Diluent → API-DS → Disintegrant → Glidant → ½ Diluent

[0344] The compositions were further mixed on the Turbula T2F blender for 20 minutes at 32 RPM. Magnesium stearate was added, and the powder blended for a further 2 minutes at 32 RPM.

[0345] Formulations of exemplary initial blends using API-DS, Batch B are presented in Table 12. Table 12. Formulations of Exemplary Initial Blends Using API-DS, Batch B Composition Formulation B1 6.75% API-DS, Batch BAttorney Docket No: 01330-0113-00PCT 92.25% StarTab®1.00% Magnesium Stearate B3 6.75% API-DS, Batch B 89.25% MCC PH102 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate B4 6.75% API-DS, Batch B 44.625% MCC PH102 44.625% SuperTab®11SD 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate

[0346] A correction factor of 1.35 was applied on the target drug loading (5% w / w free base based on a potency of 74.0% for API-DS Batch B (taking into account drug substance impurities, residuals solvent, residues of ignition, water content and counter ion)). Therefore, the drug load of the API-DS was 6.75% w / w and the diluents % (w / w) were adjusted accordingly as reflected in Table 12.

[0347] The blends were tested for blend uniformity. Results are presented in Table 13. A total of 10 aliquots were collected from the top (N=3), middle (N=4), and bottom (N=3) of the blend for testing. Table 13: Blend Uniformity Results Blend Batch Mean Recovery AV Number (90.0-110.0% Target) (<15 Target) B1 96.2% 11.7 B3 98.9% 3.6 B4 99.1% 7.9

[0348] Overall, the compositions presented a good recovery and low AV, suggesting that the screening and blending techniques adopted were useful in preparing compositions with API- DS Batch B.Attorney Docket No: 01330-0113-00PCT

[0349] Bulk and tapped density were also assessed for the above formulations. The results presented in Table 14. Table 14: Bulk and Tapped Density Results Tapped Composition Bulk Density Hausner Resulting Density (g / mL) Ratio Carr’s Flow (g / mL) Index B1 0.5702 0.7223 1.27 21.06 Passable B3 0.3843 0.4740 1.23 18.92 Fair B4 0.4623 0.5650 1.22 18.18 Fair

[0350] The blends were then compressed into tablets for hardness, thickness, friability, and disintegration assessment for both 100 mg and 600 mg tablets. Results are presented in Table 15 for the 100 mg tablet and Table 16 for the 600 mg tablet. The reported results are each calculated as averages of 3 tablets. Table 15: Thickness, Hardness, Friability, and Disintegration Time for 100 mg Tablets Composition B1 Composition B3 Composition B4 Compression Force: 1.5 mT Compression Force: 0.3 mT Compression Force: 0.6 mT Thickness: 3.02mm Thickness: 3.27mm Thickness: 2.96mm Hardness: 2.4kg Hardness: 6.1kg Hardness: 6.0kg Friability: 0.03% Friability: 0.00% Friability: 0.02% Disintegration: 3mins 20sec Disintegration: 3mins 4sec Disintegration: 4mins 20sec

[0351] Note: Initial compression forces used for Compositions B3 and B4 were 0.4 mT and 0.9 mT, respectively. This, however, resulted in a hardness of ~8kg for both and a disintegration time of ~9min for both, which is still acceptable. Additional trials confirmed that a good hardness is still achievable using a reduced compression force, with a good disintegration time and acceptable friability. Nine minutes is still an acceptable disintegration time, hence even at 8 kg hardness the tablets still behave within the range of an immediate release (IR) tablet disintegration time (USP <701>). However, at 6 kg hardness, the tablets disintegrate faster without being friable.Attorney Docket No: 01330-0113-00PCT Table 16: Thickness, Hardness, Friability, and Disintegration Time for 600 mg Tablets Composition B1 Composition B3 Composition B4 Compression Force: 2.0 mT Compression Force: 0.7 mT Compression Force: 1.5 mT Thickness: 5.17mm Thickness: 5.79mm Thickness: 5.11mm Hardness: 6.85kg Hardness: 14.09kg Hardness: 18.17kg Friability: 0.1% Friability: 0.03% Friability: 0.04% Disintegration: 2min 23sec Disintegration: 2min 36sec Disintegration: 1min 50sec

[0352] Although the friability result for Composition B1 is <1.0%, the tablets visually failed the test as they were friable presenting chipped edges and surface.

[0353] Upon assessing the results from the blends formulated with API-DS Batch A (Compositions A1, A3, and A4) and the blends formulated with API-DS Batch B (Compositions B1, B3, and B4), it can be noticed that results are overall comparable.

[0354] Table 17 shows a comparison of the bulk and tapped density of blends made with API-DS, Batch A and API-DS, Batch B. Table 17: Bulk and Tapped Density Comparison Composition 1 Composition 3 Composition 4 Test A1 B1 A3 B3 A4 B4 Bulk Density 0.5575 0.5702 0.3460 0.3843 0.4465 0.4623 (g / mL) Tapped Density 0.6585 0.7223 0.4795 0.4740 0.5570 0.5650 (g / mL) Hausner 1.18 1.27 1.39 1.23 1.25 1.22 Ratio Carr’s Index 15.30 21.06 27.90 18.92 19.80 18.18 Resulting Good Passable Poor Fair Fair Fair FlowAttorney Docket No: 01330-0113-00PCT

[0355] Compositions A1 and B1 presented a flow with reduced performance, whilst Compositions 3 presented a better flow for the blend formulated with API-DS Batch B (i.e., Composition B3). Compositions A4 and B4 presented comparable results. Visually the blends presented no difference confirming that the results are overall comparable. Blend uniformity was comparable as shown in Table 18. Table 18: Blend Uniformity Results Composition 1 Composition 3 Composition 4 Test A1 B1 A3 B3 A4 B4 Mean Recovery (Target 90.0 – 110.0%) 99.8% 96.2% 101.0% 98.9% 99.4% 99.1% AV (<15 Target)7.6 11.7 3.4 3.6 5.8 7.9

[0356] Compositions B3 and B4 tablets were also tested for content uniformity, as presented in Table 19. Table 19: Content Uniformity Results for Compositions B3 and B4 Mean Recovery AV Batch Number (90.0 – 110.0 % Target) (<15 Target) B3 98.5% 1.58 B4 98.2% 5.32

[0357] Content uniformity results for both Compositions B3 and B4 presented acceptable results. 100 mg and 600 mg tablets prepared from Composition B4 were further progressed into coating trial using a Caleva minicoater. The coating polymer was the white Opadry TF. The coating solution was prepared at 15% w / w solid in DI water and stirred until visually homogenous.

[0358] Table 20 shows the parameters for the coating trial. Table 20: Coating Trial Parameters Caleva settings for Caleva settings for Parameter 100 mg tablets of B4 600 mg tablets of B4Attorney Docket No: 01330-0113-00PCT Agitator 1%, 10.1 Hz Off Fan 50%, 11.0 m / sec 88%, 14.8 m / sec Temperature 45°C 45°C Pump 10%, 1.30 RPM 10%, 1.30 RPM Atomization Pressure 0.9 bar 0.9 bar Spray Gun Height 100mm 150mm

[0359] The selected coating solution was HPMC based and analyzed using reversed-phase HPLC to confirm specificity. The inclusion of a small percentage of HPMC in the coating solution was assessed based on new sample preparation dilutions / doses. Upon analyzing the samples, there were no significant peaks observed from the Opadry TF coating solution. Two small peaks were observed - below LOQ (0.05%), at RRT 0.62 and 0.64. Neither of the observed peaks interfere with known impurities (found at RRT 1.11, RRT 1.13, and RRT 0.53). Heckel test results

[0360] Four blends were re-prepared and submitted subjected to the Heckel test: Composition B3 (API-DS, Batch B, 100% MCC PH102 as diluent), Composition B4 (API- DS, Batch B, 50:50 MCC PH102 and SuperTab® 11 SD as diluents), Composition A3 (API- DS, Batch A, 100% MCC PH102 as diluent), and Composition A4 (API-DS, Batch A, 50:50 MCC PH102 and SuperTab® 11 SD as diluents). The aim of the Heckel test is to compress the material under controlled conditions to derive the yield pressure of the bulk material.

[0361] Strain rate sensitivity is a measurement taken from the Heckel test. By comparing the yield pressures at fast and slow compression speeds, one can assess the amount of elasticity present in the blends, the higher the elasticity the greater the issues for tableting. The resulting strain rate sensitivity graph is presented in FIG. 27. As shown, the compositions are far from elasticity and instead are within the plastic (ductile) to brittle area.

[0362] Without being bound by theory, it is believed that the results are driven by the diluents as they represent the majority of the blends compositions. In fact, if plotting MCC and lactose in FIG. 27, MCC would sit immediately under the soft / ductile area, whereas lactose would sit in the immediate bottom corner of the graph, as it’s a moderately hard / brittle material. Hence, Compositions A3 and B3 are more shifted towards the left, whilst Compositions A4 and B4 sit more towards the right of the graph.Attorney Docket No: 01330-0113-00PCT

[0363] The Heckel test is a measure of deformation, not the formation of a compact. To understand how dwell time affects bonding, the compact strength needed to be considered. The compacts produced at slow speed were good in appearance and had excellent strength. A formulation tablet with a 10mm diameter had a strength target of >12 kiloponds. The strengths at slow speed were 31.6-46.2 kiloponds. At fast speed, lamination and blistering was seen for some of the compacts. Strength was lower at 14.3-30.9 kiloponds but still exceeded the strength target for formulations. Therefore, the API-DS has the ability to form strong compacts and can contribute to the overall strength of the final formulation reducing the reliance of excipients to provide strength. This means that high formulation concentrations should be possible.

[0364] The conclusion from the strain rate sensitivity test is that the blends are unlikely to be wholly brittle and are more likely to show ductile behavior. Preparation of Additional Blends Using Alternative Grades of MCC

[0365] Four additional blends were prepared using API-DS, Batch A to determine a preferential grade of microcrystalline cellulose, with the aim of improving the flow. Specifically, excipients were screened through a 1 mm sieve without using a sieve brush. API-DS, Batch A was screened through 250µm sieve using a sieve brush. The appropriate amount of API-DS and excipients for the blend were weighed. For the blends, using an appropriate size amber jar, the materials were added in the following order:

[0366] ½ Diluent → API-DS →Disintegrant → Glidant → ½ Diluent

[0367] The blend was further mixed on the Turbula T2F blender for 20 minutes at 32 RPM. The magnesium stearate was added, and the powder blended for a further 2 minutes at 32 RPM.

[0368] Table 21 shows the formulas of additional blends using alternative grades of MCC. Table 21. Formulas of Additional Blends Using Alternative Grades of MCC Composition Formulation A5 7.00% API-DS Batch A 89.00% MCC PH302 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A6 7.00% API-DS Batch AAttorney Docket No: 01330-0113-00PCT 89.00% MCC PH200 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A7 7.00% API-DS Batch A 44.50% MCC PH302 44.50% SuperTab® 11SD 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A8 7.00% API-DS Batch A 44.50% MCC PH200 44.50% SuperTab®11SD 2 .00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate

[0369] A correction factor of 1.40 was applied on the target drug loading (5% w / w free base based on a potency of 71.3% for API-DS Batch A (taking into account drug substance impurities, residuals solvent, residues of ignition, water content and counter ion)) Therefore, the drug load of the API-DS was 7% w / w and the diluents % (w / w) were adjusted accordingly as reflected in Table 21.

[0370] MCC PH102 was then replaced by MCC PH302 and MCC PH200, the rationale behind the choice of these two grades of MCCs is explained in Table 22. Table 22: Rationale Behind the Choice of Alternative MCC Average Bulk density MCC Grade particle size (g / mL)Main application(µm) MCC PH102 (used Medium size standard MCC. in the initial 130 0.28 - 0.33 Combines good flow and high compositions) compatibility.Attorney Docket No: 01330-0113-00PCT Same quality to grade 102, but MCC PH302 130 0.35 – 0.50 increased bulk density and improved flow properties. Large size MCC grade with excellent flow properties for a MCC PH200 250 0.31 - 0.37 variety of direct compression formulations.

[0371] Bulk and tapped density were assessed for the above formulations, results presented in Table 23. Table 23: Bulk and Tapped Density Results Bulk Tapped Hausner Carr’s Resulting Composition Density Density Ratio Index Flow (g / mL) (g / mL) A5 0.4271 0.5791 1.36 26.2 Poor A6 0.3954 0.4915 1.24 19.5 Fair A7 0.4609 0.6317 1.37 27.1 Poor A8 0.4606 0.5702 1.24 19.2 Fair

[0372] The above bulk and tapped density have been compared to the previous prepared blend that included MCC PH102, findings reported in Table 24. Table 24: Blend Flow Properties and Comparisons Carr ompositionTapp ’s CBulked Hausner Resulting Density Density Index Ratio Flow (g / mL) (g / mL) A3 (MCC PH102 as 0.3460 0.4795 1.39 27.9 Poor 100% diluent) A5 0.4271 0.5791 1.36 26.2 Poor (MCC PH302 asAttorney Docket No: 01330-0113-00PCT 100% diluent) A6 (MCC PH200 as 0.3954 0.4915 1.24 19.5 Fair 100% diluent) A4 (SuperTab11® SD 0.4465 0.5570 1.25 19.8 Fair : MCC PH10250:50) A7 (SuperTab11® SD 0.4609 0.6317 1.37 27.1 Poor : MCC PH30250:50) A8 (SuperTab11® SD 0.4606 0.5702 1.24 19.2 Fair : MCC PH20050:50)

[0373] As presented in the table above, MCC PH200 improved the flow for the new composition where 100% of diluent is represented by MCC only. MCC PH200 also performed well in the composition 50:50 MCC:lactose but performed similarly to MCC PH102. MCC PH302, on the other hand, did not show significant improvement in flow.

[0374] The blends were tested for blend uniformity, results are presented in Table 25. A total of 10 aliquots were collected from the top (N=3), middle (N=4), and bottom (N=3) of the blend for testing. Table 25: Blend Uniformity Results Blend batch Mean Recovery (90.0- AV number 110.0% Target) (<15 Target) A5 103.9% 6.90 A6 102.9% 8.53 A7 104.3% 7.52 A8 98.1% 9.27Attorney Docket No: 01330-0113-00PCT

[0375] Overall, the compositions presented a good recovery and low AV. An additional sample for Composition A6 was tested (MCC PH200 as 100% diluent) as the particle size is significantly greater than the other grades. After holding the Composition A6 blend for 3 days, the average recovery was 105.8% with an AV of 22.19 (see Table 26, below), which suggests that segregation occurred overtime due to potentially greater particle size of MCC PH200. Table 26: Blend Uniformity Spread of Data for Composition A6 Mean Recovery Composition Recovery AV (90.0-110.0% A6 (90.0-110.0% Target) (<15 Target) Target) Sample 1 101.5% Sample 2 102.9% Sample 3 98.4% Sample 4114.2%Sample 5 119.5% 105.8% 22.19% Sample 6 108.6% Sample 7 98.1% Sample 8 109.5% Sample 9 95.0% Sample 10 110.2%

[0376] The four compositions were then further progressed for compressibility for further evaluations. The compressibility assessment method is outlined in Example 7. N=3 tablets were compressed from each formulation for each set of forces. The actual compression pressure applied and the tablet tensile strength averages (both expressed as MPa) from the 3 replicates were plotted to create the compression profiles as presented in FIG. 28.

[0377] From the compression profile assessment, overall the compressibility of the new blends was reduced when comparing with the profiles of the previous composition. An overall comparison of compression profiles is provided in FIG.29.Attorney Docket No: 01330-0113-00PCT Example 9. Dissolution and Stability of Exemplary Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate Pharmaceutical Compositions

[0378] The composition used for the dissolution assessment were Composition B3 and Composition A8. In both cases, 600 mg film coated tablets (30 mg dose) were used for the dissolution testing. The mean dissolution profiles are shown in FIG. 30.

[0379] As shown in FIG. 30, >80% of Compound 1 (free base) is released within the first 15 minutes which suggests that the compositions within the immediate release specification range.

[0380] Dissolution was conducted on tablets prepared using Composition A4 containing a 5 mg dose of Compound 1 and tablets prepared using Composition A4 containing a 15 mg dose of Compound 1. The in vitro dissolution profiles (0.1 HCl) of the tablets showed no significant difference, therefore no difference in pharmacokinetics is expected.

[0381] Exemplary compositions were also subjected to stability studies. For example, tablets prepared using Composition A4 containing a 5 mg dose of Compound 1 and tablets prepared using Composition A4 containing a 15 mg dose of Compound 1 were subjected to accelerated stability studies at 25°C / 60%RH for up to 36 months and 40°C / 75%RH for up to six months. No chemical degradation was observed. Additionally, there was no significant change in appearance, related substances (impurities), dissolution at 45 minutes, chiral purity, water content, and microbial levels. A shelf life of at least 21 months at 15-25°C was shown. Example 10. Additional Formulations using Different ratios of Lactose:MCC

[0382] Four additional compositions were prepared with alternative ratios of SuperTab® 11SD:MCC PH102. Excipients were screened through a 1 mm sieve without using a sieve brush. API-DS, Batch A was screened through 250 μm sieve using a sieve brush. The appropriate amount of API-DS and excipients for each blend were weighed. For each blend, using an appropriate size amber jar, the materials were added in the following order: ½ Diluent → API-DS → Disintegrant → Glidant → ½ Diluent. The blend was further mixed on the Turbula T2F blender for 20 minutes at 32 RPM. The magnesium stearate was added and the powder blended for a further 2 minutes at 32 RPM.

[0383] A salt correction factor of 1.40 was applied on the target drug loading (5% w / w free base based on a potency of 71.3% for API-DS Batch A (taking into account drug substance impurities, residuals solvent, residues of ignition, water content and counter ion)). Therefore,Attorney Docket No: 01330-0113-00PCT the drug load of the API-DS was 7% w / w and the diluents % (w / w) were adjusted accordingly as reflected in Table 27.

[0384] Table 27 shows formulations of exemplary initial blends using API-DS, Batch A. Table 27. Formulations of Exemplary Initial Blends Using API-DS, Batch A Composition Formulation A9 7.00% API-DS Batch A 64.50% SuperTab®24.50% MCC PH102 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A10 7.00% API-DS Batch A 64.50% SuperTab®24.00% MCC PH102 2.00% Crospovidone 1.50% Aerosil 1.00% Magnesium Stearate A11 7.00% API-DS Batch A 24.50% SuperTab®64.50% MCC PH102 2.00% Crospovidone 1.00% Aerosil 1.00% Magnesium Stearate A12 7.00% API-DS Batch A 24.00% SuperTab®64.50% MCC PH102 2.00% Crospovidone 1.50% Aerosil 1.00% Magnesium Stearate

[0385] The Compositions A9 and A10 were tested for blend uniformity. The results are presented in Table 28. A total of 10 aliquots were collected from the top (N=3), middle (N=4), and bottom (N=3) of the blend for testing.Attorney Docket No: 01330-0113-00PCT Table 28: Blend Uniformity Results Mean Recovery AV Composition (90.0-110.0% Target) (<15 Target) A9 100.1% 8.80 A10 100.4% 3.47 A4 (from previous studies) 99.4% 5.85

[0386] Overall, the compositions presented a good recovery and low AV and the results were comparable with Composition A4 from earlier studies. The results of a compressibility assessment performed on both Composition A9 and A10 are provided in FIG. 31. As can be observed in FIG. 31, the compressibility of Compositions A9 and A10 is notably lower for both new blends when comparing the profiles with Composition A4. Upon comparing Compositions A9 and A10, however, it can be observed that Composition A10 performs slightly better than Composition A9, potentially due to the increased %w / w of glidant. Regarding Compositions A11 and A12, the compressibility is overall comparable.

[0387] Compositions A9-A12 were also tested for bulk and tapped density. The results are presented in Table 29. It can be seen that the proposed Compositions A9-A12 with alternative ratios of MCC:lactose had poorer flows than Composition A4. Results are comparable for Compositions A9 and A10, and for Compositions A11 and A12. Composition A4 results (shown for reference in FIG. 31) performed better in terms of flow properties and in terms of compressibility.

[0388] The new proposed blends were also tested for bulk and tapped density. Results are presented in Table 29. Table 29. Bulk and Tapped Density Blends with Alternative Ratios and Original Blend Composition Bulk Tapped Blend Batch Hausner Carr’s Resulting Density Density Number Ratio Index Flow (g / mL) (g / mL) A9 0.469 0.629 1.34 25.4 Poor A10 0.456 0.627 1.37 27.3 Poor A11 0.394 0.508 1.28 21.8 Passable A12 0.393 0.499 1.28 21.7 Passable A4 0.447 0.557 1.25 19.8 FairAttorney Docket No: 01330-0113-00PCT Example 11. Flowdex Testing on Certain Compositions

[0389] Flowdex involves monitoring the rate of flow of material through an orifice which has been proposed as a better measure of powder flowability. Flowdex is a methodology used to determine the intrinsic flowability of powdered materials (in compliance with USP<1174>). The powder is loaded in a funnel positioned above disks with varying hole diameters (ranging from 4 mm to 34 mm).The powder’s ability to flow through the hole is observed. If the powder flows freely, the next larger disk is used. This process is repeated until the powder no longer flows freely through the hole. The smallest hole diameter through which the powder flows freely is recorded as the flowability index.

[0390] Flowdex testing was performed on certain compositions (e.g., Compositions B3, B4, A7-A12), as well as three reference samples. The results are shown in Table 30. Table 30: Flowdex Testing Results Composition Smallest Orifice Successfully Passed Through Reference – 100% Mannitol (Pearlitol 4 mm 200SD) Reference – 100% MCC 102 24 mm Reference – 100% SuperTab® 11 SD 6 mm B3 16 mm B4 16 mm A7 18 mm A8 8 mm A9 14 mm A10 14 mm A11 14 mm A12 14 mm

[0391] In some circumstances, a target for Flowdex should be ≤12 mm for a formulation that will perform well on a tablet press (possibly with slightly slower speeds at 12 mm), although a target of < 10mm would be more optimal. 14 mm and 16 mm compositions could be compressed into tablets at slow speeds (e.g., 5 RPM).Attorney Docket No: 01330-0113-00PCT Example 12. Additional Compositions Compositions A13-A15

[0392] A first set of additional compositions were prepared using the same ratio of mannitol and MCC (Composition A13), a reduced amount of mannitol (Composition A14), and addition of A-Tab® (Composition A15). See Tables 31-33 below. Table 31. Composition with Same Ratio of Mannitol and MCC A13 Component %w / w API-DS, Batch A 7.00 Mannitol Pearlitol Diluent 44.50 200 SD MCC PH102 Diluent 44.50 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00 Table 32. Composition with Reduced Amount of Mannitol A14 Component %w / w API-DS, Batch A 7.00 Mannitol Pearlitol Diluent 30.00 200 SD MCC PH102 Diluent 58.50 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.50 Magnesium Stearate Lubricant 1.00 Total 100.00 Table 33. Composition with Implementation of A-Tab® A15 Component %w / w API-DS, Batch A 7.00Attorney Docket No: 01330-0113-00PCT MCC PH102 Diluent 48.50 A-Tab® (DCPA) Diluent 40.00 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.50 Magnesium Stearate Lubricant 1.00 Total 100.00

[0393] Bulk and tapped density and Flowdex were measured on the blends. The results are presented in Tables 34 and 35. Table 34: Bulk and Tapped Density Results Blend Bulk Tapped Hausner Carr’s Resulting batch Density Density Ratio Index Flow number (g / mL) (g / mL) A13 0.3795 0.5216 1.37 27.2 Passable / Poor A14 0.3811 0.5089 1.34 25.0 Passable A15 0.4466 0.6351 1.42 29.7 Poor Table 35: Flowdex Results Blend batch Smallest orifice number successfully passed through A13 14mm A14 14mm A15 14mm

[0394] The results of the bulk and tapped density, and the Flowdex testing, are comparable amongst the formulations and are also comparable to other directly compressible blends (such as Composition A4). Compressibility was also assessed for Compositions A13-A15 (FIG. 32). Compressibility was slightly reduced for Compositions A13-A15 when compared to Composition A4 but the results were still acceptable. Compositions A13-A15

[0395] A second set of additional compositions were prepared using both Compound 1, Batch A and API-DS, Batch B, as shown in Tables 36-39 below.Attorney Docket No: 01330-0113-00PCT Table 36. Composition A16 (Batch A) A16 Component %w / w API-DS, Batch A 7.00 SuperTab® 11SD Diluent 24.00 MCC PH200 Diluent 65.00 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00 Table 37. Composition A17 (Batch A) A17 Component %w / w API-DS, Batch A 7.00 MCC PH200 Diluent 44.50 MCC PH102 Diluent 44.50 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00 Table 38. Composition B16 (Batch A) B16 Component %w / w API-DS, Batch A 6.75 SuperTab® 11SD Diluent 24.125 MCC PH200 Diluent 65.125 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00Attorney Docket No: 01330-0113-00PCT Table 39. Composition B17 (Batch A) B17 Component %w / w API-DS, Batch A 6.75 MCC PH200 Diluent 44.625 MCC PH102 Diluent 44.625 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00

[0396] Bulk and tapped density testing as well as Flowdex were assessed (see Table 40, below). Results from the bulk and tapped density and the Flowdex assessment were comparable amongst the compositions. Compressibility was also assessed for the additional formulations and compared with Composition A4 as presented in FIG. 33. Table 40: Bulk Density, Tapped Density, and Flowdex Results Blend Bulk Tapped Smallest Hausner Carr’s Resulting batch Density Density orifice Ratio Index Flow number (g / mL) (g / mL) (mm) A16 0.3974 0.5474 1.38 27.40 Poor 14 B16 0.3933 0.5400 1.38 27.24 Poor 16 A17 0.3802 0.4922 1.29 22.76 Passable 16 B17 0.3829 0.5144 1.34 25.57 Passable / Poor 16 A4 0.447 0.557 1.25 19.80 Fair 10 B4 0.462 0.565 1.22 18.18 Fair 12

[0397] From the compression profile, Compositions A17 and B17 with 50:50 MCC PH102 and MCC PH200 were highly compressible, requiring a lower force (~50MPa) to achieve 2MPa tensile strength. Overall, all compositions were compressible with consistent tablet weights recorded. 100 mg and 600 mg tablets from the new compositions were compressed and characterized as per Table 41 and Table 42.Attorney Docket No: 01330-0113-00PCT Table 41: 100 mg tablet compressibility data (tooling size = 6.15 round convex) Composition Compression Hardness Solid Tensile Force (KN) (kg) Fraction Strength (MPa) A16 3.10 5.79 0.77 1.84 4.35 7.73 0.80 2.58 6.12 8.41 0.81 2.88 7.50 9.31 0.82 3.24 8.86 10.36 0.84 3.67 A17 3.14 10.60 0.80 3.56 4.57 12.73 0.81 4.32 6.01 13.79 0.82 4.75 7.68 15.02 0.83 5.22 9.05 16.56 0.83 5.82 B16 3.51 7.04 0.78 2.32 4.51 8.05 0.80 2.69 5.91 8.39 0.84 2.96 7.22 9.97 0.83 3.50 8.90 10.63 0.84 3.74 B17 3.27 11.27 0.81 3.84 4.52 12.63 0.81 4.28 5.92 13.54 0.82 4.66 7.52 15.32 0.84 5.30 8.96 16.53 0.84 5.82 A4 4.02 5.13 0.74 1.67 4.91 4.63 0.75 1.50 5.89 4.83 0.76 1.64 7.95 6.25 0.78 2.07 8.83 8.51 0.77 2.96Attorney Docket No: 01330-0113-00PCT Table 42: 600 mg tablet compressibility data (tooling size = 17.5 x 8.5 caplet) Composition Compression Hardness Solid Tensile Friability Disintegration Dissolution Force (KN) (kg)* Fraction Strength (%)* (min) release % (MPa) (30 min)** A16 11.62 15.12 0.79 3.36 0.04 00:44 (coated 104.8 tablets) A17 6.35 14.74 0.71 2.67 0.01 00:28 (coated 105.4 tablets) B16 11.74 16.10 0.78 3.47 0.02 00:51 (coated 97.6 tablets) B17 6.22 15.47 0.77 2.87 0.00 00:42 (coated 100.0 tablets) A4 12.75 18.16 0.80 2.50 0.04 00:38 101.2 (uncoated tablets) B4 14.84 19.95 0.87 4.63 0.05 3:46 (coated 98.7 tablets) *uncoated tablets **coated tablets

[0398] The 600mg film coated tablets were tested for dissolution. Mean dissolution profiles are presented in FIGs. 34 and 35 for Compositions A16 and B16, and FIGs. 36 and 37 for Compositions A17 and B17. Dissolution was also assessed on Composition B4 (FIG. 38).

[0399] Content uniformity was assessed on 100 mg tablets (5 mg dose). Results are in Table 43 below. The mean recovery and AV are very similar for the Compositions A4 and B4, and slightly less comparable for Compositions A17 and B17. However, all results are within specification. Table 43. CU Results Mean Recovery Av Batch number (90.0-110.0% Target) (<15 Target) Formulation A4 100.5% 5.45 (Batch A) Formulation B4 98.2% 5.32 (Batch B)Attorney Docket No: 01330-0113-00PCT Formulation A17 (Batch 100.4% 6.40 A) Formulation B17 (Batch 93.5% 8.35 B) Composition A18

[0400] A composition with an increased amount of API-DS was prepared to access the impact on flowability and compressibility as shown in Table 44 below. The composition was prepared at a 50 g scale. Table 44. Batch A18 Blend Composition A18 Component %w / w API-DS, Batch A 14.00 MCC PH102 Diluent 41.00 SuperTab® 11SD Diluent 41.00 Crospovidone Disintegrant 2.00 Aerosil Glidant 1.00 Magnesium Stearate Lubricant 1.00 Total 100.00

[0401] The flowability of Composition A18 was assessed and compared to Composition A4. See Table 45. Table 45. Bulk, Tapped Density, and Flowdex Assessment for Compositions A18 and A4 Blend Bulk Tapped Carr’s Resulting Smallest batch Density Density Index Flow Orifice (mm) number (g / mL) (g / mL) A18 0.445 0.550 19.1 Fair 14 10 A4 0.447 0.557 19.8 Fair (performed on blend A4)Attorney Docket No: 01330-0113-00PCT

[0402] The blend was then further progressed for compression assessment. The sets of forces selected were 3422, 4991, 6462, 7933, 9404 Newton. Tablets were produced as 100 mg round and checked for weight, thickness, and hardness. N=3 tablets were produced from each set of forces. The resulting compression profile for Composition A18 is presented in FIG. 39. The profile for Composition A4 is also shown in FIG. 39 for comparison. As shown in the figure, a 2.00 mPa tensile strength could be achieved with ~3422 N force (equivalent to ~100 mPa compression pressure). The last point represents a potential failure point as there is a drop in the profile, meaning that at that particular force the material is probably over- compressed.

[0403] Slightly less force was required for the composition with the higher API-DS loading (~100 mPa vs ~120 mPa for Composition A4), confirming that a reasonable force can be used to achieve 2.00 mPa tensile strength despite the increased API-DS loading in the blend. It can be concluded that it is possible to increase the API-DS loading of the composition from 5% w / w to 10% w / w free base without hindering the blend flowability and compressibility performance.

[0404] Based on the testing discussed in Examples 8-12, it was found that compositions based on a combination of MCC (e.g., MCC PH102) and lactose (e.g., SuperTab 11 SD) provided adequate flowability and good compressibility. Compositions comprising different grades of MCC (e.g., MCC PH102 and MCC PH200) also provided good compressibility.Attorney Docket No: 01330-0113-00PCT EQUIVALENTS The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof. As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., + / -5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

Claims

1. Attorney Docket No: 01330-0113-00PCT CLAIMS What is claimed:

1. A pharmaceutical composition comprising: (a) a hydrogen sulfate salt of Compound 1:Compound 1 or a hydrate or solvate thereof, and (b) two pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a di(hydrogen sulfate) or hydrate or solvate thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a hydrate.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is a trihydrate.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.Attorney Docket No: 01330-0113-00PCT 7. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ.

9. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.7° 2θ.

10. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.0° 2θ.

11. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.7° 2θ, and about 15.0° 2θ.

12. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ about 10.2° 2θ, about 11.7° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.0° 2θ, about 15.7° 2θ, about 19.0° 2θ, and about 19.6° 2θ.

13. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction patternAttorney Docket No: 01330-0113-00PCT comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.2° 2θ and about 15.0° 2θ.

14. The pharmaceutical composition according to any one of claims 1-6, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as that of FIG. 1A.

15. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an FT-IR spectrum substantially the same as that of FIG.

16.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a melting onset as measured by DSC in a sealed aluminum pan with a pierced lid of about 144°C.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a DSC thermogram substantially the same as that of FIG.

4.

18. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 1 µm to about 20 µm, an average d50 particle size of from about 10 µm to about 50 µm, and / or an average d90 particle size of from about 40 µm to about 180 µm.

19. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an average d10 particle size of from about 2 µm to about 10 µm, an average d50 particle size of from about 15 µm to about 45 µm, and / or an average d90 particle size of from about 50 µm to about 170 µm.Attorney Docket No: 01330-0113-00PCT 20. The pharmaceutical composition according to any one of the preceding claims, wherein at least one of the two excipients is a diluent.

21. The pharmaceutical composition according to any one of the preceding claims, wherein both of the two excipients are diluents.

22. The pharmaceutical composition according to claim 20 or 21, wherein the diluent or diluents are chosen from microcrystalline cellulose, lactose, starch, mannitol, and dicalcium phosphate.

23. The pharmaceutical composition according to claim 22, wherein the diluent or diluents are microcrystalline cellulose.

24. The pharmaceutical composition according to claim 22, wherein the diluent or diluents are lactose.

25. The pharmaceutical composition according to claim 21, wherein the diluents are microcrystalline cellulose and lactose.

26. The pharmaceutical composition according to any one of claims 22, 24, and 25, wherein the lactose is lactose monohydrate.

27. The pharmaceutical composition according to any one of claims 22, 23, and 25, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL, or an average particle size of about 130 µm and a bulk density of from about 0.35 to about 0.50 g / mL, or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

28. The pharmaceutical composition according to claim 27, wherein the microcrystalline cellulose has an average particle size of about 130 µm and a bulk density of from about 0.28 to about 0.33 g / mL or an average particle size of about 250 µm and a bulk density of from about 0.31 to about 0.37 g / mL.

29. A pharmaceutical composition comprising: (b) Compound 1 or a hydrate or solvate thereof:Attorney Docket No: 01330-0113-00PCTCompound 1 or a pharmaceutical salt thereof, and (c) a diluent.

30. The pharmaceutical composition according to claim 30, wherein the diluent is chosen from microcrystalline cellulose, lactose, and starch.

31. The pharmaceutical composition according to claim 31, wherein the diluent is microcrystalline cellulose.

32. The pharmaceutical composition according to claim 31, wherein the diluent is lactose.

33. The pharmaceutical composition according to any one of claims 30-33, wherein the composition comprises a second diluent.

34. The pharmaceutical composition according to claim 34, wherein the second diluent is the same as the first diluent.

35. The pharmaceutical composition according to claim 35, wherein the first and second diluents are microcrystalline cellulose.

36. The pharmaceutical composition according to claim 34, wherein the second diluent is different than the first diluent.

37. The pharmaceutical composition according to claim 35, wherein the first diluent is microcrystalline cellulose and the second diluent is lactose.Attorney Docket No: 01330-0113-00PCT 38. The pharmaceutical composition according to any one of claims 20-37, wherein the total weight of the diluent or diluents in the composition is from about 50% to about 95% of the composition.

39. The pharmaceutical composition according to claim 38, wherein the total weight of the diluent or diluents in the composition is from about 70% to about 95% of the composition.

40. The pharmaceutical composition according to claim 39, wherein the total weight of the diluent or diluents in the composition is from about 80% to about 90% w / w of the composition.

41. The pharmaceutical composition according to any one of the preceding claims, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of from about 5% to about 14% w / w of the composition.

42. The pharmaceutical composition according to claim 41, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of from about 6% to about 7% w / w of the composition.

43. The pharmaceutical composition according to claim 41, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of about 7% w / w of the composition.

44. The pharmaceutical composition according to claim 41, wherein the Compound 1 hydrogen sulfate or hydrate or solvate thereof, or the Compound 1 or salt or hydrate or solvate thereof, is present in an amount of about 6.75% w / w of the composition.

45. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises a disintegrant.

46. The pharmaceutical composition according to claim 45, wherein the disintegrant is crospovidone.Attorney Docket No: 01330-0113-00PCT 47. The pharmaceutical composition according to claim 45 or 46, wherein the disintegrant is present in an amount of from about 2% to about 5% w / w of the composition.

48. The pharmaceutical composition according to any one of claims 45-47, wherein the disintegrant is present in an amount of about 2% w / w of the composition.

49. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises a glidant.

50. The pharmaceutical composition according to claim 49, wherein the glidant is a colloidal silicon dioxide.

51. The pharmaceutical composition according to claim 49 or 50, wherein the glidant is present in an amount from about 1% to about 3% w / w of the composition.

52. The pharmaceutical composition according to claim 51, wherein the glidant is present in an amount of about 1% w / w of the composition.

53. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises a lubricant.

54. The pharmaceutical composition according to claim 53, wherein the lubricant is magnesium stearate.

55. The pharmaceutical composition according to claim 53 or 54, wherein the lubricant is present in an amount of about 1% w / w of the composition.

56. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises a dose of from about 1 mg and about 50 mg of Compound 1.

57. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises a dose of from about 5 mg to about 30 mg of Compound 1.

58. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises a dose of about 5 mg of Compound 1.Attorney Docket No: 01330-0113-00PCT 59. The pharmaceutical composition according to any one of claims 1-57, wherein the composition comprises a dose of about 10 mg of Compound 1.

60. The pharmaceutical composition according to any one of claims 1-57, wherein the composition comprises a dose of about 20 mg of Compound 1.

61. The pharmaceutical composition according to any one of claims 1-57, wherein the composition comprises a dose of about 30 mg of Compound 1.

62. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of a tablet.

63. The pharmaceutical composition according to claim 62, wherein the tablet size is from about 100 mg to about 600 mg.

64. The pharmaceutical composition according to claim 62, wherein the tablet size is about 100 mg.

65. The pharmaceutical composition according to claim 62, wherein the tablet size is about 200 mg.

66. The pharmaceutical composition according to claim 62, wherein the tablet size is about 400 mg.

67. The pharmaceutical composition according to claim 62, wherein the tablet size is about 600 mg.

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