BR112019006506B1 - TABLETS COMPRISING 2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOLE-5-YL) PYRIDIN-3-YL)METHOXY) BENZALDEHYDE AND USE THEREOF - Google Patents

Abstract

The present invention relates to high potency/high drug loading tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ("Compound 1"), dispersible tablets comprising Compound 1, processes for manufacturing said tablets, and methods for treating patients with the tablets. Compound 1 is useful for treating hematologic disorders such as sickle cell disease, lung disease such as idiopathic pulmonary fibrosis, and hypoxic and hypoxic conditions.

Description

CROSS-REFERENCE TO RELATED ORDERS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application 62/407,406, filed October 12, 2016, and U.S. Provisional Patent Application 62/553,716, filed September 1, 2017, which are incorporated herein by reference in their entirety.

FIELD

[0002] Provided herein are high potency/high drug loading tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (hereinafter "Compound 1" or "voxelotor"), formulations and compositions of tablet 1, and processes for manufacturing said tablets. The present disclosure also provides rapidly disintegrating dispersible tablets of tablet 1. Methods of treating patients with the tablets are also included. Compound 1 is useful for treating hematologic disorders such as sickle cell disease, lung disease such as idiopathic pulmonary fibrosis, and hypoxic and hypoxic conditions.

BACKGROUND

[0003] It has been reported that approximately 50% of patients in developed countries do not take their medications as prescribed, that the complex medication regimen is a contributing factor to poor medication adherence, and that adherence stands between treatment and outcomes.

[0004] Medication non-adherence is estimated to cost the healthcare system $100 billion to $300 billion per year, and several studies have shown that high rates of non-adherence directly correlate with poor clinical outcomes. In addition, simple dosing, such as one pill per day, helps maximize adherence, and medications that reduce the number of pills per day help eliminate some of the known barriers to adherence.

[0005] Compound 1 is a small molecule active pharmaceutical ingredient in the clinical stage of development for the treatment of sickle cell disease, lung disease such as idiopathic pulmonary fibrosis and hypoxic and hypoxic conditions. Clinical doses of tablet 1 in adults may be considered high. Clinical doses include compound 1 in the range of 500 mg to 1000 mg, or up to 1500 mg, administered orally once daily in either 100 or 300 mg capsules. The high dose 300 mg capsules are size 0 HPMC capsules and contain more than 80% of tablet 1. For example, a size 0 capsule measures 21.6 mm in length x 7.64 mm in diameter and only 300 mg of the drug from tablet 1 can be loaded in such capsule. Therefore, for the capsule formulation, 300 mg is the maximum feasible potency due to the density characteristics and the fixed fill volume and shell dimensions used in the size 0 capsule.

[0006] Accordingly, there is a need for the development of a pharmaceutical formulation containing compound 1 that is suitable for producing alternative dosage forms such as tablets that contain varying amounts of higher doses of tablet 1 to minimize the number of pills to be swallowed by a patient (tablet load) per dose, are sized appropriately for ease of swallowing, and release compound 1 in a manner that leads to the desired therapeutic effect. Another important advantage of tablet formulations over capsules is the ability to achieve commercial volumes and use high-speed manufacturing equipment while maintaining low product costs. The present disclosure achieves this and related needs.

SUMMARY

[0007] Provided herein are pharmaceutical compositions that are amenable to large-scale manufacturing of high-dose tablets (loaded with high drug concentration) of tablet 1, including Form II. Such compositions may have high tablet hardness and low friability, be easily swallowed by patients, and/or release compound 1 in a manner that leads to the desired therapeutic effect. Also provided herein are tablets that may provide a wide range of tablet strengths to achieve both high dosage requirements and low dosage requirements.

[0008] In a first aspect is a tablet comprising from about 50% to about 70% by weight of compound 1 and a microcrystalline cellulose as a filler provided that the at least one microcrystalline cellulose is a high compaction microcrystalline cellulose and wherein the % by weight is relative to the total weight of the tablet.

[0009] Also provided herein are dispersible tablets of tablet 1, wherein the tablet rapidly disintegrates in liquid. In some embodiments, the tablet rapidly disintegrates in less than about 10 mL of liquid. Said tablets can be readily administered to patients, such as patients between the ages of 9 months to about 11 years who have difficulty swallowing.

[00010] Some embodiments herein also provide methods of treating a condition associated with oxygen deficiency in a patient in need thereof comprising administering to the patient a tablet or dispersible tablet as described herein.

[00011] Also provided herein are methods of manufacturing tablets described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[00012] Figure 1 shows in vitro dissolution profiles of Form II tablet 1, tablets G1 and G2, compared to the reference capsule product. Tablets G1 were of 100 mg strength; tablets G2 were of 100 mg and 300 mg strengths with the film coating as in Example 4. Capsules were of 300 mg strength.

[00013] Figure 2 provides a visual comparison of the size differences between a 300 mg strength capsule (on the left side), a 300 mg strength tablet 1 tablet (in the middle), and a 900 mg strength tablet 1 tablet (on the right side).

MODALITIES

[00014] In embodiment 1a, the tablet of the first aspect comprises from about 50% to about 65% by weight of compound 1. In one embodiment, the tablet comprises compound 1 in an amount of from about 50% to about 65% by weight of the tablet. In a sub-embodiment of embodiment 1a, the tablet comprises compound 1 in an amount of about 65% by weight of the tablet. In a second sub-embodiment of embodiment 1a, the tablet comprises compound 1 in an amount of about 60% by weight of the tablet. In a third sub-embodiment of embodiment 1a, the tablet comprises compound 1 in an amount of about 60% ± 5% by weight of the tablet. In a fourth sub-embodiment of embodiment 1a, the tablet comprises compound 1 in an amount of about 60% ± 2% by weight of the tablet. In a fifth sub-embodiment of embodiment 1a, the tablet comprises compound 1 in an amount of about 60% by weight of the tablet.

[00015] In embodiment 1b, the tablet of the first aspect and embodiment 1a and subembodiments contained therein, the tablet comprises a high-compacting microcrystalline cellulose in an amount of from about 20% to about 40% by weight of the tablet. In a subembodiment of embodiment 1b, the tablet comprises a high-compacting microcrystalline cellulose in an amount of about 30% by weight of the tablet. In another subembodiment of embodiment 1b, the tablet comprises a high-compacting microcrystalline cellulose in an amount of about 35% by weight of the tablet. In yet another subembodiment of embodiment 1b, the tablet comprises a high-compacting microcrystalline cellulose in an amount of 35% ± 2% by weight of the tablet. In yet another subembodiment of embodiment 1b, the tablet comprises a high-compacting microcrystalline cellulose in an amount of 35% ± 2% by weight of the tablet. In yet another sub-embodiment of embodiment 1b, the tablet comprises a high-compacting microcrystalline cellulose in an amount of 35% ± 2% by weight of the tablet. In yet another sub-embodiment of embodiment 1b and sub-embodiments contained therein, the microcrystalline cellulose is a high-compacting microcrystalline cellulose. In yet another sub-embodiment of embodiment 1b and sub-embodiments contained therein, the high-compacting microcrystalline cellulose is Ceolus™ UF-711. In another sub-embodiment of embodiment 1b and sub-embodiments contained therein, the high-compacting microcrystalline cellulose is Ceolus™ KG-1000 or KG-802.

[00016] In embodiment 1c, the tablet of the first aspect and embodiments 1a and 1b and sub-embodiments contained therein, compound 1 is a substantially pure crystalline ansolvate form (Form II) characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each ±0.2° 2θ). In an embodiment of embodiment 1c, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% Form I and/or Form N.

[00017] In embodiment 1d, the tablet of the first aspect and embodiments 1a and 1b and sub-embodiments contained therein, the tablet consists essentially of tablet 1 as a crystalline ansolvate form (Form II) characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ).

[00018] In embodiment 1e, the tablet of the first aspect, embodiments 1a, 1b, 1c, and 1d, and subembodiments contained therein further comprise a disintegrant wherein the amount of disintegrant is from 0% to about 10% by weight of the tablet. In a subembodiment of embodiment 1e, the amount of disintegrant is from about 0.75% to about 1.5% by weight of the tablet. In another subembodiment of embodiment 1e, the amount of disintegrant is from about 1% to about 1.5% by weight of the tablet. In another subembodiment of embodiment 1e, the amount of disintegrant is 1.25 ± 0.2% by weight of the tablet. In still another subembodiment of embodiment 1e, and subembodiments contained therein, the disintegrant is croscarmellose sodium.

[00019] In embodiment 1f, the tablet of the first, second, third, fourth, and fifth aspects, embodiments 1a, 1b, 1c, 1d, and 1e, and subembodiments contained therein, the tablet further comprises a lubricant, wherein the amount of lubricant is from about 1.75% to about 2.75% by weight of the tablet. In a subembodiment of embodiment 1f, the amount of lubricant is from about 2.0% to about 2.5% by weight of the tablet. In another subembodiment of embodiment 1f, the amount of lubricant is 2.25 ± 0.2% w/w of the tablet. In another subembodiment of embodiment 1f, and subembodiments contained therein, the lubricant is magnesium stearate.

[00020] In embodiment 1g, the tablet of the first aspect, embodiments 1a and 1b, and subembodiments contained therein further comprises a surfactant wherein the amount of surfactant is from about 1% to about 2% by weight of the tablet. In one subembodiment of embodiment 1g, the amount of surfactant is 1.5 ± 0.2% by weight of the tablet. In another subembodiment of embodiment 1g, and subembodiments contained therein, the surfactant is sodium lauryl sulfate.

[00021] In a second aspect, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 60% by weight of compound 1; a high compaction microcrystalline cellulose; optionally a disintegrant; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[00022] In embodiment 2a, the granular component of the second aspect comprises: a high compaction microcrystalline cellulose in an amount of about 27.50% by weight of the tablet; a disintegrant is present in an amount of about 1% by weight of the tablet; and a lubricant is present in an amount of about 1.50% by weight of the tablet.

[00023] In a sub-modality of modality 2a:

[00024] the amount of high compaction microcrystalline cellulose is 27.50 ± 2% by weight of the tablet; the amount of disintegrant is 1 ± 0.2% by weight of the tablet; and the amount of lubricant is 1.50 ± 0.2% by weight of the tablet.

[00025] In embodiment 2b, the tablet of embodiment 2a and sub-embodiments thereof, the high compaction microcrystalline cellulose is Ceolus™ UF-711; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and compound 1 is a substantially pure crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ± 0.2°2θ). In a sub-embodiment of embodiment 2b, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% in Form I and/or Form N; and the surfactant is absent.

[00026] In a third aspect, provided herein is a tablet comprising a granular component wherein the granular component consists essentially of: about 60% by weight of compound 1; a high compaction microcrystalline cellulose; optionally a disintegrant; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[00027] In embodiment 3a, the granular component of the third aspect comprises: a high compaction microcrystalline cellulose in an amount of about 27.50% by weight of the tablet; the disintegrant is present in about 1% by weight of the tablet; and the lubricant is present in an amount of about 1.50% by weight of the tablet; and optionally about 1.5% by weight of a surfactant.

[00028] In a sub-embodiment of embodiment 3a: the amount of high compaction microcrystalline cellulose is 27.50 ± 2% by weight of the tablet; the amount of disintegrant is 1 ± 0.2% by weight of the tablet; the amount of lubricant is 1.50 ± 0.2% by weight of the tablet; the surfactant is absent.

[00029] In embodiment 3b, the tablet of embodiment 2a and sub-embodiments thereof, the high compaction microcrystalline cellulose is Ceolus™ UF-711; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and compound 1 is a substantially pure crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In a sub-embodiment of embodiments 3b, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% in Form I and/or Form N and the surfactant is absent.

[00030] In embodiment 3c, the tablet of the second and third aspects and embodiments contained therein (e.g., 2a, 2b, 3a, and 3b) further comprises an extragranular component.

[00031] In embodiment 3d, the extragranular component of embodiment 3c comprises: a microcrystalline cellulose; a disintegrant; optionally a surfactant; a lubricant; and optionally a coating; provided that at least one of the intragranular or extragranular component of the tablet contains a surfactant.

[00032] In embodiment 3f, the tablet of embodiments 3d wherein: the amount of extragranular microcrystalline cellulose is about 7.50% by weight of the tablet; the amount of extragranular disintegrant is about 0.25% by weight of the tablet; a surfactant is present in an amount of about 1.50% by weight of the tablet; and the amount of extragranular lubricant is about 0.75% by weight of the tablet.

[00033] In embodiment 3g, the tablet of embodiment 3f wherein the microcrystalline cellulose is a high compaction microcrystalline cellulose selected from CeolusTM UF-711, CeolusTM KG-1000 or KG-802, preferably CeolusTM UF-711; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate and the surfactant is sodium lauryl sulfate.

[00034] In embodiment 3h, the extragranular component of embodiment 3c consists essentially of: a microcrystalline cellulose; a disintegrant; optionally a surfactant; a lubricant, and optionally a coating; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[00035] In embodiment 3i, the tablet of embodiments 3h comprises: the amount of extragranular microcrystalline cellulose is about 7.50% by weight of the tablet; the amount of extragranular disintegrant is about 0.25% by weight of the tablet; a surfactant is present and the amount is about 1.50% by weight of the tablet; and the amount of extragranular lubricant is about 0.75% by weight of the tablet.

[00036] In embodiment 3j, the tablet of embodiment 3i comprises a microcrystalline cellulose wherein the microcrystalline cellulose is a CeolusTM UF-711 high compaction microcrystalline cellulose; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and the surfactant is sodium lauryl sulfate.

[00037] In embodiment 4, the tablet of the first, second and third aspects, embodiments 1a, 1b, 3(a-j) and embodiments contained therein the tablet comprises from about 300 mg to about 900 mg of tablet 1.

[00038] In embodiment 4a, the tablet comprises 300 mg, 400 mg, 500 mg, 750 mg, or 900 mg. In a sub-embodiment of embodiment 4a, the tablet comprises 300 mg of tablet 1. In a sub-embodiment of embodiment 4a, the tablet comprises 900 mg of tablet 1. In a sub-embodiment of embodiment 4a, the tablet comprises 1500 mg of tablet 1.

[00039] In another embodiment it is a tablet comprising from about 50% to about 70% by weight of compound 1 and a microcrystalline cellulose as a filler provided that the at least one microcrystalline cellulose is a high compaction microcrystalline cellulose; wherein the % by weight is relative to the total weight of the tablet. In another embodiment it is a tablet comprising from about 30% to about 70% by weight of compound 1 and a microcrystalline cellulose as a filler provided that the at least one microcrystalline cellulose is a high compaction microcrystalline cellulose; wherein the % by weight is relative to the total weight of the tablet.

[00040] In one embodiment, the tablet comprises from about 50% to about 65% by weight of compound 1. In one embodiment, the tablet comprises about 65% by weight of compound 1. In one embodiment, the tablet comprises about 60% by weight of compound 1. In one embodiment, the tablet comprises about 60% ± 5% by weight of compound 1. In one embodiment, the tablet comprises about 60 ± 2% by weight of compound 1. In one embodiment, the tablet comprises about 60% by weight of compound 1.

[00041] In another embodiment, the tablet comprises from about 20% to about 40% of a high-compression microcrystalline cellulose by weight of the tablet. In another embodiment, the tablet comprises about 30% of a high-compression microcrystalline cellulose by weight of the tablet. In another embodiment, the tablet comprises about 35% of a high-compression microcrystalline cellulose by weight of the tablet. In yet another embodiment, the tablet comprises about 35 ± 2% of a high-compression microcrystalline cellulose by weight of the tablet. In yet another embodiment, the tablet comprises about 35% of a high-compression microcrystalline cellulose by weight of the tablet. In yet another embodiment, the tablet comprises about 35 ± 2% of a high-compression microcrystalline cellulose by weight of the tablet. In one embodiment, the microcrystalline cellulose is a high-compression microcrystalline cellulose. In yet another embodiment, the high compaction microcrystalline cellulose is CeolusTM UF-711. In another embodiment, the high compaction microcrystalline cellulose is CeolusTM KG-1000 or KG-802.

[00042] In another embodiment, the tablet comprises compound 1 as a substantially pure crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each ±0.2° 2θ). In one embodiment, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each ±0.2° 2θ) and 5% Form I and/or Form N.

[00043] In another embodiment, the tablet consists essentially of tablet 1 as a crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).

[00044] In one embodiment, the tablets described herein further comprise a disintegrant wherein the amount of disintegrant is from 0% to about 10% by weight of the tablet. In one embodiment, the amount of disintegrant is from about 0.75% to about 1.5% by weight of the tablet. In another embodiment, the amount of disintegrant is from about 1% to about 1.5% by weight of the tablet. In another embodiment, the amount of disintegrant is 1.25 ± 0.2% by weight of the tablet. In yet another embodiment, the disintegrant is croscarmellose sodium.

[00045] In another embodiment, the tablets described herein further comprise a lubricant, wherein the amount of lubricant is from about 1.75% to about 2.75% by weight of the tablet. In one embodiment, the amount of lubricant is from about 2.0% to about 2.5% by weight of the tablet. In another embodiment, the amount of lubricant is 2.25 ± 0.2% w/w of the tablet. In another embodiment, the lubricant is magnesium stearate.

[00046] In another embodiment, the tablets described herein further comprise a surfactant wherein the amount of surfactant is from about 1% to about 2% by weight of the tablet. In one embodiment, the surfactant comprises about 1.5% by weight of the tablet. In one embodiment, the amount of surfactant is 1.5 ± 0.2% by weight of the tablet. In another embodiment, the surfactant is sodium lauryl sulfate.

[00047] In another embodiment, the tablets described herein further comprise a fluidizer, wherein the fluidizer is in an amount of less than about 2% by weight of the tablet.

[00048] In another aspect, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 60% by weight of compound 1; a high compaction microcrystalline cellulose; optionally a disintegrant; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[00049] In one embodiment, the granular component comprises: a high compaction microcrystalline cellulose in an amount of about 27.50% by weight of the tablet; a disintegrant in an amount of about 1% by weight of the tablet; and a lubricant in an amount of about 1.50% by weight of the tablet.

[00050] In one embodiment the granular component comprises: high compaction microcrystalline cellulose in an amount of 27.50 ± 2% by weight of the tablet; disintegrant in an amount of 1 ± 0.2% by weight of the tablet; and lubricant in an amount of 1.50 ± 0.2% by weight of the tablet.

[00051] In one embodiment, the high compaction microcrystalline cellulose is Ceolus™ UF-711; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and Compound 1 is a substantially pure crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% Form I and/or Form N; and surfactant is absent.

[00052] In another aspect, provided herein is a tablet comprising a granular component consisting essentially of: about 60% by weight of compound 1; a high compaction microcrystalline cellulose; optionally a disintegrant; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[00053] In one embodiment, the granular component comprises: a high compaction microcrystalline cellulose in an amount of about 27.50% by weight of the tablet; a disintegrant in an amount of about 1% by weight of the tablet; a lubricant in an amount of about 1.50% by weight of the tablet; and optionally about 1.5% by weight of a surfactant.

[00054] In one embodiment, the granular component comprises: a high compaction microcrystalline cellulose in an amount of about 27.50% by weight of the tablet; a disintegrant in an amount of about 1% by weight of the tablet; a lubricant in an amount of about 1.50% by weight of the tablet; and optionally a surfactant in an amount of about 1.5% by weight of the tablet.

[00055] In one embodiment, the granular component comprises: high compaction microcrystalline cellulose in an amount of 27.50 ± 2% by weight of the tablet; disintegrant in an amount of 1 ± 0.2% by weight of the tablet; lubricant in an amount of 1.50 ± 0.2% by weight of the tablet; and surfactant is absent.

[00056] In one embodiment, the high compaction microcrystalline cellulose is Ceolus™ UF-711; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate; and Compound 1 is a substantially pure crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% Form I and/or Form N and the surfactant is absent.

[00057] In one embodiment, the tablet further comprises an extragranular component.

[00058] In one embodiment, the extragranular component comprises: a microcrystalline cellulose; a disintegrant; optionally a surfactant; a lubricant; and optionally a coating; provided that at least one of the intragranular or extragranular component of the tablet contains a surfactant.

[00059] In one embodiment, a tablet described herein comprises: an extragranular microcrystalline cellulose in an amount of about 7.50% by weight of the tablet; an extragranular disintegrant in an amount of about 0.25% by weight of the tablet; a surfactant in an amount of about 1.50% by weight of the tablet; and an extragranular lubricant in an amount of about 0.75% by weight of the tablet.

[00060] In one embodiment, a tablet described herein comprises: an extragranular microcrystalline cellulose in an amount of about 7.50% by weight of the tablet; an extragranular disintegrant in an amount of about 0.25% by weight of the tablet; an extragranular surfactant in an amount that is about 1.50% by weight of the tablet; and an extragranular lubricant in an amount of about 0.75% by weight of the tablet.

[00061] In one embodiment, a tablet described herein comprises: an extragranular microcrystalline cellulose in an amount of from about 5% to about 10% by weight of the tablet; an extragranular disintegrant in an amount of from about 0.1% to about 0.5% by weight of the tablet; a surfactant in an amount of from about 1% to about 2% by weight of the tablet; and an extragranular lubricant in an amount of from about 0.5% to about 1% by weight of the tablet.

[00062] In one embodiment, the microcrystalline cellulose is a high compaction microcrystalline cellulose selected from Ceolus™ UF-711, Ceolus™ KG-1000, or KG-802. In one embodiment, the high compaction microcrystalline cellulose is Ceolus™ UF-711, the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and the surfactant is sodium lauryl sulfate. In one embodiment, the high compaction microcrystalline cellulose is Ceolus™ UF-711, the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, the surfactant is sodium lauryl sulfate, and the fluidifier is colloidal silicon dioxide. In one embodiment, the extragranular microcrystalline cellulose is high compaction microcrystalline cellulose, the extragranular disintegrant is croscarmellose sodium, the extragranular lubricant is magnesium stearate; and the extragranular surfactant is present and is sodium lauryl sulfate. In one embodiment, the high compaction microcrystalline cellulose is CeolusTM UF-711.

[00063] In one embodiment, the extragranular component consists essentially of: a microcrystalline cellulose; a disintegrant; optionally a surfactant; a lubricant; and optionally a coating; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[00064] In one embodiment, the tablets described herein comprise: an extragranular microcrystalline cellulose in an amount of about 7.50% by weight of the tablet; an extragranular disintegrant in an amount of about 0.25% by weight of the tablet; a surfactant in an amount of about 1.50% by weight of the tablet; and an extragranular lubricant in an amount of about 0.75% by weight of the tablet.

[00065] In one embodiment, a tablet described herein comprises: an extragranular microcrystalline cellulose in an amount of from about 5% to about 10% by weight of the tablet; an extragranular disintegrant in an amount of from about 0.1% to about 0.5% by weight of the tablet; a surfactant in an amount of from about 1% to about 2% by weight of the tablet; and an extragranular lubricant in an amount of from about 0.5% to about 1% by weight of the tablet.

[00066] In one embodiment, a tablet described herein comprises: an extragranular microcrystalline cellulose in an amount of from about 5% to about 10% by weight of the tablet; an extragranular disintegrant in an amount of from about 0.1% to about 0.5% by weight of the tablet; a surfactant in an amount of from about 1% to about 2% by weight of the tablet; an extragranular lubricant in an amount of from about 0.5% to about 1% by weight of the tablet; and (vii) optionally a fluidizer in an amount of less than about 2% by weight of the tablet.

[00067] In one embodiment, the microcrystalline cellulose is a CeolusTM UF-711 high compaction microcrystalline cellulose; the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and the surfactant is sodium lauryl sulfate.

[00068] In one embodiment, the tablets described herein comprise from about 300 mg to about 900 mg of tablet 1.

[00069] In one embodiment, the tablets described herein comprise 300 mg, 400 mg, 500 mg, 750 mg, or 900 mg. In one embodiment, the tablets described herein comprise 300 mg of tablet 1. In one embodiment, the tablets described herein comprise 900 mg of tablet 1.

[00070] In one embodiment, the dispersible tablets described herein comprise: about 30% to about 70% by weight of compound 1; filler; disintegrant; fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[00071] In one embodiment, the dispersible tablets described herein comprise: about 30% to about 70% by weight of compound 1; a filler; a disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[00072] In one embodiment, the tablets described herein comprise: about 30% to about 70% by weight of compound 1; a filler; less than about 2% by weight of disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[00073] In one embodiment, the dispersible tablets described herein comprise: about 60% by weight of Compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[00074] In a fourth aspect, there is provided a method of increasing the affinity of hemoglobin for oxygen in a patient comprising administering to the patient in need thereof a tablet described herein, wherein the tablet comprises a therapeutically effective amount of tablet 1. In one embodiment, the therapeutic amount of tablet 1 is 50 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg per day. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg.

[00075] In a fifth aspect, there is provided a method of treating a condition associated with oxygen deficiency in a patient having a condition associated with oxygen deficiency. In one embodiment, the method comprises administering to the patient in need thereof a tablet as described herein comprising a therapeutically effective amount of tablet 1. In one embodiment, the condition is sickle cell disease, cancer, a lung disorder such as interstitial pulmonary fibrosis, stroke, high altitude vertigo, an ulcer, a pressure ulcer, acute respiratory distress syndrome, acute lung injury, or a wound. In one embodiment, the condition is idiopathic pulmonary fibrosis. In one embodiment, the therapeutic amount of tablet 1 is 50 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 900 or 1500 mg once daily. In one embodiment, the therapeutic amount of tablet 1 is 600 mg per day. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg.

DETAILED DESCRIPTION DEFINITIONS

[00076] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used herein, the terms below have the following meanings unless otherwise specified. Any methods, devices, and materials similar or equivalent to those described herein may be used in practicing the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present description. All references herein are incorporated by reference in their entirety.

[00077] Headings used in this application are for reference purposes only and do not limit this description in any way.

[00078] It is noted here that as used in this specification and the appended claims, the singular forms "a" "an" and "the" and the like include plural referents unless the context clearly dictates otherwise.

[00079] The term "about" or "approximately" means within ± 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In one embodiment, about means ± 5%. In another embodiment, about means ± 4% of a given value or range. In another embodiment, about means ± 3% of a given value or range. In another embodiment, about means ± 2% of a given value or range. In another embodiment, about means ± 1% of a given value or range. In another embodiment, about means ± 0.5% of a given value or range. In another embodiment, about means ± 0.05% of a given value or range.

[00080] It should be understood that "w/w" refers to the percentage weight of an agent or excipient relative to the total weight of the tablet only. Percentage weights described herein do not include the weight of coatings as described herein unless explicitly stated as such.

[00081] As used herein "substantially pure" should refer to the ansolvate Form II of tablet 1 associated with about <10% either Form I and/or Form N, preferably <5% Form I and/or Form N; and most preferably it should refer to about <2% Form I and/or Form N. When the Form II polymorph of tablet 1 is formulated as a pharmaceutical composition, "substantially pure" should preferably refer to about <15% Form I and/or Form N of the polymorph of tablet 1; preferably the term should refer to about <10% Form I and/or Form N of the polymorph of tablet 1 and more preferably the term should refer to about <5% Form I and/or Form N of the polymorph of tablet 1. Form I of tablet 1 is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°2θ (each ±0.2°2θ); and Form N of tablet 1 is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48°2θ (each ±0.2°2θ).

[00082] "UF-711" as used in accordance with its ordinary and common usage in the art refers to a microcrystalline cellulose (MCC) (compendial name: microcrystalline cellulose, NF, Ph.Eur., JP - Chemical formula (C6HIO05)Π) marketed under the trade name CEOLUS®, grade UF-711. UF-711 typically has a powder/medium grade particle size of about 50 μm and a bulk density of about 0.2-0.26 g/cm3 (0.22 g/cm3). UF-711 is typically characterized by about 2% to about 6% loss on drying and has an angle of repose of about 42 degrees. UF-711 typically has a compactibility index of about 1.5. UF-711 as used herein includes microcrystalline cellulose produced under the CEOLUS UF brand name of Asahi Kasei and any microcrystalline cellulose having substantially similar or identical properties.

[00083] The term "administration" refers to introducing an agent into a patient. The therapeutic amount may be administered, which may be determined by the attending physician or the like. An oral form of administration is preferred. The related terms and phrases "administer" and "administration of" when used in connection with a compound or tablet (and grammatical equivalents) refer to both direct administration, which may be administration to a patient by a medical professional or through self-administration by the patient, and/or indirect administration, which may be the act of prescribing a drug. Administration involves delivering the drug to the patient.

[00084] The "crystalline ansolvate" of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Compound 1) is a solid crystalline form of the free base of tablet 1, such as, for example, Crystalline Form I, Crystalline Form II or Crystalline Form N as disclosed in International Application No. WO 2015/120133 A1 (see, for example, pages 3-9 and pages 51-54), the disclosure of which is incorporated herein by reference in its entirety. Compound 1 (also known as "voxelotor") has the structure:

[00085] "Characterization" refers to obtaining data which can be used to identify the solid form of a compound, for example, to identify whether the solid form is amorphous or crystalline and whether it is unsolvated or solvated. The process by which solid forms are characterized involves analyzing data collected on the polymorphic forms in a manner that allows one skilled in the art to distinguish a solid form from other solid forms containing the same material. The chemical identity of solid forms can often be determined with solution state techniques such as 13C NMR or 1H NMR. While these can help identify a material, and a solvent molecule for a solvate, such solution state techniques themselves cannot provide information about the solid state. There are, however, solid-state analytical techniques that can be used to provide information about solid-state structure and differentiate between polymorphic solid forms, such as single-crystal X-ray diffraction, X-ray powder diffraction (XRPD), solid-state nuclear magnetic resonance (SS-NMR), and infrared and Raman spectroscopy, and thermal techniques such as differential scanning calorimetry (DSC), solid-state 13C-NMR, thermogravimetry (TG), melting point, and hot-stage microscopy.

[00086] To "characterize" the solid form of a compound, one may, for example, collect XRPD data on the solid forms of the compound and compare the XRPD peaks of the forms. For example, the collection of peaks that distinguish, for example, Form II from other known forms is a collection of peaks that can be used to characterize Form II. Those skilled in the art will recognize that multiple forms exist, including multiple forms using the same analytical technique to characterize solid forms. Additional peaks could also be used, but are not required, to characterize the form and comprise an entire diffraction pattern. Although all peaks within an entire XRPD pattern can be used to characterize a given form, a subset of that data can, and typically is, used to characterize the form.

[00087] An XRPD pattern is an x-y plot with diffraction angle (typically °2θ) on the x-axis and intensity on the y-axis. The peaks within this pattern can be used to characterize a solid crystalline form. As with any data measurement, there is variability in XRPD data. Data are often represented only by the diffraction angle of the peaks rather than including the intensity of the peaks since the peaks can be particularly sensitive to sample preparation (e.g., particle size, moisture content, solvent content, and preferred orientation effects that influence sensitivity), such that samples of the same material prepared under different conditions may yield slightly different patterns; this variability is generally greater than the variability in diffraction angles. Diffraction angle variability can also be sensitive to sample preparation. Other sources of variability come from instrument parameters and processing of the raw X-ray data: different X-ray instruments operate using different parameters and these can lead to slightly different XRPD patterns from the same solid form, and similarly different software packages process X-ray data differently and this also leads to variability. These and other sources of variability are known in pharmaceutical engineering. Due to these sources of variability, it is common to attribute a variability of ±0.2° 2θ to the diffraction angles in XRPD patterns.

[00088] The term "dose" or "dosage" refers to the total amount of active materials (e.g., compound 1 disclosed herein) administered to a patient in a single day (24-hour period). The desired dose may be administered once daily. Alternatively, the desired dose may be administered in one, two, three, four, or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms "dose" and "dosage" are used interchangeably herein.

[00089] As defined herein, where the mass of a compound 1 is specified, for example, 300 mg or 900 mg of tablet 1, wherein the amount corresponds to the mass of tablet 1 in its free base form in a single tablet.

[00090] The term "hemoglobin" as used herein refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle cell hemoglobin (HbS).

[00091] The term "sickle cell disease" refers to diseases mediated by sickle hemoglobin (HbS) that result from a single point mutation in hemoglobin (Hb). Sickle cell diseases include sickle cell anemia, sickle hemoglobin C disease (HbSC), sickle beta-plus thalassemia (HbS/β), and sickle beta-zero thalassemia (HbS/β0).

[00092] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or agent that when administered to a patient suffering from a condition will have the intended therapeutic effect, e.g., alleviating, ameliorating, palliating, or eliminating one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur through the administration of one dose, and may occur only after the administration of a series of doses, and may be administered in one dosage form or multiples of the same dose. For example, 900 mg of the drug may be administered in a single 900 mg tablet or three 300 mg tablets. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating hemoglobin S-related disorders, refers to an amount of the agent that alleviates, ameliorates, palliates, or eliminates one or more manifestations of the hemoglobin S-related disorders in the patient.

[00093] The term "pharmaceutically acceptable" refers to generally safe and non-toxic for in vivo, preferably human, administration.

[00094] The term "patient" refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein may be a human. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or young adult. In some embodiments, the patient is from about 9 months to about 11 years of age. In some embodiments, the patient is from about 9 months to about 11 years of age and has difficulty swallowing.

[00095] "Treatment", "treating" and "treating" are defined as acting upon a disease, disorder or condition with an agent to reduce or ameliorate the harmful or any other undesirable effects of the disease, disorder or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient and includes: (a) reducing the risk of the condition occurring in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) preventing the condition from developing, and/or (c) alleviating the condition, i.e., causing regression of the condition and/or alleviating one or more symptoms of the condition. For the purpose of treating sickle cell disease, beneficial or desired clinical outcomes include, but are not limited to, multi-lineage hematologic improvement, reduction in the number of blood transfusions required, reduction in infections, reduced bleeding, and the like. For the purpose of treating interstitial pulmonary fibrosis, beneficial or desired clinical outcomes include, but are not limited to, reduction of hypoxia, reduction of fibrosis, and the like.

[00096] As used herein, "% w/w" refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component 1 is present in an amount of 50% in a 100 mg composition, component 1 is present in an amount of 50 mg. In some embodiments, the composition refers to a formulation as described herein or a tablet as described herein.

[00097] As used herein, "rapidly disintegrates" or "rapidly disintegrating" refers to, in some embodiments, disintegration (of, e.g., a tablet as described herein) in a small amount of liquid in less than about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute. In some embodiments, the dispersible tablet disintegrates in a liquid in less than 1 minute. In some embodiments, a dispersible tablet disintegrates in less than about 10 mL, less than about 8 mL, less than about 7 mL, less than about 6 mL, or less than about 5 mL of liquid. In some embodiments, a dispersible tablet disintegrates in about 5 mL to about 30 mL, about 5 mL to about 25 mL, or about 5 mL to about 20 mL of liquid. In some embodiments, a dispersible tablet disintegrates in less than about 30 mL or less than about 25 mL of liquid.

TABLETS

[00098] Many small molecule active pharmaceutical ingredients (APIs) can be formulated into low-potency tablets because the physicochemical properties of the excipients used in the formulation dominate the properties of the solid composition rather than the physicochemical properties of the API. As drug loading increases the physicochemical properties of the drug, the drug substance becomes progressively dominant in the tablet manufacturing process. Because APIs can have a broad spectrum of physicochemical properties and are not selected based on the physicochemical properties that favorably contribute to the manufacturability and stability of a formulation, it is quite common for the physicochemical properties of the API to present the greatest obstacles to creating a high-potency formulation that works.

[00099] Compound 1 is a BCS II compound, where its solubility is the primary biopharmaceutical factor limiting absorption. Compound 1 exists in a form as a crystalline ansolvate form characterized by at least two, three, or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ) (see, e.g., PCT Application Publication No. WO 2015/120133 A1, incorporated herein by reference in its entirety and for all purposes). This form may also be hereinafter referred to as Form II. The physicochemical properties of tablet 1, including its Form II, are not sufficiently conductive (compared to other drug substances in the formulation) to produce a high dosage form of tablet 1. For example, Form II of tablet 1 is considered to be poorly water soluble, lipophilic and has a relatively low melting point. The bulk density of Form II of tablet 1 is considered to be low and its flowability is considered to be poor. Upon crushing, the flowability decreases. The compression characteristics of Form II of tablet 1 are also considered to be poor, exhibiting low tensile strength that does not increase significantly with compression force. Form II of tablet 1 is also prone to sticking to steel surfaces, such as in tablet processing equipment.

[000100] Furthermore, another crystalline ansolvate form of tablet 1, referred to as Form N, is known. Form N has an enantiotropic relationship with Form II, with a transition temperature approximately in the range of 30-40°C. Therefore, at temperatures (e.g. storage) below 40°C, e.g. at 25°C, compound 1 is more thermodynamically stable as Form II and at temperatures above 40°C, e.g. at 50°C, compound 1 is more thermodynamically stable as Form N. In order to design tablets containing compound 1, the physicochemical property limitations of tablet 1 above and the high dose requirements need to be accommodated while ensuring that the tablets have dissolution properties that lead to a therapeutic effect.

[000101] Described herein are tablets and dispersible tablets comprising compound 1. It is also contemplated that the components of such tablets may also be comprised in a pharmaceutical composition or formulation as described herein. Such compositions may be precursors to the tablets as described herein or may be other formulations known in the art, including but not limited to sachets.

[000102] In one embodiment, the tablets described herein comprise compound 1 as a substantially pure crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In another embodiment, the tablets described herein consist essentially of tablet 1 as a crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In another embodiment, the crystalline ansolvate form of tablet 1 is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).

[000103] In one embodiment, the tablets described herein comprise compound 1 that is 95 wt % Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ) and 5 wt % of compound 1 is Form I and/or Form N. In certain embodiments, the w/w of Form II to Form I/Form N is 99%/1%; 98%/2%; 97%/3%; 96%/4%, 95%/5%; 94%/6%; 93%/7%; 92%/8%, 91%/9%, or 90%/10%. In certain embodiments, the w/w of Form II to Form I/Form N is 99.5%/0.5%; 99.6/0.4%; 99.7%/0.3%; 99.8%/0.2%; 99.9%/0.1%; or 99.95%/0.05%.

[000104] In one embodiment, the tablets described herein comprise compound 1 that is at least 95% by weight of Form II characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 96% by weight of Form II characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 97% by weight of Form II characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 98% by weight of Form II characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99% by weight of Form II characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).

[000105] In one embodiment, the tablets described herein comprise compound 1 that is at least 95% by weight of Form II characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 96% by weight of Form II characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 97% by weight of Form II characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 98% by weight of Form II characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99% by weight of Form II characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).

[000106] In one embodiment, the tablets described herein comprise compound 1 that is at least 95% by weight of Form II characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 96% by weight of Form II characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 97% by weight of Form II characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 98% by weight of Form II characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99% by weight of Form II characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).

[000107] In one embodiment, the tablets described herein comprise compound 1 that is at least 95% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 96% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 97% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 98% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99.5% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ). In one embodiment, the tablets described herein comprise compound 1 that is at least 99.9% by weight of Form II characterized by X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ).

[000108] The tablets described herein may comprise compound 1 (e.g., Form I, Form II, or Form N) in an amount of about: 40% to about 80%; 40% to about 70%; 40% to about 60%; 50% to about 80%; 50% to about 70%; or 50% to about 65% w/w. In one embodiment, the tablets described herein comprise about 50% to about 70% or about 50% to about 65% w/w of tablet 1. The tablets described herein may comprise at least about: 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% w/w of tablet 1. The tablets described herein may comprise at least about: 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (±2%) w/w of tablet 1. The tablets described herein may comprise at least about: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (±5%) w/w of tablet 1. In one embodiment, the tablets described herein include about: 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% w/w of tablet 1. In one embodiment, the tablets described herein include about: 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (±2%) w/w of tablet 1. In one embodiment, the tablets described herein include about: 25%, 30%, or 35% w/w of tablet 1. In one embodiment, the tablets described herein include about: 25%, 30%, or 35% (±2%) w/w of tablet 1. In one embodiment, the tablets described herein include about: 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (±5%) w/w of tablet 1. In some embodiments, the tablets described herein comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about: 20% to about 40%; 30% to about 80%; 30% to about 70%; or 30% to about 60% w/w. In some embodiments, the tablets described herein comprise compound 1 Form II in an amount of from about 30% to about 70% w/w. In some embodiments, the tablets described herein comprise compound 1 Form II in an amount of from about 40% to about 70% w/w.

[000109] The tablets described herein may comprise compound 1 (e.g. Form I, Form II or Form N) in an amount of about: 300 mg, 450 mg, 600 mg, 750 mg, 900 mg, 1200 mg, 1500 mg or 2000 mg. The tablets described herein may comprise compound 1 (e.g. Form I, Form II or Form N) in an amount of at least about: 300 mg, 450 mg, 600 mg, 750 mg, 900 mg, 1200 mg, 1500 mg or 2000 mg. The tablets described herein may comprise compound 1 (e.g. Form I, Form II or Form N) in an amount of about: 300 mg, 750 mg or 900 mg. The tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about: 300 mg to about 2000 mg; 600 mg to about 2000 mg; or 900 mg to about 1500 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 50 mg to about 2000 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 50 mg to about 900 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 300 mg to about 1500 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g., Form I, Form II, or Form N) in an amount of from about 900 mg to about 1500 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g., Form I, Form II, or Form N) in an amount of from about 100 mg to about 600 mg.

[000110] In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 50 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 100 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 200 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 300 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g. Form I, Form II, or Form N) in an amount of about 450 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g., Form I, Form II, or Form N) in an amount of about 600 mg. In some embodiments, the tablets described herein can comprise compound 1 (e.g., Form I, Form II, or Form N) in an amount of about 900 mg.

[000111] In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 50 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 100 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 300 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 450 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 600 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 900 mg. In some embodiments, the tablets described herein can comprise compound 1 Form II in an amount of about 1500 mg.

[000112] The tablet of the present disclosure comprises excipients such as pharmaceutically acceptable filler (also known as diluent), disintegrant, lubricant and surfactant (also known as a wetting agent). In some embodiments, the tablets described herein further comprise a fluidifier. Excipients may have two or more functions in a pharmaceutical composition. The characterization herein of a specific excipient as having a certain function, e.g., filler, disintegrant, etc., should not be construed as limiting that function. Additional information on excipients can be found in standard reference works such as Handbook of Pharmaceutical Excipients, 3rd ed. (Kibbe, ed. (2000), Washington: American Pharmaceutical Association). While it is often possible for formulators skilled in the art to interchange a functional excipient in a tablet as an alternative in the tablet of the present disclosure, in some embodiments, a filler (diluent) has a specific need to be highly compactable (also referred to herein as highly compressible). The high compactibility of said excipients can achieve a high drug loading in a single tablet of reasonable size and at suitably high tensile strength to yield a robust tablet that survives pharmaceutical processing, packaging and handling. An example of said fillers is high compressibility grades of microcrystalline cellulose (MCC). In one embodiment, the drug loading of tablet 1 can be maximized by including a highly compactable excipient as described herein.

[000113] Specialty grades of highly compactable MCC are commercially available, such as Ceolus™ UF-711, KG-802, and KG-1000 (e.g., from Asahi Kasei). In one embodiment, the highly compactable MCC is Ceolus™ UF-711. In one embodiment, the highly compactable MCC is KG-802 or KG-1000. In one embodiment, the highly compactable MCC is KG-802. In one embodiment, the highly compactable MCC is KG-1000. In one embodiment, the highly compactable MCC is Ceolus™ UF-711 or an equivalent highly compactable MCC. In one embodiment, the highly compactable MCC is KG-802 or KG-1000 or an equivalent highly compactable MCC. In one embodiment, the highly compactable MCC is KG-802 or an equivalent highly compactable MCC. In one embodiment, the highly compressible MCC is KG-1000 or an equivalent highly compressible MCC.

[000114] In one embodiment, the highly compactable MCC is present in about: 20% to about 50%; 20% to about 40%; 20 to about 35%; 20% to about 30%; 25% to about 40%; 25% to about 35%; 30% to about 40%; or 30% to about 35% w/w. In one embodiment, the highly compactable MCC is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w. In one embodiment, the highly compactable MCC is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±2%). In one embodiment, the highly compactable MCC is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±5%).

[000115] In one embodiment, the highly compactable MCC is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w. In one embodiment, the highly compactable MCC is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±2%). In one embodiment, the highly compactable MCC is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±5%).

[000116] MCC has unique particle morphology that can give increased compressibility on a unit mass basis. In one embodiment, the tablets described herein comprise UF-711 where the UF-711 increases the high drug loading of the tablet 1 compared to tablets without UF-711. Said tablets have high tablet hardness and lack the difficulty in flowability typically found for specialty grades of MCC with high compressibility. The increases in flowability can increase reliability and scalability when using dry granulation methods described herein on a commercial manufacturing scale. It has been found, inter alia, that the highly compactable grade of MCC UF-711 also acts as a binder to hold the granules together. In one embodiment, the use of MCC UF-711 obviates the need for an additional excipient specifically with the binder function, such as hypromellose.

[000117] A comparison of MCC grades is available from the Asahi Kasei CeolusTM website. Compactibility (used interchangeably with the term compressibility) refers to the degree of plastic deformation that a material undergoes upon the imposition of a mechanical load. Under increasing mechanical loads, such as in a hydraulic tablet press, a compressible material will continue to increase in density as the volume occupied by a given mass is reduced under the force of the load. Compressible materials yield increasing tensile strength (tablet hardness) as the force of the mechanical load increases. Incompressible materials reach a plateau of hardness even at low loading forces, and the resulting compact or tablet will lack intergrity and will turn to powder rather than remaining intact as a discrete hard compacted mass. "Highly compactable" grades of MCC are considered to be those that yield greater compactibility than PH-101 or PH-102, common MCC grades.

[000118] The compressibility of MCC grade UF-711 is 50% greater than that of conventional MCC grade PH-101. Furthermore, using angle of repose as an indicator of flow properties, grade UF-711 has better flow than PH-101, and flows equally well as PH-102, despite having increased compactibility than either PH-101 or PH-102. This is unexpected since high compressibility grades of MCC often have worse flow properties in exchange for increased compactibility. These two properties of UF-711 were surprisingly useful for high drug loading blends of Compound 1 and tablets as they facilitate high tablet hardness. In one embodiment, the compactibility of UF-711 allows for greater drug loading than would otherwise be expected. In another embodiment, the tablets described herein include pharmaceutical excipients such as filler(s) and optionally with a fluidizer and/or binding agent to prepare a mixture having compressibility and fluidity properties similar to those of UF-711 for use in preparing tablets with high tablet strength 1.

[000119] In some embodiments, other grades of microcrystalline cellulose (MCC) known in the art and commercially available can be used. In some embodiments, microcrystalline cellulose (MCC) that has lower compactability than UF-711 can be used. In some embodiments, the microcrystalline cellulose is PH-101, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-310, or PH-302. In some embodiments, the microcrystalline cellulose is PH-101, PH-102, PH-301, PH-302, PH-200, or UF-702. Other grades of microcrystalline cellulose include various grades of MCC Vivapur® and Emcocel®.

[000120] In some embodiments, the filler is microcrystalline cellulose, lactose monohydrate, starch, mannitol, sorbitol, dextrose, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray dried lactose, pregelatinized starch, compressible sugar such as Di-Pac® (Amstar), hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, sucrose-based diluents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride; inositol, bentonite, or combinations thereof.

[000121] In one embodiment, the filler is present in about: 20% to about 50%; 20% to about 40%; 20 to about 35%; 20% to about 30%; 25% to about 40%; 25% to about 35%; 30% to about 40%; or 30% to about 35% w/w. In one embodiment, the filler is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w. In one embodiment, the filler is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±2%). In one embodiment, the filler is present in an amount of about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±5%).

[000122] In one embodiment, the filler is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w. In one embodiment, the filler is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±2%). In one embodiment, the filler is present in an amount of at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w/w (±5%).

[000123] Other functional excipients may include disintegrants, lubricants, surfactants, and binders. In one example, said excipients include croscarmellose sodium, magnesium stearate, and sodium lauryl sulfate, respectively. In one embodiment, said excipients include croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and sodium lauryl sulfate. Other useful excipients include those described herein, such as a fluidifier. In one embodiment, the tablets described herein comprise a low percentage content (e.g., about <1, 2, 3, 4, 5, or 10%) of one or more excipients on a mass basis.

[000124] In certain embodiments, the formulations may also include a disintegrant. A "disintegrant" as used herein refers to an excipient that can rupture or disintegrate the pharmaceutical dosage form when it comes into contact with, for example, gastrointestinal fluid. Suitable disintegrants include, either individually or in combination, starches including pregelatinized starch and sodium starch glycolate; clays; magnesium aluminosilicates; cellulose-based disintegrants such as powdered cellulose, microcrystalline cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin, and tragacanth gums; colloidal silicon dioxide; and the like. In one embodiment, the disintegrant is carmellose sodium. In one embodiment, the disintegrant is powdered cellulose, microcrystalline cellulose, methyl cellulose, or low substituted hydroxypropyl cellulose, or a combination thereof. In one embodiment, the disintegrant is carmellose, carmellose calcium, carmellose sodium, or croscarmellose sodium, or a combination thereof. In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the disintegrant is colloidal silicon dioxide.

[000125] In one embodiment, the disintegrant is present in an amount of about: 0% to about 10%; 0% to about 5%; 0.5% to about 5%; 0.5% to about 2%; 0.75% to about 2%; 0.75% to about 1.5%; 1% to about 5%; or 1% to about 1.5% w/w. In one embodiment, the disintegrant is present in an amount of about 0.25% to about 10%; 0.25% to about 5%; 0.25% to about 4%; 0.25% to about 3.5%; 0.25% to about 3%; 0.25% to about 2.5% w/w, 0.25% to about 2% w/w, or about 0.25% to about 1.5% w/w. In one embodiment, the disintegrant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w. In one embodiment, the disintegrant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (±0.1%) w/w. In one embodiment, the disintegrant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (±0.2%) w/w. In one embodiment, the disintegrant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w. In one embodiment, the disintegrant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (±0.1%) w/w. In one embodiment, the disintegrant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (±0.2%) w/w. In said embodiments, the disintegrant can be croscarmellose sodium.

[000126] In certain embodiments, the formulations may include surfactants (also known as wetting agents). Surfactants are typically selected to maintain the drug or drugs in close association with water, a condition believed to improve the bioavailability of the composition. Non-limiting examples of surfactants that may be used as wetting agents include, either individually or in combination, quaternary ammonium compounds, e.g., benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride; sodium dioctyl sulfosuccinate; polyoxyethylene alkylphenyl ethers, e.g., nonoxynol 9, nonoxynol 10, and octoxynol 9; poloxamers (block copolymers of polyoxyethylene and polyoxypropylene); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20, steareth-2, steareth-10, steareth-20, steareth-100 and polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, for example polyoxyethylene (20) stearate, polyoxyethylene (40) stearate and polyoxyethylene (100) stearate; sorbitan esters; polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80; propylene glycol fatty acid esters, for example propylene glycol laurate; sodium lauryl sulfate; fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate; glyceryl fatty acid esters, for example glyceryl monooleate, glyceryl monostearate and glyceryl palmitostearate; sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; tyloxapol; and the like.

[000127] In one embodiment, the surfactant is sodium lauryl sulfate (SLS). In one embodiment, 1.5% SLS was used. In vitro dissolution and in vivo bioavailability studies in beagles demonstrated that where 1.5% SLS was included, complete dissolution of Form II of tablet 1 occurred in vitro, and comparable bioavailability in beagles was achieved relative to formulations lacking high lubricant levels. Thus, the binding properties of Form II of tablet 1 can be minimized and/or eliminated with a high level (e.g., greater than about 0.5, 1, 3, or 5%) of lubricant magnesium stearate, and the potential impact of the high lubricant level on drug release was overcome through the use of a commonly used surfactant, SLS, at 1.5% w/w, which is at an acceptable concentration.

[000128] In one embodiment, the surfactant is present in an amount of about: 0.5% to about 5%; 0.5% to about 2.5%; 0.5% to about 2%; 1% to about 5%; 1% to about 2.5%; or 1% to about 1.5% w/w. In one embodiment, the surfactant is present in an amount of about: 0% to about 5%; 0% to about 2%; 0.5% to about 3.5%; 0.5% to about 3%; 0.5% to about 2%; or 0.5% to about 1.5% w/w. In one embodiment, the surfactant is present in an amount of about 1% to about 2%. In one embodiment, the surfactant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w. In one embodiment, the surfactant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.1%). In one embodiment, the surfactant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.2%). In one embodiment, the surfactant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w. In one embodiment, the surfactant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.1%). In one embodiment, the surfactant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.2%). In one embodiment, the surfactant is present in an amount of less than about 5%, less than about 4%, less than about 3%, or less than about 2%. In said embodiments, the surfactant can be SLS. In some embodiments, the formulations described herein do not include a surfactant.

[000129] In certain embodiments, the formulation may contain a lubricant. Lubricants may reduce friction between a tabletting mix and tabletting equipment during compression of tablet formulations. Exemplary lubricants include, either individually or in combination, glyceryl behenate, stearic acid, and salts thereof, including magnesium, calcium, and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and the like. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is magnesium stearate present in an amount of from about 1.75% to about 2.75% by weight of the tablet. In one embodiment, the lubricant is sodium benzoate, sodium acetate, or sodium fumarate. In one embodiment, the lubricant is polyvinyl alcohol. In one embodiment, the lubricant is sodium lauryl sulfate or magnesium lauryl sulfate.

[000130] In one embodiment, the lubricant is present in an amount of about: 0.5% to about 5%; 0.5% to about 2.5%; 0.5% to about 2%; 1% to about 5%; 1% to about 2.5%; 1% to about 2%; 1.75% to about 2.75%; or 2% to about 2.5% w/w. In one embodiment, the lubricant is present in an amount of about: 0.5% to about 5%; 0.5% to about 2.75%, or about 0.5% to about 2%. In one embodiment, the lubricant is present in an amount of about 1.75% to about 2.75%. In one embodiment, the lubricant is present in an amount of about 0.5% to about 2.75%. In one embodiment, the lubricant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w. In one embodiment, the lubricant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.1%). In one embodiment, the lubricant is present in an amount of about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.2%). In one embodiment, the lubricant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w. In one embodiment, the lubricant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.1%). In one embodiment, the lubricant is present in an amount of at least about: 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, or 5% w/w (±0.2%). In the aforementioned embodiments, the lubricant may be magnesium stearate.

[000131] In one embodiment, tablets comprising Form II of tablet 1 comprise a higher level of lubricant (e.g., greater than about 1%) compared to standard tablets. The higher levels of lubricant magnesium stearate may increase the hydrophobicity of the pharmaceutical preparations.

[000132] In certain embodiments, the formulation may include a binder. Binding agents or adhesives are useful excipients, particularly where the composition is in the form of a tablet. Said binding agents or adhesives should impart sufficient cohesion to the mixture being tableted to permit normal processing operations such as sizing, lubricating, compression, and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Exemplary binding agents and adhesives include, individually or in combination, acacia, tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC or hypromellose), hydroxypropylcellulose, hydroxyethylcellulose, and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and alginic acid salts, e.g. sodium alginate; magnesium aluminosilicates; bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum; polysaccharide acids; and the like.

[000133] In one embodiment, the one or more binding agents, if present, comprise about 0.1% to about 25%, for example about 0.1% to about 10%, about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition. In one embodiment, the one or more binding agents, if present, comprise about: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w. In one embodiment, UF-711 is used at a weight percentage disclosed herein and provides sufficient granule binding properties to maintain intact compacts throughout granule milling. Accordingly, in specific embodiments, the tablets described herein include UF-711 in an amount wherein UF-711 acts as a filler and a binder.

[000134] In certain embodiments, the formulation may contain a fluidizer. Fluidizers are often used to improve flow properties and reduce static in a tablet blend. Exemplary fluidizers include, either individually or in combination, colloidal silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate, and metal stearates. In some embodiments, the fluidizer is talc. In some embodiments, the fluidizer is colloidal silicon dioxide.

[000135] In one embodiment, the one or more fluidizers, if present, comprise about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition. In one embodiment, the one or more fluidizers, if present, comprise about: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w. In one embodiment, the one or more fluidizers, if present, comprise about 0.01% to about 2% w/w. In some embodiments, the fluidizer is no more than about 9%, 8%, 7%, 6%, or 5% w/w. In some embodiments, the fluidizer is less than about 3% w/w, 2.5% w/w, or 2% w/w. In some embodiments, the fluidizer is less than about 2% w/w. In some embodiments, the fluidizer is in an amount of about 0.75% by weight of the tablet. In one embodiment, the fluidizer is talc and colloidal silicon dioxide, either individually or in combination. In specific embodiments, the tablets described herein do not comprise a fluidizer or flow aid. In certain embodiments, adequate fluidity of the mixture for the purposes of feeding the compaction zone in, for example, a pharmaceutical cylindrical compaction dry granulation machine is achieved in the absence of a fluidizer or flow aid. In one embodiment, the fluidifier is added to both the intragranular component and the extragranular component or to one of the granular components.

[000136] Other excipients such as colorants (coloring agents), coating polymers, flavors (flavoring agents) and sweeteners are known in the pharmaceutical art and can be used in compositions of the present disclosure. In one embodiment, the tablets described herein include a coating surrounding the core described herein comprising compound 1. Tablets can be coated using formulations known in the art, such as, for example, excipients such as talc, polyvinyl alcohol and PEG (e.g., PEG 4000 and PEG 6000). In some embodiments, the coating polymer can be hydroxypropyl methyl cellulose (HPMC). When coated, the tablets comprise a core that is coated with a non-functional film or release-modifying enteric or coating.

[000137] In some embodiments, the tablets described herein comprise a sweetener (also known as a sweetening agent). In some embodiments, the sweetener may improve the palatability of the tablet by reducing bitterness and thereby improving the acceptability of the formulation to patients, such as a patient from about 9 months to about 11 years of age. Non-limiting examples of a sweetener are sucrose, xylitol, maltitol, mannitol, sorbitol, sucralose, sodium saccharin, acesulfame potassium, and others known to those of skill in the art. In some embodiments, one or more sweeteners may be used. In some embodiments, the sweetener is sucralose.

[000138] In some embodiments, the one or more sweeteners, if present, comprise about 2% to about 20%, or about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 3%, by weight of the composition. In one embodiment, the one or more sweeteners, if present, comprise about: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w.

[000139] Also provided herein are tablets as described herein further comprising a flavoring agent. The flavoring agent may enhance the taste of the tablet to increase its palatability to patients. A flavoring agent includes, but is not limited to, grape, orange, cherry, mango, and tropical. In some embodiments, a flavoring agent is of an artificial origin, a natural origin, or a combination of natural and artificial origins. In some embodiments, one or more flavoring agents may be used. In some embodiments, the flavoring agent is an artificial grape flavor.

[000140] In some embodiments, the one or more flavoring agents, if present, comprise about 1% to about 5%, or about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 3%, by weight of the composition. In one embodiment, the one or more flavoring agents, if present, comprise about: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w.

[000141] Also provided herein are tablets as described herein further comprising a coloring agent. Coloring agents may be used to improve the appearance of the tablet. Non-limiting examples of a coloring agent are dyes and pigments, including but not limited to iron oxide pigment. In some embodiments, the coloring agent is iron oxide yellow.

[000142] In some embodiments, the one or more coloring agents, if present, comprise about 0% to about 1%, 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 3%, by weight of the composition. In one embodiment, the one or more coloring agents, if present, comprise about: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w.

[000143] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 60% by weight of compound 1; a high compaction microcrystalline cellulose as described herein; optionally a disintegrant as described herein; a lubricant as described herein; optionally a surfactant as described herein; and optionally a binder as described herein; wherein the weight percentage is relative to the total weight of the tablet.

[000144] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 60% by weight of compound 1; a high compaction microcrystalline cellulose as described herein; optionally a disintegrant as described herein; a lubricant as described herein; optionally a surfactant as described herein; optionally a binder as described herein; and optionally a fluidifier as described herein; wherein the weight percentage is relative to the total weight of the tablet.

[000145] In one embodiment, the granular component comprises:

[000146] a high compaction microcrystalline cellulose as described herein in an amount of about 27.50% by weight of the tablet; a disintegrant as described herein is present in an amount of about 1% by weight of the tablet; and a lubricant as described herein is present in an amount of about 1.50% by weight of the tablet.

[000147] In one embodiment, the granular component comprises: high compaction microcrystalline cellulose as described herein in an amount of about 27.50 ± 2% by weight of the tablet; a disintegrant as described herein in an amount of about 1 ± 0.2% by weight of the tablet; and a lubricant as described herein in an amount of about 1.50 ± 0.2% by weight of the tablet.

[000148] In one embodiment, the intragranular component comprises: high compaction microcrystalline cellulose as described herein in an amount of 27% ± 2% by weight of the tablet; disintegrant as described herein in an amount of 1% ± 0.2% by weight of the tablet; lubricant as described herein in an amount of 1.5% ± 0.2% by weight of the tablet; and fluidifier in an amount of 0.5% ± 0.2% by weight of the tablet.

[000149] The high compaction microcrystalline cellulose of said granular components may be CeolusTM UF-711. The disintegrant of said granular components may be croscarmellose sodium. The lubricant of said granular components may be magnesium stearate. Compound 1 of said granular components may be a substantially pure form of crystalline ansolvate characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), preferably. Compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ) and 5% in Form I and/or Form N; and surfactant is absent.

[000150] In some embodiments, the high compaction microcrystalline cellulose is Ceolus™ UF-711; the disintegrant is croscarmellose sodium; the lubricant is magnesium stearate; Compound 1 is a substantially pure crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92°2θ (each ±0.2°2θ); and the surfactant is absent.

[000151] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component consists essentially of: about 60% by weight of compound 1; a high compaction microcrystalline cellulose as described herein; optionally a disintegrant as described herein; a lubricant as described herein;

[000152] optionally a surfactant as described herein; and optionally a binder as described herein; wherein the weight percentage is relative to the total weight of the tablet.

[000153] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component consists essentially of: about 60% by weight of compound 1; a high compaction microcrystalline cellulose as described herein; optionally a disintegrant as described herein; a lubricant as described herein; optionally a surfactant as described herein; optionally a binder as described herein; and optionally a fluidifier; wherein the weight percentage is relative to the total weight of the tablet.

[000154] In one embodiment, the granular component comprises: a high compaction microcrystalline cellulose as described herein in an amount of about 27.50% by weight of the tablet; a disintegrant as described herein in an amount of about 1% by weight of the tablet; and a lubricant as described herein in an amount of about 1.50% by weight of the tablet; and optionally about 1.5% by weight of a surfactant as described herein.

[000155] In one embodiment, the granular component comprises: the amount of high compaction microcrystalline cellulose is about 27.50% by weight of the tablet; the amount of disintegrant is about 1% by weight of the tablet; the amount of lubricant is about 1.50% by weight of the tablet; and optionally, the amount of surfactant is about 1.5% by weight of the tablet.

[000156] In one embodiment, the intragranular component comprises: a high compaction microcrystalline cellulose as described herein in an amount of about 27% by weight of the tablet; a disintegrant as described herein in an amount of about 1% by weight of the tablet; and a lubricant as described herein in an amount of about 1.50% by weight of the tablet; optionally about 1.5% by weight of a surfactant as described herein; and optionally about 0.5% by weight of a fluidifier as described herein.

[000157] In another embodiment, the granular component comprises: a high compaction microcrystalline cellulose as described herein in an amount of about 27.50 ± 2% by weight of the tablet; a disintegrant as described herein is 1 ± 0.2% by weight of the tablet; a lubricant as described herein is 1.50 ± 0.2% by weight of the tablet; and the surfactant as described herein is absent.

[000158] In another embodiment, the intragranular component comprises: a high compaction microcrystalline cellulose as described herein in an amount of about 27% ± 2% by weight of the tablet; a disintegrant as described herein is 1 ± 0.2% by weight of the tablet; a lubricant as described herein is 1.50 ± 0.2% by weight of the tablet; the surfactant as described herein is absent; and optionally about 0.5% by weight of a fluidifier as described herein.

[000159] The high compaction microcrystalline cellulose of said granular components may be CeolusTM UF-711. The disintegrant of said granular components may be croscarmellose sodium. The lubricant of said granular components may be magnesium stearate. Compound 1 of said granular components may be a substantially pure crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), preferably Compound 1 is 95% in crystalline ansolvate form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ) and 5% in Form I and/or Form N and surfactant is absent.

[000160] In certain embodiments, the tablets described herein further comprise an extragranular component, which comprises: a microcrystalline cellulose as described herein; a disintegrant as described herein; optionally a surfactant as described herein; a lubricant as described herein; and optionally a coating as described herein; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[000161] In certain embodiments, the tablets described herein further comprise an extragranular component, which comprises: a microcrystalline cellulose as described herein; a disintegrant as described herein; optionally a surfactant as described herein; a lubricant as described herein; optionally a coating as described herein; and optionally a fluidifier as described herein; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[000162] In certain embodiments, the extragranular components described herein do not include Compound 1.

[000163] In one embodiment, the extragranular component comprises: an amount of extragranular microcrystalline cellulose as described herein of about 7.50% by weight of the tablet; an amount of extragranular disintegrant as described herein of about 0.25% by weight of the tablet; a surfactant as described herein in an amount of about 1.50% by weight of the tablet; and an amount of extragranular lubricant as described herein of about 0.75% by weight of the tablet.

[000164] In one embodiment, the extragranular component comprises: an amount of extragranular microcrystalline cellulose as described herein of about 7.50% by weight of the tablet; an amount of extragranular disintegrant as described herein of about 0.25% by weight of the tablet; a surfactant as described herein in an amount of about 1.50% by weight of the tablet;

[000165] an amount of extragranular lubricant as described herein of about 0.75% by weight of the tablet; and optionally a fluidifier.

[000166] In one embodiment, the extragranular component comprises: an extragranular microcrystalline cellulose in an amount of from about 5% to about 10% by weight of the tablet; an extragranular disintegrant in an amount of from about 0.1% to about 0.5% by weight of the tablet; a surfactant in an amount of from about 1% to about 2% by weight of the tablet; and an extragranular lubricant in an amount of from about 0.5% to about 1% by weight of the tablet.

[000167] The microcrystalline cellulose of the extragranular component may be a high compaction microcrystalline cellulose selected from CeolusTM UF-711, CeolusTM KG-1000 or KG-802, preferably CeolusTM UF-711. The disintegrant of the extragranular component may be croscarmellose sodium. The lubricant of the extragranular component may be magnesium stearate. The surfactant of the extragranular component may be sodium lauryl sulfate.

[000168] In one embodiment, the extragranular component consists essentially of: a microcrystalline cellulose as described herein; a disintegrant as described herein; optionally a surfactant as described herein; a lubricant as described herein; and optionally a coating as described herein; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[000169] In one embodiment, the extragranular component consists essentially of: a microcrystalline cellulose as described herein; a disintegrant as described herein; optionally a surfactant as described herein; a lubricant as described herein; optionally a coating as described herein; and optionally a fluidifier as described herein; provided that at least one of the intragranular or extragranular components of the tablet contains a surfactant.

[000170] In one embodiment, the extragranular component comprises: an amount of extragranular microcrystalline cellulose as described herein of about 7.50% by weight of the tablet; an amount of extragranular disintegrant as described herein of about 0.25% by weight of the tablet; a surfactant is present and the amount as described herein is about 1.50% by weight of the tablet; and an amount of extragranular lubricant as described herein of about 0.75% by weight of the tablet.

[000171] In one embodiment, the extragranular component described herein comprises: an extragranular microcrystalline cellulose in an amount of from about 5% to about 10% by weight of the tablet; an extragranular disintegrant in an amount of from about 0.1% to about 0.5% by weight of the tablet; a surfactant in an amount of from about 1% to about 2% by weight of the tablet; and an extragranular lubricant in an amount of from about 0.5% to about 1% by weight of the tablet.

[000172] The microcrystalline cellulose of the extragranular component may be a high-compacting microcrystalline cellulose. The microcrystalline cellulose of the extragranular component may be a high-compacting microcrystalline cellulose CeolusTM UF-711. The disintegrant of the extragranular component may be croscarmellose sodium. The lubricant of the extragranular component may be magnesium stearate. The surfactant of the extragranular component may be sodium lauryl sulfate.

[000173] Furthermore, provided herein is a tablet comprising: an intragranular component comprising: 60 wt % 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde as a crystalline form characterized by two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ); 27.50 wt % Ceolus™ UF-711 microcrystalline cellulose; 1.0 wt % croscarmellose sodium; and 1.50 wt % magnesium stearate; and an extragranular component comprising: 9.0% by weight of CeolusTM UF-711 microcrystalline cellulose; 0.25% by weight of croscarmellose sodium; and 0.75% by weight of magnesium stearate; wherein the percentage by weight is relative to the total weight of the tablet.

[000174] Furthermore, provided herein is a tablet comprising: an intragranular component comprising: 60 wt % 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde as a crystalline form characterized by two, three or four X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ); 27.50 wt % Ceolus™ UF-711 microcrystalline cellulose; 1.0 wt % croscarmellose sodium; and 1.50 wt % magnesium stearate; and an extragranular component comprising: 7.50% by weight of CeolusTM UF-711 microcrystalline cellulose; 0.25% by weight of croscarmellose sodium; 0.75% by weight of magnesium stearate; and 1.50% by weight of sodium lauryl sulfate;

[000175] The tablets described herein having inter- and extragranular components may contain amounts of tablet 1 as described herein (e.g. about 300 mg to about 900 mg; or about 300, 400, 500, 750 or 900 mg).

[000176] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 30% to about 70% by weight of compound 1; a filler; a disintegrant; a fluidifier; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[000177] Furthermore, provided herein is a tablet comprising a granular component wherein the granular component comprises: about 60% by weight of compound 1; a filler; a disintegrant; a fluidifier; a lubricant; optionally a surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[000178] Some embodiments provide a tablet comprising a granular component wherein the granular component comprises: about 60 wt % Compound 1; about 27.5 wt % filler; about 1 wt % disintegrant; about 1.25 wt % fluidifier; about 1.5 wt % lubricant; optionally about 1.5 wt % surfactant; and optionally a binder; wherein the weight percentage is relative to the total weight of the tablet.

[000179] Some embodiments provide a tablet comprising a granular component wherein the granular component comprises: about 60 wt % Compound 1; about 27.5 wt % Filler; about 1 wt % Disintegrant; about 1.25 wt % Fluidizer; about 1.5 wt % Lubricant; optionally about 2.5 wt % Sweetener; optionally about 0.5 wt % Flavoring Agent; and optionally about 0.2 wt % Colorant. wherein the weight percent is relative to the total weight of the tablet.

[000180] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; optionally a sweetener; optionally a flavoring agent; and optionally a coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000181] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; optionally about 1% to about 3% by weight of sweetener; optionally about 0.2% to about 1.5% by weight of flavoring agent; and optionally about 0.1% to about 1% by weight of coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000182] In one embodiment, provided herein is a tablet comprising: about 50% to about 65% by weight of compound 1; a filler; a surfactant; and about 0.01% to about 2% by weight of fluidifier; wherein the weight percentage is relative to the total weight of the tablet.

[000183] In one embodiment, provided herein is a tablet comprising: about 50% to about 65% by weight of compound 1; about 20% to about 35% by weight of filler; about 0.5% to about 2% by weight of surfactant; and about 0.01% to about 2% by weight of fluidifier; wherein the weight percentage is relative to the total weight of the tablet.

[000184] Also provided herein are dispersible tablets, wherein the tablets rapidly disintegrate in a small amount of liquid for administration to a patient. In some embodiments, the tablets described herein may be crushed and mixed with a suitable vehicle, such as food, for administration to a patient. Tablets as described herein may be useful for pediatric patients or patients who have difficulty swallowing capsules or tablets.

[000185] In some embodiments, the dispersible tablets provided herein disintegrate in a liquid in less than about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute. In some embodiments, the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000186] In some embodiments, the tablet rapidly disintegrates in less than about 15 mL, about 14 mL, about 13 mL, about 12 mL, about 11 mL, 10 mL, about 9 mL, about 8 mL, about 6 mL, or about 5 mL of liquid. In some embodiments, the tablet rapidly disintegrates in about 10 mL, about 9 mL, about 8 mL, about 6 mL, or about 5 mL of liquid. In some embodiments, the tablet rapidly disintegrates in less than about 5 mL, about 4 mL, or 3 mL of liquid.

[000187] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; filler; disintegrant; fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000188] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; filler; disintegrant; fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000189] In one embodiment, provided herein is a tablet comprising: about 30% to about 70% by weight of compound 1; a filler; a disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28 and wherein the weight percentage is relative to the total weight of the tablet.

[000190] In one embodiment, provided herein is a tablet comprising: about 30% to about 70% by weight of compound 1; a filler; less than about 2% by weight of disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000191] In one embodiment, provided herein is a tablet comprising: about 60% by weight of compound 1; a filler; a disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000192] In one embodiment, provided herein is a tablet comprising: about 60% by weight of compound 1; a filler; less than about 2% by weight of disintegrant; a fluidifier; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000193] In one embodiment, provided herein is a tablet comprising: about 30% to about 70% by weight of compound 1; a filler; a disintegrant; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000194] In one embodiment, provided herein is a tablet comprising: about 30% to about 70% by weight of compound 1; a filler; less than about 2% by weight of disintegrant; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000195] In one embodiment, provided herein is a tablet comprising: about 60% by weight of compound 1; a filler; a disintegrant; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000196] In one embodiment, provided herein is a tablet comprising: about 60% by weight of compound 1; a filler; less than about 2% by weight of disintegrant; a lubricant; a surfactant; and optionally a binder; wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the weight percentage is relative to the total weight of the tablet.

[000197] In some embodiments, the amount of disintegrant to filler is in the ratio of about 0:35, 1:60; about 1:56; about 1:55; about 1:50; about 1:45; about 1:40; about 1:35; about 1:30; about 1:25; about 1:20; about 1:15; about 1:10; about 1:7; and about 1:5. In some embodiments, the amount of disintegrant to filler is in the ratio of between about 0:35 to about 1:5. In some embodiments, the amount of disintegrant to filler is in the ratio of between about 0:35 to about 1:7. In some embodiments, the amount of disintegrant to filler is in the ratio of between about 1:60 to about 1:7. In some embodiments, the amount of disintegrant to filler is in a ratio of between about 1:56 to about 1:7. In some embodiments, the amount of disintegrant to filler is in a ratio of between about 1:50 to about 1:10. In some embodiments, the amount of disintegrant to filler is in a ratio of between about 1:40 to about 1:20. In some embodiments, the amount of disintegrant to filler is in a ratio of between about 1:25 to about 1:35. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:30. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:29. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:28. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:27. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:26. In some embodiments, the amount of disintegrant to filler is in a ratio of about 1:25.

[000198] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates into a liquid in less than 1 minute.

[000199] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates into a liquid in less than 1 minute.

[000200] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates into a liquid in less than 1 minute.

[000201] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000202] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates into a liquid in less than 1 minute.

[000203] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates into a liquid in less than 1 minute.

[000204] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000205] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000206] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000207] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000208] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and a lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000209] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; and about 1% to about 5% by weight of lubricant; wherein the weight percentage is relative to the total weight of the tablet.

[000210] In some embodiments, the dispersible tablet further comprises a sweetener, a colorant, a flavoring agent, or a combination thereof.

[000211] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000212] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000213] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000214] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000215] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; about 1% to about 3% by weight of sweetener; about 0.2% to about 1.5% by weight of flavoring agent; and about 0.1% to about 1% by weight of coloring agent; wherein the weight percent is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000216] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000217] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; sucralose; artificial grape flavor; iron oxide epigment; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000218] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; about 1% to about 3% by weight of sweetener; about 0.2% to about 1.5% by weight of flavoring agent; and about 0.1% to about 1% by weight of coloring agent; wherein the weight percent is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000219] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; about 1% to about 3% by weight of sucralose; about 0.2% to about 1.5% by weight of artificial grape flavor; and about 0.1% to about 1% by weight of iron oxide pigment; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute.

[000220] In one embodiment, provided herein is a dispersible tablet comprising: about 30% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000221] In one embodiment, provided herein is a dispersible tablet comprising: about 50% to about 70% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000222] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; a lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000223] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percentage is relative to the total weight of the tablet.

[000224] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of filler; about 1% to about 2% by weight of disintegrant; less than about 2% by weight of fluidifier; about 1% to about 5% by weight of lubricant; about 1% to about 3% by weight of sweetener; about 0.2% to about 1.5% by weight of flavoring agent; and about 0.1% to about 1% by weight of coloring agent; wherein the weight percent is relative to the total weight of the tablet.

[000225] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; a sweetener; a flavoring agent; and a coloring agent; wherein the weight percent is relative to the total weight of the tablet.

[000226] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% by weight of magnesium stearate; about 1% to about 3% by weight of sweetener; about 0.2% to about 1.5% by weight of a flavoring agent; and about 0.1% to about 1% by weight of a coloring agent; wherein the weight percent is relative to the total weight of the tablet.

[000227] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight microcrystalline cellulose; about 1% to about 2% by weight croscarmellose sodium; less than about 2% by weight colloidal silicon dioxide; about 1% to about 5% magnesium stearate; sucralose; artificial grape flavor; iron oxide epigment; wherein the weight percentage is relative to the total weight of the tablet.

[000228] In one embodiment, provided herein is a dispersible tablet comprising: about 60% by weight of compound 1 Form II; about 20% to about 35% by weight of microcrystalline cellulose; about 1% to about 2% by weight of croscarmellose sodium; less than about 2% by weight of colloidal silicon dioxide; about 1% to about 5% magnesium stearate; about 1% to about 3% by weight of sucralose; about 0.2% to about 1.5% by weight of artificial grape flavor; and about 0.1% to about 1% by weight of iron oxide pigment; wherein the weight percent is relative to the total weight of the tablet.

[000229] In one embodiment, provided herein is a dispersible tablet comprising: an intragranular component comprising: about 58 wt % of compound 1 Form II; about 26 wt % microcrystalline cellulose; about 1 wt % croscarmellose sodium; about 1.5 wt % magnesium stearate; about 0.5 wt % colloidal silicon dioxide; and an extragranular component comprising: about 8 wt % microcrystalline cellulose; about 0.25 wt % croscarmellose sodium; about 0.8 wt % magnesium stearate; about 2.5 wt % sucralose; (g) about 0.5 wt % artificial grape flavor; (h) about 0.2 wt % iron oxide pigment; and (viii) about 0.2% by weight of colloidal silicon dioxide; wherein the weight percentage is relative to the total weight of the tablet.

MANUFACTURING PROCESSES

[000230] In one aspect, the tablets of the present disclosure may be prepared by the dry granulation process. In one embodiment, the dry granulation process comprises: mixing compound 1 with excipients and compacting the mixture to form a compact mass. In another embodiment, the compacts are crushed to form dense flowable granules. The granular product is mixed with an extragranular component and pressed into tablets. Compaction may be done by conventional equipment. In one embodiment, the mixed API and excipients are passed through a roller compactor, for example a Gerteis Minipactor, or Gerteis Macropactor, for compaction.

[000231] In one embodiment, a grade of MCC that increases the compressibility of the total mixture can yield drug loadings (w/w) of about: 40%-80%, 50%-80%, or 50%-70%. In one embodiment, a grade of MCC that increases the compressibility of the total mixture can yield drug loadings (w/w) of about: 40%, 50%, 55%, 60%, 65%, 66%, 68%, 70%, 72%, 75%, 80% or more. In one embodiment, a grade of MCC that increases the compressibility of the total mixture may yield drug loadings (w/w) of at least: 40%, 50%, 55%, 60%, 65%, 66%, 68%, 70%, 72%, 75%, 80% or more. Said drug yields may be useful in scale-up manufacturing mode, e.g., suitable for large-scale manufacturing purposes, in particular high tablet hardness and low friability.

[000232] In one embodiment, the tablets described herein include a drug loading of about 60%. At the 60% loading, 300 mg of Form II of tablet 1 may be released from a total tablet core weight of 500 mg. In one embodiment, the tablet is sized sufficiently to allow patients to swallow the tablet without difficulty. The dry granulation process described herein may be used to manufacture tablets comprising varying amounts of tablet 1. For example, the common blend may be compressed to produce 300 mg, 600 mg, or 900 mg tablets. For a 900 mg tablet, a total tablet core weight of 1,500 mg is required. In some embodiments, for a 900 mg tablet, a total tablet core weight of 1,500 mg or 1,511 mg is required. In one embodiment, the tablet is sized sufficiently to allow patients to swallow the tablet without difficulty. In one embodiment, the tablets described herein provide advantages for ease of administration by patients over other dosages and forms of administration, which may result in greater patient engagement and improved clinical outcomes.

[000233] In some embodiments, the tablets described herein may be prepared by a wet granulation process. Wet granulation includes, but is not limited to, high/low shear wet granulation and fluid bed granulation. In some embodiments, Compound 1 and excipients (e.g., binder, disintegrant, surfactant, sweeteners, flavoring agents, and/or other excipients) are processed in a wet granulator and subsequently dried. The resulting granules are sized through a milling process, then mixed with fluidizers and/or lubricants.

[000234] Various compression forces may be used to produce the tablets. The selected force used to compress tablets described herein meets USP requirements for disintegration time. In some embodiments, the force selected for compression of a dispersible tablet described herein allows for faster disintegration of the tablet resulting in a flocculent suspension when the dispersible tablet is added to liquid for administration.

METHODS

[000235] The tablets described herein are useful for treating conditions associated with oxygen deficiency in a patient in need thereof and regardless of the patient's age. Provided herein are methods for increasing the affinity of hemoglobin for oxygen in a patient. In one embodiment, the methods comprise administering to the patient in need thereof a tablet described herein comprising a therapeutically effective amount of tablet 1. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg per day. In another embodiment, the therapeutic amount of tablet 1 is 600 mg. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg. In some embodiments, the therapeutic amount of tablet 1 is 50 mg to 2000 mg per day. In some embodiments, the therapeutic amount of tablet 1 is 50 mg to 1500 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 900 mg to 1500 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 1200 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 900 mg per day. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 900 mg to about 1500 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg to 900 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein the administration is 1 to 5 times daily. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein the patient is simultaneously administered 1 to 5 tablets. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 900 mg of tablet 1 and wherein administration is once daily.

[000236] Also provided herein are methods for increasing the affinity of hemoglobin for oxygen in a patient, wherein the patient is about 9 months to about 11 years of age. In one embodiment, the methods comprise administering to the patient in need thereof a tablet described herein comprising a therapeutically effective amount of tablet 1. In some embodiments, the tablet is mixed with a suitable carrier, such as food, prior to administration. In said embodiments, the tablet is crushed, mixed with food, and subsequently administered to the patient. In some embodiments, the therapeutic amount of tablet 1 is 50 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg per day. In some embodiments, the therapeutic amount of tablet 1 is 50 mg to 1500 mg per day. In some embodiments, the therapeutic amount of tablet 1 is 100 mg to 600 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 900 mg per day. In another embodiment, the therapeutic amount of tablet 1 is 600 mg. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg to 600 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg to 300 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg of tablet 1 and wherein administration of the tablet is from 1 to 9 times per day. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein administration of the tablet is from 1 to 3 times per day. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg of tablet 1 and wherein the patient is simultaneously administered 1 to 9 tablets. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein the patient is simultaneously administered 1 to 3 tablets.

[000237] Also provided herein are methods for increasing the affinity of hemoglobin for oxygen in a patient, wherein the patient is about 9 months to about 11 years of age. In one embodiment, the methods comprise administering to the patient in need thereof a dispersible tablet described herein comprising a therapeutically effective amount of tablet 1. In some embodiments, the dispersible tablet is dissolved in a liquid prior to administration thereof to the patient. In some embodiments, the dispersible tablet is added to a liquid to be dispersed prior to administration thereof to the patient. In some embodiments, the liquid is water or another beverage for consumption. In some embodiments, the dispersible tablet is dissolved in a liquid (e.g., in a cup) prior to administration thereof to the patient, the liquid is administered to the patient, and the cup is further rinsed with additional liquid, which is also administered to the patient. In some embodiments, the therapeutic amount of tablet 1 is from 50 mg to 2000 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg per day. In some embodiments, the therapeutic amount of tablet 1 is 100 mg to 600 mg per day. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 900 mg per day. In another embodiment, the therapeutic amount of tablet 1 is 600 mg. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg to 600 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg to 300 mg of tablet 1. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg of tablet 1 and wherein administration of the tablet is 1 to 9 times daily. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein administration of the tablet is 1 to 3 times daily. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 100 mg of tablet 1 and wherein the patient is simultaneously administered 1 to 9 tablets. In another embodiment, the methods comprise administering to the patient in need thereof a tablet described herein, wherein the tablet comprises about 300 mg of tablet 1 and wherein the patient is simultaneously administered 1 to 3 tablets.

[000238] Furthermore, provided herein are methods for treating a condition associated with oxygen deficiency in a patient. In one embodiment, the method comprises administering to the patient having a condition associated with oxygen deficiency; a tablet described herein comprising a therapeutically effective amount of tablet 1. In one embodiment, the condition is sickle cell disease, cancer, a lung disorder such as interstitial pulmonary fibrosis, stroke, high altitude vertigo, an ulcer, a pressure ulcer, Alzheimer's disease, acute respiratory distress syndrome, acute lung injury, or a wound. In one embodiment, the condition is sickle cell disease, cancer, a lung disorder such as interstitial pulmonary fibrosis, stroke, high altitude vertigo, an ulcer, a pressure ulcer, Alzheimer's disease, acute respiratory distress syndrome, acute lung injury, or a wound. In one embodiment, the condition is sickle cell disease, cancer, a lung disorder such as interstitial pulmonary fibrosis, stroke, high altitude vertigo, an ulcer, a pressure ulcer, Alzheimer's disease, acute respiratory distress syndrome, acute lung injury, or a wound. In one embodiment, the condition is sickle cell disease. In one embodiment, the condition is a lung disorder. In one embodiment, the lung disorder is interstitial pulmonary fibrosis. In one embodiment, the lung disorder is idiopathic pulmonary fibrosis. In one embodiment, the therapeutic amount of tablet 1 is 600 mg to 2000 mg once daily. In another embodiment, the therapeutic amount of tablet 1 is 600 mg. In another embodiment, the therapeutic amount of tablet 1 is 900 mg. In another embodiment, the therapeutic amount of tablet 1 is 1500 mg.

[000239] In one embodiment, the therapeutically effective amount of tablet 1 is 600 to 2000 mg once daily. In one embodiment, the therapeutically effective amount of tablet 1 is 900 mg or 1500 mg once daily. In one embodiment, the tablet contains 300, 750, or 900 mg of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.

[000240] It is understood that modifications that do not substantially affect the activity of the various embodiments of this disclosure are also included within the definition of the disclosure provided herein. Accordingly, the following examples are intended to illustrate, but not limit, the present disclosure.

EXAMPLES EXAMPLE 1: Compression profile of Form II of tablet 1

[000241] The compressibility of crystalline Form II tablet 1 (“API”) was determined by compressing pure, unformulated API into 200 mg tablets on a hydraulic press using a 5/16th inch diameter, standard concave round tool. The resulting tablets were measured for thickness using a digital caliper, and for tensile strength using a durometer. Table 1 shows the results of this compressibility study using 3 samples of Form II tablet 1 (Lots 1a, 1b, and 2). Lots 1a and 2 were directly from the API manufacturing process, but from different API suppliers. Lot 1b was prepared by taking Lot 1a and subjecting it to hammer crushing to cause particle size reduction. Table 1

[000242] The compression profiles in Table 1 indicate low tablet hardness and that Form II tablet 1 is a relatively incompressible solid. The implication of this is that compression of pure API does not achieve a tensile strength relevant to pharmaceutical tablet manufacturing. Furthermore, Form II tablet 1 exhibits a flat or slightly negative hardness response resulting from increasing compressive force. Thus, compression at higher forces does not allow tablets with higher tensile strengths to be manufactured. Consequently, pure API tablets would have poor integrity and would be excessively friable, prone to breakage during the manufacturing process, packaging, shipping and storage in bottles or blisters. Comminution of a batch of API did not result in appreciably increased tablet hardness. Increasing compression force, if any, resulted in slight overcompression (slightly decreasing hardness at higher compression force). This may arise from the rupture of crystals and agglomerates at higher tablet compression force. Overall, the compression profile of Form II tablet 1 is not acceptable as a neat API and necessitates formulation with excipients to overcome the poor compression properties.

Example 2: Formulation and fabrication of G1 and G2 prototypes (laboratory scale)

[000243] Tablet 1 Form II tablets were prepared in 2 similar formulations: G1 and G2. G2 was the same as G1 in terms of composition, except that it also contained 1.5% sodium lauryl sulfate in the extragranular phase, and a concomitant 1.5% reduction in the extragranular level of MCC extragranular filler. Tables 2 and 3 below give the compositions. The tablets were prepared using the following sequence of manufacturing steps:

[000244] Tablet Form II 1 was blended with the intragranular amounts of microcrystalline cellulose and croscarmellose sodium, and then further blended with the intragranular amount of magnesium stearate. The powder premix was dry granulated using a roller mill, and then milled to produce granules. The granules were blended with the extragranular amounts of microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate (for G2 only), and then further blended with the extragranular amount of magnesium stearate. The final blend was compressed into tablets using a tablet press. Table 2: Composition of Tablet Form II G1 Formulation 1. 300 mg and 100 mg Tablet Strengths Table 3: Composition of G2 Form II formulation of Tablet 1. 300 mg and 100 mg strength tablets

Example 3: Accelerated stability testing of G1 and G2 prototypes

[000245] G2 tablets were tested for stability under stressed storage conditions to expedite stability testing. G2 100 mg tablets were packaged in high density polyethylene bottles and induction sealed with an aluminum foil inner face cap. The bottles were stored in an environmental chamber at 40°C, 75% relative humidity (RH), and also in a chamber at 25°C, 60% RH to replicate ICH (International Conference on Harmonization) storage conditions. The tablets were tested at time zero and after 1 month of storage for appearance, assay, impurities, and dissolution properties. Table 4 summarizes the stability results. Table 4: Stability data for 100 mg strength tablets of Tablet 1 Form II

[000246] The stability data demonstrate no significant changes in appearance, no assay losses, no growth of impurities or degradants, and complete dissolution release within experimental limits. Thus, the G2 tablet has good stability characteristics with no major chemical incompatibilities between the Form II tablet 1 and the compounded excipients. Since the G2 tablets of the Form II tablet 1 with 300 mg and higher strengths are made using a common blend, the stability properties of the 100 mg strength tablet are representative of all strengths, such as the 300 - 900 mg strengths.

Example 4: In vitro dissolution testing of prototype formulations G1 and G2

[000247] A dissolution test was conducted to compare the G1 and G2 tablet formulations and a formulated capsule product. This used a USP paddle dissolution apparatus and method. Each of six dissolution vessels was filled with 900 mL of dissolution medium including 0.1 N hydrochloric acid and 0.5% Tween 80 surfactant; the paddle was rotated at 75 RPM, and the extent of release was determined by concentration measurements at a UV absorbance detection wavelength of 345 nm. The compositions of the capsule shells; compound 1, Form II capsules; and compound 1, Form II plain placebo capsules are given in Tables 5, 6, and 7, respectively. The dissolution profiles are given in Figure 1. The G2 tablet formulation was tested in both the coated state (100 mg) and the higher potency film coated state (300 mg).Table 5: Capsule shell composition NF = National Formulary; Ph. Eur. = European Pharmacopoeia; USP = United States Pharmacopoeia; JP = Japanese PharmacopoeiaTable 6: Quantitative Composition of Tablet 1, Form II Capsules (300 mg)

[000248] The composition of Compound 1, Form II plain placebo capsules is provided below in Table 7.Table 7: Composition of Compound 1, Form II plain placebo capsules # Avicel pH-102, or equivalent

[000249] The dissolution data (Figure 1) show that tablet formulations G1 and G2 achieved each pharmaceutically useful release consistent with products with an immediate release profile. Formulation G2 is superior to G1 in that it achieves the most rapid and complete release profile compared to G1 and the capsule product. This indicates that the SLS surfactant in G2 is aiding in the release of Form II tablet 1 from the highly compressed tablet state in a manner that replicates the sustained release from the uncompressed state in capsules, and with a faster release rate. Furthermore, the capsule product has historically been used in clinical trials where doses in the range of 300 - 900 mg have demonstrated efficacy in the treatment of patients suffering from SCD. Thus, these data are confirming that SLS surfactant is a surprisingly useful functional excipient for producing pharmaceutically useful tablets of Form II tablet 1 as shown in the dissolution profile as compared to formulation G1. The G1 formulation in vivo also showed a reasonable bioavailability profile. These data also showed that the G2 tablet formulation has release properties by USP dissolution methods that are independent of tablet strength as well as independent of film coating versus uncoated tablet cores.

Example 5: In vivo absorption study (dog PK) of G1 and G2 formulations and capsule products

[000250] An oral release study in a beagle dog was performed to evaluate the absorption characteristics of G1 and G2 tablets, and compared them to the capsule product. Each prototype was prepared in a 100 mg potency. Table 8 summarizes the results of this study. Relative bioavailability to the capsule product was calculated on a relative basis to compare the systemic exposure of G1 and G2 tablets to the capsules.Table 8 CV% is the coefficient of variation expressed as a percentage

[000251] The pharmacokinetic data reveal that in vivo the G1 and G2 tablets have pharmaceutically useful absorption characteristics. Surprisingly, and consistent with the dissolution behavior, the G2 tablet formulation exhibited equivalent exposure to the capsules, which have previously demonstrated human clinical efficacy in the treatment of SCD in the 300-900 mg dose range. It is very useful that the G2 tablets (containing 1.5% SLS surfactant) are able to achieve comparable systemic exposure despite being subjected to high mechanical compression forces. This allows the Form II tablet 1 to be provided at significantly higher doses per tablet unit (versus per capsule), and without any loss in the extent of release or absorption. What is further surprising is that the SLS surfactant demonstrates a reduction in the variability of the Cmax and AUC PK parameters. Reducing the variability of Cmax is particularly useful for managing potential side effects, which are often most extreme at the Cmax state where the exposure concentration is at its peak. By reducing Cmax variability, the risk of some patients experiencing Cmax-related toxicities is reduced and G2 is therefore a more biopharmaceutically robust product. The variability in Cmax after capsule dosing in the same beagles was observed to be 31.5% and 50.1%. Although SLS functions as a surfactant to aid in wetting the powder in an aqueous medium, it was observed here that SLS is very useful in reducing Cmax variability which has benefits for the safety and overall toxicity profile of tablet 1. Similarly, AUC exposure was reduced to a very favorable level of variability in the G2 tablet product, with CV% = 21.8%. The capsule product in these beagles showed AUC variability of 30.4% and 52.2%. Thus, both the G1 and G2 tablets exhibited less variability in AUC exposure than the capsules, and in fact the G2 tablet formulation showed the least variability of these products. A CV% of 21.8% is favorably low in a beagle study and still supports the pharmaceutical utility of both the G1 and G2 tablet formulations.

Example 6: Production of tablet product G2 on a 5 kg batch scale

[000252] The 300 mg strength G2 tablet formulation was scaled up to a batch size of 5,720 kg and run under GMP conditions to manufacture clinical test tablets of Tablet 1 Form II. By the process described in stepwise fashion in Example 3a, 3.3 kg of Tablet 1 Form II and corresponding amounts of intragranular excipients excluding magnesium stearate were blended in a V-blender at a speed of 25 rpm, and a mixing time of 10 minutes. This premix was passed through a co-crusher at 655 rpm to ensure that all agglomerates were crushed to a free-flowing powder. The intragranular magnesium stearate was added, and the premix was further blended in the V-blender at 25 rpm for 3 minutes. The premix was processed in a roller compactor at a gap width of 1.5 mm, force of 3.5 kN/cm and roller speed of 3 rpm. The ribbon compacts were crushed into granules using a 1.00 mm sized screen and granulator rotor. The extragranular excipient was mixed with the granules, excluding magnesium stearate, for 25 rpm, 7 min. Then additionally mixed with the extragranular amount of magnesium stearate for 3 min at 25 rpm.

[000253] Tablets were compressed from the final blend at a compression force of 18.6 kN, a pre-compression force of 1.6 kN, and a press speed of 20 rpm on a 9-station rotary tablet press. The tablets had an average hardness of 12.9 kp, exhibited very low or negligible friability (weight loss of 0.1% and 0.0% for 6.5 g tablets tumbled on a USP Friability Tester for 4 minutes). The tablets disintegrated rapidly in water at 37°C (1 min 4 sec, and 1 min 10 sec) as tested by the USP disintegration method.

[000254] The tablets were film coated with an Opadry II cosmetic coating at a target rate of 15g/min of the coating suspension until a film coating weight gain of 4% was achieved. The tablets were tested by validated analytical methods that meet the quality acceptance criteria, and released for human clinical use.

Example 7: Compound 1 tablets with fluidifier

[000255] Tablets of tablet 1 Form II and a fluidifier were prepared according to the examples provided herein. These tablets are summarized in Table 9a and 9b. Table 9a: Composition of high-potency tablets of tablet 1 Form II with fluidifier a From a plant sourceb The colloidal silicon dioxide component can be adjusted between intragranular and extragranular additionsTable 9b: Composition of Form II high-strength tabletstablet 1 with fluidifier a From a vegetable source such as the colloidal silicon dioxide component can be adjusted between intragranular and extragranular additions

Example 8: Dispersible tablets

[000256] Form II dispersible tablets of tablet 1 were prepared according to the examples provided herein without the addition of a film coating.

[000257] Dispersible tablets having 300 mg or 900 mg of Form II tablet 1 are summarized in Table 10.Table 10: Compositions of Form II dispersible tablets of tablet 1 in the 300 mg and 900 mg strengths a From a plant sourceb The colloidal silicon dioxide component can be adjusted between intragranular and extragranular additions

[000258] Dispersible tablets having 50 mg or 100 mg of Form II tablet 1 are summarized in Table 11.Table 11

Example 9: Assessment of the impact of disinfectant levels on dispersible tablets

[000259] One of the salient features of a dispersible tablet is to have rapid dispersion in a small volume of solution, in addition to having other standardized tablet characteristics, such as tablet hardness and friability, within an acceptable range. Tablet hardness and friability are also important because high friability in tablets leads to tablet breakage during processing, packaging and shipping. Typically, hardness is directly proportional to dispersion time, but indirectly proportional to friability within a certain range. In order to achieve rapid dispersion times with acceptable tablet hardness and friability, dispersible tablets typically include a higher percentage of disintegrants (also called a superdisintegrant and generally in the range of 5 to 20% w/w) compared to standard non-dispersible tablets. Surprisingly, as shown in Table 12, a dispersible tablet having only 1.25% w/w croscarmellose sodium exhibited superior dispersion characteristics (i.e., rapid disintegration times) with dispersion times of less than 60 seconds, while maintaining acceptable tablet hardness and friability.

[000260] The impact of disintegrant levels on dispersible tablets of Tablet 1 with increasing amounts of croscarmellose sodium was evaluated and the results are summarized in Table 12. The 300 mg strength dispersible tablets (and compressed at 2500 psi using a hand tablet press) used for these studies are also summarized in Table 12. These tablets were prepared as follows.

[000261] A dry granulation process using a roller compactor was used for preparation of the tablet mix and tablets were compressed using a hand-held tablet press.

[000262] Premix: All intragranular excipients were weighed and sieved to remove any agglomerates.

[000263] Roller Compaction (Dry Granulation) and Crushing: The premix (intragranular) was then passed through a small-scale top-bench roller compactor and a crusher to obtain the granulation mix (intragranular portion).

[000264] Final Blend: The extragranular components were weighed and sieved to remove any agglomerates. The intragranular and extragranular components were then blended together using a small-scale bench top bottle blender to obtain the final blend (master blend) for tablet compression.

[000265] Tablet Compression: 300mg dispersible tablets were prepared from the final blend using a hand-operated tablet press. The pressed tablets were evaluated for tablet hardness, thickness, friability and dispersion time.

[000266] The characterization of the tablets was performed as follows:

[000267] Tablet Hardness and Thickness: Tablet hardness or tablet breaking strength as per the United States Pharmacopeia ("USP") is a measure of the mechanical integrity of tablets. Tablet hardness, along with thickness, was measured using a standard hardness tester as described in the USP.

[000268] Tablet Friability: As per the USP, tablet friability is a test of the ability of tablets to withstand mechanical stresses that determine their resistance to scraping and surface abrasion when rotating them on a rotating cylinder. The percentage weight loss after rotating is referred to as tablet friability. Tablet friability for compound 1 was tested using a friability tester designed to USP specifications. Dispersion Time: This study simulates a possible method of administering dispersible tablets to a patient. The method involves adding a dispersible tablet to a premeasured amount of water in a plastic dosage cup. The water is absorbed into the tablet and rapidly disintegrates to form a fine dispersion; the time it takes for the tablet to disperse completely in the water (without any hard tablet aggregates or unmoistened tablet core) is the dispersion time. Table 12 IG: intragranular portion; EG: extragranular portion; ND: undetermined

[000269] As shown in Table 12, at 0% croscarmellose sodium, the tablets took more than 5 minutes to disperse and the quality of dispersion (as observed visually) was also poor. It is contemplated that the larger particles of these tablets could potentially impact the mouthfeel after administration, such as producing an unpleasant mouthfeel, which would negatively impact patient compliance with the dosing regimen.

[000270] As the percentage of croscarmellose sodium was increased from 0% to 0.625% w/w of the tablet, the dispersion time showed significant improvement. A fine dispersion (as observed visually) was formed in less than 60 seconds. It is contemplated that these fine dispersed particles would produce less mouthfeel, which would improve patient compliance with the dosage regimen.

[000271] These data demonstrate the uniqueness of the dispersible tablets described herein; specifically, even with a small amount of croscarmellose sodium (e.g., 0.625% w/w of the tablet), a significant improvement in dispersion time and dispersion quality was observed.

[000272] As shown in Table 12, a dispersible tablet with 1.25% w/w croscarmellose sodium exhibited superior dispersion characteristics (i.e., rapid disintegration times) with dispersion times of less than 60 seconds while having acceptable tablet hardness and friability.

[000273] Interestingly, it was observed that no further improvement in dispersion time was observed as the percentage of croscarmellose sodium was increased from 1.25% to 5.3% w/w. These data demonstrate that, despite typical dispersible tablets, the dispersible tablets described herein do not require a high amount of croscarmellose sodium. Consequently, a desirable amount of a filler (such as microcrystalline cellulose) in the tablets can be maintained for tablet hardness and friability.

[000274] As shown in Table 12, there was no impact from the addition of the disintegrant even as an intragranular component or extragranular component.

[000275] Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific examples and studies detailed above are merely illustrative of the invention. It should be understood that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the claims that follow.

Claims (34)

1. Dispersible tablet characterized by the fact that it comprises:(i) from 50% to 70% by weight of Compound 1 of formula: (ii) from 20% to 35% by weight of microcrystalline cellulose;(iii) from 1% to 2% by weight of croscarmellose sodium;(iv) less than 2% by weight of colloidal silicon dioxide; and(v) from 1% to 5% by weight of magnesium stearate;wherein the percentage by weight is relative to the total weight of the tablet. 2. Tablet characterized by the fact that it comprises:(i) from 30% to 70% by weight of compound 1 of formula: (ii) microcrystalline cellulose; (iii) less than 2% by weight of croscarmellose sodium; (iv) colloidal silicon dioxide; (v) magnesium stearate; (vi) sodium lauryl sulfate; and (vii) optionally a binder; wherein the amount of croscarmellose sodium to microcrystalline cellulose is in a ratio of 1:28 and wherein the weight percentage is relative to the total weight of the tablet. 3. Tablet characterized by the fact that it comprises: (i) from 50% to 70% by weight of Compound 1 of formula; (ii) from 30% to 40% by weight of microcrystalline cellulose;(iii) from 0.25% to 3% by weight of croscarmellose sodium;(iv) from 1% to 5% by weight of magnesium stearate;(v) from 0.5% to 2.5% by weight of sodium lauryl sulfate;(vi) from 0.25% to 5% by weight of colloidal silicon dioxide;wherein the percentage by weight is relative to the total weight of the tablet. 4. Tablet according to claim 3, characterized in that it comprises: (i) 35% by weight of microcrystalline cellulose; (ii) 1.25% by weight of croscarmellose sodium; (iii) 2% by weight of magnesium stearate; (iv) 1.5% by weight of sodium lauryl sulfate. 5. The tablet of claim 3, wherein the tablet comprises from 300 mg to 900 mg of Compound 1. 6. Tablet according to claim 3, characterized in that it comprises 60% by weight of Compound 1. 7. Tablet according to claim 3, characterized in that it comprises 35% by weight of microcrystalline cellulose. 8. Tablet according to claim 3, characterized in that it comprises 1.25% by weight of croscarmellose sodium. 9. Tablet according to claim 3, characterized in that it comprises 2% magnesium stearate. 10. Tablet according to claim 3, characterized in that it comprises 1.5% sodium lauryl sulfate. 11. The tablet of claim 3, wherein the tablet comprises from 100 to 600 mg of Compound 1. 12. Use of a tablet characterized by the fact that it is to prepare a medicament to treat sickle cell disease in a patient, in which the tablet comprises: (i) from 50% to 70% by weight of Compound 1 of formula; (ii) from 30% to 40% by weight of microcrystalline cellulose;(iii) from 0.25% to 3% by weight of croscarmellose sodium;(iv) from 1% to 5% by weight of magnesium stearate;(v) from 0.5% to 2.5% by weight of sodium lauryl sulfate;(vi) from 0.25% to 5% by weight of colloidal silicon dioxide;wherein the percentage by weight is relative to the total weight of the tablet. 13. Use according to claim 12, characterized in that the tablet comprises from 300 to 900 mg of Compound 1. 14. Use according to claim 12, characterized in that the patient is administered 900 mg or 1500 mg of Compound 1 once daily. 15. Use according to claim 12, characterized in that the tablet contains 300, 500, 750 or 900 mg of Compound 1. 16. Dispersible tablet according to claim 1, characterized in that it further comprises: (vi) a sweetener; (vii) a flavoring agent; and (viii) a coloring agent. 17. Dispersible tablet according to claim 16, characterized in that the filler is microcrystalline cellulose. 18. Dispersible tablet according to claim 16, characterized in that the disintegrant is croscarmellose sodium. 19. Dispersible tablet according to claim 16, characterized in that the fluidifier is colloidal silicon dioxide. 20. Dispersible tablet according to claim 16, characterized in that the lubricant is magnesium stearate. 21. Dispersible tablet according to claim 16, characterized in that the sweetener is sucrose, xylitol, maltitol, mannitol, sorbitol, sucralose, sodium saccharin, acesulfame potassium or aspartame. 22. Dispersible tablet according to claim 1, characterized by the fact that it comprises: (i) from 50% to 70% by weight of Compound I; (ii) from 20% to 35% by weight of microcrystalline cellulose; (iii) from 1% to 2% by weight of croscarmellose sodium; (iv) less than 2% by weight of colloidal silicon dioxide; (v) from 1% to 5% by weight of magnesium stearate; (vi) optionally from 1% to 3% by weight of sweetener; (vii) optionally from 0.2% to 1.5% by weight of flavoring agent; and (viii) optionally from 0.1% to 1% by weight of coloring agent. 23. The dispersible tablet of claim 22, wherein the tablet comprises Compound 1 in an amount of: 300 mg, 450 mg, 600 mg, 750 mg, 900 mg, 1200 mg or 1500 mg. 24. The dispersible tablet of claim 22, wherein the tablet comprises Compound 1 in an amount of 300 mg. 25. Dispersible tablet according to claim 1, characterized in that the amount of disintegrant to the filler is in a ratio of 1:28. 26. Dispersible tablet characterized by the fact that it comprises:(i) 60% by weight of crystalline Compound 1 of formula: wherein Compound 1 is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each ± 0.2° 2θ); (ii) from 20% to 35% by weight of microcrystalline cellulose; (iii) from 1% to 2% by weight of croscarmellose sodium; (iv) less than 2% by weight of colloidal silicon dioxide; (v) from 1% to 5% by weight of magnesium stearate; (vi) a sweetener; (vii) a flavoring agent; and (viii) a coloring agent; wherein the weight percentage is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute. 27. Dispersible tablet, characterized by the fact that it comprises:(i) 60% ± 5% by weight of Compound 1 of formula: (ii) 20% to 35% by weight of microcrystalline cellulose; (iii) 1% to 2% by weight of croscarmellose sodium; (iv) less than 2% by weight of colloidal silicon dioxide; (v) 1% to 5% by weight of magnesium stearate; (vi) a sweetener; (vii) a flavoring agent; and (viii) a coloring agent; wherein the weight percentage is relative to the total weight of the tablet. 28. The dispersible tablet of claim 27, wherein Compound 1 is a crystalline ansolvate form defined by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ± 0.2° 2θ). 29. Dispersible tablet, characterized by the fact that it comprises:(i) an intragranular component comprising:(a) 58% by weight of Compound 1 of formula: (b) 26% by weight of microcrystalline cellulose; (c) 1% by weight of croscarmellose sodium; (d) 1.5% by weight of magnesium stearate; (e) 0.5% by weight of colloidal silicon dioxide; and (ii) an extragranular component comprising: (a) 8% by weight of microcrystalline cellulose; (b) 0.25% by weight of croscarmellose sodium; (c) 0.8% by weight of magnesium stearate; (d) 2.5% by weight of sucrose; (e) 0.2% by weight of colloidal silicon dioxide; wherein the percentage by weight is relative to the total weight of the tablet. 30. The dispersible tablet of claim 29, wherein Compound 1 is in a form of a crystalline ansolvate defined by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ± 0.2° 2θ). 31. Dispersible tablet according to claim 29, characterized in that the extragranular component further comprises artificial grape flavor. 32. Dispersible tablet according to claim 29, characterized in that the extragranular component further comprises iron oxide pigment. 33. Dispersible tablet according to any one of claims 1 and 16 to 32, characterized in that it is for use in a method for treating sickle cell disease. 34. Dispersible tablet according to claim 33, characterized in that the dispersible tablet is dispersed in a liquid prior to its administration to the patient.