WO2025221962A1 - Irak4 degrader formulations and uses thereof - Google Patents

Abstract

The present invention provides spray-dried formulations comprising and IRAK4 degrader, and methods of use thereof.

Description

IRAK4 DEGRADER FORMULATIONS AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/635,473, filed April 17, 2024. the content of which is herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to spray-dried formulations of IRAK4 degrader 5-(( lR,4R)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)- 3 -methyl-2 -oxo-2, 3 -dihydro- IH-benzo [d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 - yl)methyl)cyclohexyl)- lH-pyrazol-4-yl)pyrazolo[ l,5-a]pyrimidine-3-carboxamide (Compound A) with improved dissolution profiles, and methods of use thereof.

BACKGROUND OF THE INVENTION

[0003] Formulation of a drug product needs to be carefully designed when the Active Pharmaceutical Ingredient (API) exhibits poor solubility and/or poor bioavailability. The Biophannaccutical Classification System (BCS) arranges these APIs in class II (poor solubility) and class IV (poor solubility and poor bioavailability). Accordingly, these class II and IV APIs pose a challenge in the dissolution from the final formulation and with 40% of marketed products and 70 - 90% of New Chemical Entities (NCE) having these BCS classifications, this challenge affects the majority of formulation work. Greater lipophilicity, higher molecular weights, and the resulting poor water solubility represent rising trends in combinatorial chemistry and new drug design.

[0004] Poor aqueous solubility is often linked to the stable, crystalline state of the API. This state can be overcome by disruption of the crystalline lattice and the manufacturing of the amorphous state. Ulis state displays a higher energy form but is less stable than the crystalline counterpart of the same API. Due to this higher energy state, the amorphous form leads to an increased apparent solubility that results in a supersaturated state and improved bioavailability in the Gastrointestinal Tract (GIT).

[0005] Target Protein-Degrading (TPD) compounds (e.g., IRAK4 degraders) are a new class of heterobifunctional compounds with higher molecular weight then typical Small Molecule Inhibitors (SMIs). A need exists to develop new formulations for IRAK4 degraders with improved dissolution profiles for the treatment of patients with unmet medical needs. Such new formulations are provided herein. SUMMARY OF THE INVENTION

[0006] It has been found that certain formulations comprising IRAK4 degrader 5-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3 -dihydro- IH-benzo [d] imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 - yl)methyl)cyclohexyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound A) of the invention have improved dissolution profiles.

[0007] In one embodiment of the present disclosure, there is provided a spray-dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is toluene sulfonic acid. In some embodiments, the acid is tartaric acid. In some embodiments, the acid is malic acid. In some embodiments, the acid is fumaric acid. In some instances, the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M, HPMCAS-L, HPMCAS-H, TPGS, and MCC, preferably HPMCAS-M. The spray-dned formulation may include about 1:3 wt/wt of Compound A:HPMCAS-M. In certain aspects, the spray-dried formulation comprises about 1: 1 mol/mol of Compound A:acid. In other aspects, the spray-dried formulation does not contain a cyclodextrin compound. In one embodiment of the present disclosure, there is provided a unit dosage form comprising the spray-dried formulation disclosed herein.

[0008] In further embodiments of the present disclosure, there is provided a method for treating an autoimmune/autoinflammatory disease or a hematological malignancy in a patient, comprising administering (e.g., orally) to the patient a therapeutically effective amount of Compound A provided in a spray-dried formulation or the unit dosage form described herein. In some aspects, the autoimmune/autoinflammatory disease is selected from a cutaneous, rheumatic, and gastrointestinal autoimmune/autoinflammatory disease. In some aspects, the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).

[0009] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information and procedures and are each hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF FIGURES [0010] FIG. 1 shows XRPD pattern overlays of the mixture of Compound A free base and HPMCAS- MG (1) and the mixture of Compound A free base and HPMCAS-MG with different acids: HC1 (2); H2SO4 (3), TSA (4), L-tartaric acid (5), malic acid (6), and fumaric acid (7).

[0011] FIG. 2 shows two stage dissolution results.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Certain Embodiments of the Invention

[0012] Compound A is a potent, highly selective, orally administered heterobifunctional small molecule therapeutic targeting IRAK4 and the E3 ligase CRBN to mediate the selective degradation of IRAK4 via the ubiquitin-proteasome system.

[0013] Compound A is composed of a CRBN-targeting ligand and an IRAK4-targeting ligand joined by a chemical linker. Compound A forms a ternary complex through non-covalent binding to both CRBN and IRAK4, bringing the E3 ligase (CRBN) in close proximity to IRAK4, that now serves as its neosubstrate. This proximity leads to IRAK4 ubiquitination and proteosomal degradation and eventual release of Compound A, which is then free to mediate additional rounds of ternary complex formation and IRAK4 degradation.

[0014] In vitro and in vivo studies confirmed the ability of Compound A to selectively degrade its intended target. IRAK4, and to inhibit downstream production of disease relevant proinflammatory cytokines and chemokines. In vitro, Compound A’s ability to degrade IRAK4 across species was confirmed in a study of mouse and rat splenocytes and dog, monkey, and human PBMCs, where similar DCso values w ere observed across all species (<10 nM). Across a series of in vitro studies in human peripheral blood mononuclear cells (PBMCs), whole blood, and OCI-LY10 cells, Compound A robustly reduced IRAK4 levels, with DC50 values consistently in the low nM range. Multiple in vitro cytokine release assays confirmed Compound A’s ability to inhibit TLR agonist (lipopolysaccharide and R848) and IL-10-induced proinflammatory cytokine production (including IL-6, TNF-a, granulocyte-macrophage colony-stimulating factor, and IL-8) in PBMCs with IC50 values also in the low nM range. Lastly, mass spectrometry' (MS) proteomic analysis of PBMCs treated with Compound A demonstrated tire compound’s selectivity for its target, with IRAK4 being the only protein degraded of more than 9,000 proteins sampled.

[0015] In vivo, murine models of inflammation demonstrated the ability of Compound A-induced IRAK4 degradation to impact TLR- and IL-10-mediated Thl and Th 17 inflammation as well as neutrophil migration. In the mouse air pouch model of MSU-crystal induced (TLR 2/4-dependent) inflammation, 3 days twice daily administration of Compound A at doses ranging from 30 to 100 mg/kg not only significantly reduced IRAK4 levels in the spleen, but also significantly reduced the inflammatory exudate, including reduction of neutrophils and IL- 10. Similar findings were observed in the imiquimod psoriasis model (TLR 7/8-dependent), where administration of Compound A resulted in dose-dependent degradation of IRAK4 in the spleen and skin associated with reduction in skin thickness as well as significant reduction of IL-ip(p<0.0001) and IL-6 (p<0.05; 300 mg/kg only) in the skin. Overall, efficacy was associated with achieving at least 80% or more IRAK4 knockdown in associated tissues in the model systems.

[0016] In vivo phannacokinetics (PK) / pharmacodynamics (PD) studies in mice and dogs demonstrated potent IRAK4 degradation by Compound A. In wild-type mice, a single oral dose of Compound A at 300 mg/kg resulted in nearly 100% degradation of IRAK4 in the skin and approximately 66% degradation in the spleen, which was sustained for at least 48-hour post-dose. In both the skin and spleen, maximal PD effects were achieved after tmax at each dose level. In dogs, 7 days of oral administration at doses up to 10 mg/kg/day also led to marked reduction of IRAK4 in the skin and in PBMCs. with Compound A trough plasma concentration levels as low as 3 nM inducing >85% degradation of IRAK4 in the PBMCs and degradation below tire limit of quantitation in the skin. Recovery of IRAK4 levels was noted by 96 to 168 hr following last dose in dogs, demonstrating the reversible nature of Compound A induced degradation. Together, these studies point to the potent, on-target, and reversible effects of Compound A against IRAK4.

[0017] In in vivo pharmacokinetic (PK) studies conducted in rats, dogs, and monkeys, Compound A PK was characterized by moderate to high clearance, high volume of distribution at steady state, a moderate terminal half-life, and low to moderate bioavailability. Compound A exhibited low solubility, moderate permeability, and was identified as a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. Compound A was highly bound to plasma proteins across nonclinical species and humans and did not significantly partition into red blood cells. In distribution studies in rats, Compound A extensively distributed into tissues, but had limited penetration into the central nervous system (CNS).

[0018] In vitro and in vivo metabolism studies showed that Compound A underwent oxidative metabolism via cytochrome P450 (CYP). An excretion study conducted in bile duct-cannulated (BDC) rats showed negligible renal clearance of Compound A, and minor to moderate bi liary and intestinal excretion as parent drug. Metabolites generated in liver microsomes from humans were also detected in those from rat, dog, and monkey. In the in vitro drug-drug interaction studies, Compound A demonstrated potential time dependent inhibition (TDI) of CYP2C19 and CYP3A4 and inhibited BCRP efflux, and therefore has the potential to be a perpetrator to sensitive CYP2C19, CYP3A4, and BCRP substrates. Conversely, Compound A is primarily metabolized by CYP3 A4 and is substrate of P-gp and BCRP and has the potential to be a victim when co-dosing with strong or moderate inhibitors or inducers of the enzymes.

[0019] Accordingly, in some embodiments, the present disclosure provides a method for treating a cutaneous autoimmunc/autoinflammatory disease in a patient, such as atopic dermatitis (AD) and hidradenitis suppurativa (HS), comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[0020] In some embodiments, the present disclosure provides a method for treating AD in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[0021] In some embodiments, the present disclosure provides a method for treating HS in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[0022] In some embodiments, the present disclosure provides a unit dosage form comprising a spray- dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[0023] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word ' comprise" and variations thereof, such as, "comprises" and “comprising"’ are to be constmed in an open, inclusive sense, that is. as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0024] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the tenn “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

2. Definitions

[0025] As used in the specification and appended claims, unless specified to the contrary', the following terms and abbreviations have the meaning indicated:

[0026] “Compound A” refers to IRAK4 degrader 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]hcptan-5-yl)- N-(3-(difluoromethyl)-l-(( lr,4R)-4-((4-((3-( l-(2, 6-dioxopiperidin-3-yl)-3-methyl-2 -oxo-2, 3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, of formula:

In some embodiments. Compound A or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound A or a phannaceutically acceptable salt thereof, is in crystal form.

[0027] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group fonned with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, malic acid, tartaric acid, citric acid, fumaric acid, succinic acid, malonic acid, or toluene sulfonic acid by using other methods used in the art such as ion exchange.

[0028] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Cj 4alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0029] As used herein, the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%. 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

3. Description of Exemplary Methods and Uses [0030] In some embodiments, the present invention provides a method for treating an autoimmune/autoinflammatory disease or a hematological malignancy in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein. In some embodiments, the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease.

[0031] In some embodiments, the present disclosure provides a method for treating a cutaneous autoimmune/autoinflammatory disease in a patient, such as atopic dermatitis (AD) and hidradenitis suppurativa (HS), comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a phannaceutically acceptable polymer, and an acid, as described herein.

[0032] In some embodiments, the present disclosure provides a method for treating AD in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a phannaceutically acceptable polymer, and an acid as described herein.

[0033] In some embodiments, the present disclosure provides a method for treating HS in a patient, comprising administering to the patient a spray-dried fonnulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid as described herein.

[0034] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0035] As used herein, a patient or subject "in need of prevention," "in need of treatment," or "in need thereof," refers to one, who by the judgment of an appropriate medical practitioner (e.g. , a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non-human mammals), would reasonably benefit from a given treatment or therapy .

[0036] A "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent, such as Compound A. is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as AD, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. Hie ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0037] In preferred embodiments, a therapeutically effective amount of the drug, such as Compound A, promotes regression to the point of eliminating the disease. In addition, the terms "effective" and "effectiveness" with regard to a treatment includes both phannacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the Compound A to treat the disease in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.

[0038] As used herein, the terms ‘‘therapeutic benefit” or "benefit from therapy" refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.

[0039] Tire tenn “patient” or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0040] In some embodiments, a method of the present invention comprises orally administering a spray-dried formulation as described herein. In some embodiments, a method of the present invention comprises administering a unit dosage form comprising a spray-dried formulation as described herein.

[0041] In some embodiments, a method of the present invention comprises orally administering about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, about 300 mg, about 400 mg, or about 500 mg of Compound A in a spray-dried fonnulation comprising a phannaceutically acceptable polymer and an acid, as described herein, once a day in a single dose.

[0042] In certain embodiments, a method of the present invention comprises daily administering up to about 200 mg of Compound A in a spray-dried formulation comprising a pharmaceutically acceptable polymer and an acid, as described herein. In certain embodiments, a method of the present invention comprises daily administering up to about 200 mg of Compound A in a unit dosage fomr comprising a spray-dried formulation comprising a phannaceutically acceptable polymer and an acid, as described herein.

4. Description of Exemplary Formulations and Dosage Forms

[0043] Compound A demonstrates low aqueous solubility of < 3mg/mL across the physiological pH range with medium penneability. Only slight increases of solubility were observed in bio-relevant fluid at pH 6.5 (FaSSIF < 12 nig/mL) due to the presence of bile salt. Compound A can be classified tentatively as a BCS II compound. Challenges were encountered with oral administration of the standard formulation with crystalline Compound A HC1 in preclinical species in early non-GLP studies. Thus, an enabling formulation approach was explored to improve the apparent solubility and potentially enhance the oral bioavailability of Compound A in the GLP toxicology program in rat and dog.

[0044] A range of enabling formulations were evaluated namely lipids, co-solvent with lipid combinations, amorphous solid dispersion (ASD) with different polymers and cyclodextrin solution to optimize the pharmacokinetic profile of Compound A. A 25% hydroxypropyl-beta-cyclodextrin (HP CD) Compound A solution at 30 mg/mL was developed which offered 2 - 4-fold increased exposure in rat and dog versus all other formulations studied.

[0045] To improve the apparent solubility in aqueous vehicle, the ASD containing Compound A and HP[3CD was prepared via the spray drying process, resulting in tire spray dried dispersion (SDD). The 20% Compound A and 80% HP0CD SDD was used in the GLP toxicology program, in both rat and dog. The GLP test article was formulated as a solution by dissolving the SDD in 0.1 M acetate at pH 3.5 with the final concentration of 25% HP0CD (w/v).

[0046] Tire first-in-human (FIH) dosage form was built off the knowledge gained during the GLP toxicology formulation. Hie SDD using HP0CD was the initial base case with efforts to improve drug loading. Crystalline Compound A was also investigated to understand if a less complex dosage form could be developed as compared to the HP0CD based SDD tablet.

[0047] An initial FIH formulation screening PK study was performed in dog. The results indicated that the standard immediate release (IR) crystalline tablet resulted in significantly lower exposures compared to the HPMCAS-M based SDD tablet. Hie results also indicated that addition of HP0CD to the HPMCAS-M based SDD tablet provided further exposure enhancement as compared to the SDD tablet without HP0CD. Based on these results, an IR tablet dosage form containing Compound A : HPMCAS-M (25:75) SDD with HP0CD : Compound A (3: 1) was selected for further development. In an effort to reduce the tablet weight, an additional formulation with reduced amounts of HP0CD was also developed, comprised of Compound A : HPMCAS-M (25:75) SDD with HPpCD : Compound A (1.6: 1).

[0048] A second preclinical PK dog study was conducted to compare the GLP tox solution to two tablet formulations with 3.0: 1 and 1.6: 1 ratios of HP0CD : Compound A. Hie results of this study demonstrate that the GLP tox solution resulted in higher exposure than the tablet formulations potentially due to the differences in dosage form (solution vs solid tablet). The results also illustrated that the exposure of Compound A from the two tablet formulations are comparable and tablet hardness has no negative impact in terms of exposure for either formulation. However, the exposure variability of the 1.6: 1 HP0CD : Compound A tablet is lower as compared to the 3.0: 1 HPpCD : Compound A tablets. Furthermore, the core tablet weight of the 1.6: 1 HP0CD : Compound A formulation is less than 3.0: 1 HP0CD : Compound A (800 mg vs 1000 mg). Thus, the 1.6: 1 HP0CD : Compound A HPMCAS-M based SDD IR tablet formulation was selected to support the FIH trial.

[0049] Tire present invention provides a spray-dried formulation that provides improved dissolution profiles. In some embodiments, the fonnulation as described herein has a dissolution profile that does not require the use of solubility enhancer (e.g., HPJ3CD). Furthermore, the present invention provides the unexpected result that the spray-dried formulations having the provided acids provide improved dissolution profiles over the same formulation without an added acid.

[0050] In some embodiments, the present invention provides a spray-dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid.

[0051] In some embodiments, a spray-dried formulation of the present invention comprises a phannaceutically acceptable polymer. In some embodiment, a pharmaceutically acceptable polymer is polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA). In some embodiment, a phannaceutically acceptable polymer is hypromellose (HPMC). In some embodiment, a pharmaceutically acceptable polymer is hypromellose phthalate (HPMCP-55). In some embodiment, a pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS). In some embodiments, the HPMCAS is a particular chemical and/or physical grade. In some embodiments, a HPMCAS has a L, M, or H chemical grade that varies in acetyl and succinoyl group substitution, hr some embodiments, HPMCAS has a fine (F) or granular (G) physical grade that differs in particle size. In some embodiment, a pharmaceutically acceptable polymer is hypromellose acetate succinate M grade (HPMCAS-M). In some embodiments, HPMCAS-M is HPMCAS-MF or HPMCAS-MG. In some embodiment, a phannaceutically acceptable polymer is hypromellose acetate succinate H grade (HPMCAS-H). In some embodiments, HPMCAS-H is HPMCAS- HF or HPMCAS-HG. In some embodiment, a phannaceutically acceptable poly mer is hypromellose acetate succinate L grade (HPMCAS-L). In some embodiments, HPMCAS-L is HPMCAS-LF or HPMCAS-LG. In some embodiment, a pharmaceutically acceptable polymer is vitamin E TPGS (TPGS). In some embodiment, a phannaceutically acceptable polymer is microcrystalline cellulose (MCC).

[0052] In some embodiments, a spray-dried formulation comprises about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95% wt/wt Compound A. In some embodiments, a spray- dried formulation comprises about 10-75% wt/wt Compound A. In some embodiments, a spray-dried formulation comprises about 10-70. about 15-65. about 15-60, about 15-55, about 20-50. about 20-45. or about 20-40% wt/wt Compound A.

[0053] In some embodiments, a spray-dried formulation comprises about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95% wt/wt phannaceutically acceptable polymer. In some embodiments, a spray-dried formulation comprises about 25-90% wt/wt pharmaceutically acceptable polymer. In some embodiments, a spray-dried formulation comprises about 30-90, about 35-85, about 40- 85, about 40-80, about 45-80, about 45-75, or about 50-75% wt/wt pharmaceutically acceptable polymer. [0054] In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 wt/wt of Compound A:pharmaceutically acceptable polymer. In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 wt/wt of pharmaceutically acceptable polymer: Compound A. In some embodiments, a spray -dried formulation comprises about 1: 10, 1 :9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 w t/w t of Compound A:HPMCAS-M. In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1 : 1 wt/wt of HPMCAS-M:Compound A. In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6. 1:5, 1:4, 1:3, 1:2, or 1: 1 wt/wt of Compound A:HPMCAS-L. In some embodiments, a spray-dried formulation comprises about 1: 10. 1:9, 1:8. 1:7, 1:6. 1:5, 1:4, 1:3, 1:2, or 1: 1 wt/wt of HPMCAS-L: Compound A. In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1 :3, 1:2, or 1: 1 wt/wt of Compound A:HPMCAS-H. In some embodiments, a spray- dried formulation comprises about 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 wt/wt of HPMCAS- H:Compound A.

[0055] In some embodiments, a spray -dried fonnulation comprises about 1:3 wt/wt of Compound A: pharmaceutically acceptable polymer. In some embodiments, a spray-dried formulation comprises about 1:3 wt/wt of Compound A:HPMCAS-M. In some embodiments, a spray-dried formulation comprises about 1:3 wt/wt of Compound A:HPMCAS-MG.

[0056] In some embodiments, a spray-dried formulation of the present invention comprises an acid. In some embodiments, the acid is any of the acids described herein. In some embodiments the acid is an inorganic acid or an organic acid. In some embodiments, an inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, an organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methanesulfonic acid, or p-toluene sulfonic acid.

[0057] In some embodiments, a spray-dried fonnulation of the present invention comprises an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is toluene sulfonic acid. In some embodiments, the acid is tartaric acid. In some embodiments, the acid is malic acid. In some embodiments, the acid is fumaric acid. In some embodiments, a spray-dried formulation of the present invention comprises an acid selected from the group consisting of sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid. In some embodiments, the acid is not hydrochloric acid. [0058] In some embodiments, a spray-dried formulation comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 % wt/wt acid. In some embodiments, a spray-dried formulation comprises about 1-10 % wt/wt acid. In some embodiments, a spray -dried formulation comprises about 1-5, about 2-6, about 3-7, about 4-8, or about 5-10 %wt/wt acid.

[0059] In some embodiments, a spray-dried fonnulation comprises about the about 1: 10, 1:9, 1:8. 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 mol/mol of Compound A:acid. In some embodiments, a spray-dried formulation comprises about 1: 10, 1:9, 1:8, 1 :7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1: 1 mol/mol of acid: Compound A. In some embodiments, a spray-dried formulation comprises about 1: 1 mol/mol of Compound A:sulfuric acid. In some embodiments, a spray-dried formulation comprises about 1: 1 mol/mol of Compound A:toluene sulfonic acid. In some embodiments, a spray-dried fonnulation comprises about 1: 1 mol/mol of Compound A: tartaric acid. In some embodiments, a spray-dried fonnulation comprises about 1 : 1 mol/mol of Compound Amalie acid. In some embodiments, a spray-dried formulation comprises about 1 : 1 mol/mol of Compound A:fumaric acid.

[0060] In some embodiments, the present invention provides a spray-dried fonnulation that does not contain a cyclodextrin compound. In some embodiments, the cyclodextrin compound is hydroxypropyl- beta-cyclodextrin (HPpCD) or the like.

[0061] In some embodiments, the present invention provides a unit dosage form comprising the spray- dried formulation comprising Compound A. a pharmaceutically acceptable polymer, and an acid, described herein. In some embodiments, a unit dosage form of the present invention can be solid dosage form suitable for oral administration. In some embodiments, the unit dosage form includes capsules, tablets, pills, powders, and granules.

[0062] In some embodiments, the present invention provides a preparation for oral administration comprising:

(a) Compound A. wherein Compound A is 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3- (difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo [1,5 -a]pyrimidine -3 -carboxamide ;

(b) a phannaceutically acceptable polymer; and

(c) an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid. wherein said compound is spray-dried with said pharmaceutically acceptable polymer and acid as described herein.

[0063] In some embodiments, a unit dosage form of the present invention comprises one or more phannaceutically acceptable excipient or carrier, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide. In some embodiments, an IR tablet of the present invention comprises one or more pharmaceutically acceptable excipient or carrier including, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. It will be understood by those in the art that some substances serve more than one purpose in a pharmaceutical composition. For instance, some substances are binders that help hold a tablet together after compression, yet are also disintegrants that help break the tablet apart once it reaches the target delivery site. Selection of excipients and amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works available in the art.

[0064] Suitable binders include, but are not limited to, starch (including potato starch, com starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose (HEC), carboxymethyl cellulose and the like), veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binding agents also include, e.g., acacia, agar, alginic acid, carbomers, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil. polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

[0065] Suitable fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0066] In some embodiments, a unit dosage form of the invention comprises a filler. In some embodiments, a filler is selected from mannitol, microcrystalline cellulose, or a mixture thereof.

[0067] In some embodiments, a unit dosage form of the invention comprises a disintegrant. Suitable disintegrants include, but arc not limited to, agar; bentonite; celluloses, such as mcthylccllulosc and carboxymethylcellulose: wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp: cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystallinc cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre -gelatinized starch; clays; aligns; and mixtures thereof.

[0068] In some embodiments, a unit dosage of the present invention comprises one or more glidants. Suitable glidants include, but are not limited to. colloidal silicon dioxide (CAB-O-SIL) and asbestos-free talc.

[0069] In some embodiments, a unit dosage of the present invention comprises one or more lubricants. Suitable lubricants include, but are not limited to, sodium stearyl fumarate, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil. cottonseed oil, sunflower oil. sesame oil. olive oil. com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof.

[0070] In certain embodiments, a unit dosage form of the present invention comprises one or more diluents. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.. EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include, e.g., ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, confectioner's sugar, dextrates. dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powered cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-.beta.-cyclodextrin. talc, tragacanth, trehalose, and xylitol.

[0071] In some embodiments, a unit dosage form of the present invention comprises one or more coloring agents. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof, e.g., Opadry® coloring agents. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble fomi of the dye. [0072] In some embodiments, a unit dosage form of the present invention comprises one or more flavoring agents. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.

[0073] In certain embodiments, a unit dosage form of the present invention comprises one or more sweetening agents. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0074] In certain embodiments, a unit dosage form of the present invention comprises one or more emulsifying agents. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN®20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0075] In certain embodiments, a unit dosage form of the present invention comprises one or more suspending and dispersing agents. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0076] In certain embodiments, a unit dosage form of the present invention comprises one or more preservatives. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add. sodium benzoate and alcohol.

[0077] In certain embodiments, a unit dosage form of the present invention comprises one or more wetting agents. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0078] In certain embodiments, a unit dosage form of the present invention comprises one or more solvents. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.

[0079] In certain embodiments, a unit dosage form of the present invention comprises one or more non-aqueous liquids. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0080] In certain embodiments, a unit dosage form of the present invention comprises one or more sources of carbon dioxide. Suitable sources of carbon dioxide include, but are not limited to. sodium bicarbonate and sodium carbonate.

[0081] In certain embodiments, a unit dosage of the present invention can be a multiple compressed tablet, an enteric-coating tablet, or a sugar-coated or fdm-coated tablet. Enteric-coated tablets are compressed tablets coated with substances that resist tire action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Entericcoatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[0082] A unit dosage of the present invention can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. [0083] In some embodiments, the present invention provides a spray-dried formulation for increasing the dissolution rate of a compound when exposed to an aqueous medium or body fluid. In some embodiments, the said spray-dried formulation comprises Compound A, a pharmaceutically acceptable polymer, and an acid selected from tire group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid.

[0084] In some embodiments, the aqueous medium is FaSSGF media. In some embodiments, the aqueous medium is FaSSIF media. In some embodiments, the aqueous medium is FaSSGF and FaSSIF media. In some embodiments, the aqueous medium is FaSSGF followed by FaSSIF media (e.g.. two-stage dissolution media). In some embodiments, the supersaturation of Compound A is achieved in 150 to 180 mins. In some embodiments, the supersaturation of Compound A is achieved in 150 to 180 mins in two- stage dissolution media. In some embodiments, the release of Compound A is greater than 14% from 120 to 180 mins. In some embodiments, the release of Compound A is greater than 14% from 120 to 180 mins in two-stage dissolution media. In some embodiments, the release of Compound A is greater than 15% from 120 to 180 mins. In some embodiments, the release of Compound A is greater than 15% from 120 to 180 mins in two-stage dissolution media. In some embodiments, the release of Compound A is about 16% from 120 to 180 mins. In some embodiments, the release of Compound A is about 16% from 120 to 180 mins in two-stage dissolution media.

[0085] In some embodiments, the body fluid is a liquid within the body of an organism. In some embodiments, the body fluid is an intracellular fluid or an extracellular fluid. In some embodiments, the extracellular fluid is an interstitial fluid or intravascular fluid (e.g., blood plasma).

[0086] In some embodiments, a spray-dried formulation of the present invention has higher release than the same formulation without an added acid. In some embodiments, a spray-dried formulation of the present invention has a release of greater than 14% at 120-180 minutes in tw o-stage dissolution media. In some embodiments, a spray -dried formulation of the present invention has a release of greater than 15% at 120-180 minutes in two-stage dissolution media. In some embodiments, a spray-dried formulation of the present invention has a release of about 16% at 120-180 minutes in two-stage dissolution media.

[0087] In some embodiments, a spray-dried formulation of the present invention has an overall release of greater than 12% at 330 minutes in two-stage dissolution media. In some embodiments, a spray-dried formulation of the present invention has an overall release of greater than 13% at 330 minutes in two-stage dissolution media. In some embodiments, a spray-dried formulation of the present invention has an overall release of about 14% at 330 minutes in two-stage dissolution media.

[0088] In some embodiments, the release of Compound A in two-stage dissolution media is as described in Table 12, below.

[0089] In some embodiments, the present invention provides a process for preparing a spray-dried formulation for increasing the dissolution rate of Compound A when exposed to an aqueous medium or body fluid, wherein Compound A is 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3- (difluoromethyl)- 1 -((1 r,4R)-4-((4-(( 3 -( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl -2 -oxo-2, 3 -dihydro- 1 H- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, comprising the steps:

(a) combine dichloromethane, methanol, and water under stirring;

(b) dissolve Compound A and HPMCAS-M to the solution of step (a) to about 7% solid content;

(c) add an acid to the solution of part (b);

(d) concentrate the solution of part (c) to dryness; and

(e) spray-drying the formulation.

[0090] In some embodiments, the dichloromethane, methanol, and water in step (a) is 74:24:2 wt/wt/wt. In some embodiments, the Compound A and HPMCAS-M in step (b) is about 1:3 wt/wt of Compound A:HPMCAS-M. In some embodiments, HPMCAS-M is HPMCAS-MG. In some embodiments, the acid of step (c) is about 1: 1 mol/mol of Compound A:acid. In some embodiments, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid. In some embodiments, the process for preparing a spray-dried formulation for increasing the dissolution rate of Compound A when exposed to an aqueous medium or body fluid is as described in Example 1, below .

5. Methods and Uses for Treating Disease

[0091] In some embodiments, the present invention provides a method for treating an autoimmune/autoinflammatory disease or a hematological malignancy in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein. In some embodiments, the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease.

[0092] In some embodiments, the autoimmune/autoinflammatory disease includes inflammatory or allergic conditions of the skin, for example psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dennatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet Syndrome, pyoderma gangrenosum, and other inflammatory' or allergic conditions of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact demratitis, atopic dennatitis. alopecia areata, erythema multifonna, dennatitis herpetifonnis, sclerodenna, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus. paraneoplastic pemphigus, epidermolysis bullosa acquisita, or hidradenitis suppurativa.

[0093] In some embodiments, the spray-dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory' disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodenna, Wegener granulomatosis, dennatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney' disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary’ biliary' cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid- induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dennatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0094] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), adult onset Still’s disease, macrophage activation syndrome (MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.

[0095] In some embodiments the inflammatory disease which can be treated is a TH 17 mediated disease. In some embodiments the TH17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[0096] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0097] In some embodiments, the present disclosure provides a method for treating a cutaneous autoimmunc/autoinflammatory disease in a patient, such as atopic dennatitis (AD) and hidradenitis suppurativa (HS), comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the present disclosure provides a method for treating AD in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[0099] In some embodiments, the present disclosure provides a method for treating HS in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein.

[00100] In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis (RA) in a patient, comprising administering to the patient a spray-dried formulation comprising a therapeutically effective amount of Compound A. a pharmaceutically acceptable polymer, and an acid, as described herein.

[0100] In some embodiments, the present disclosure provides a method for treating hematological malignancy in a patient, comprising administering to tire patient a spray-dried formulation comprising a therapeutically effective amount of Compound A, a pharmaceutically acceptable polymer, and an acid, as described herein. In some embodiments, the hematological malignancy is leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia. acute lymphocytic leukemia. B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, or MDS.

[0101] The following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

[0102] Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2019/133531 and WO 2020/010227, the contents of which are incorporated herein by reference in their entireties.

[0103] List of Abbreviations

Example 1. Spray dried dispersions (SDD) of Compound A [0104] Spray dried dispersions (SDD) of Compound A using free base and various acids (HC1, H2SO4, toluene sulfonic acid, L-tartaric acid, malic acid and fumaric acid) were prepared and characterized. After preparation, a decimate dissolution method was designed to determine the difference between seven SDDs of Compound A.

Summary of Results

[0105] The starting material Compound A HC1 salt was 98.75% pure and has irregular plate shaped morphology.

[0106] The SDD of Compound A HC1 salt was amorphous in nature with sphere shaped morphology. Glass transition temperature (T_g) was 136 °C. Assay of SDD was 100.8% with drug loading (DL of 25%) and purity was 98.68%.

[0107] The solubility of Compound A HC1 salt in gastric medium was 5.8 pg/mL at room temperature.

[0108] 37 g of Compound A HC1 salt was converted to Compound A free base and was used for the SDDs manufacturing. The 'H NMR showed consistent spectra compared to the reference. The residual chloride is less than 0.05% confirming complete conversion of HC1 salt to free base. The assay is 90% and purity was 98.45% area.

[0109] The spray drying was performed using Buchi 290 with the following main process parameters: Feed rate: 40% (approximately 15 g/minute); Inlet temperature: 89-90 °C; Outlet temperature: 53-59 °C. The batch size w as targeted to be 10 g of final solid and the yield before secondary drying w'as 70%. Other details are listed in Table 9. All seven SDDs prepared were confirmed to be amorphous in nature based on XRPD, PLM and DSC-TGA testing.

[0110] No significant difference were found between seven different SDDs when tested by single stage dissolution test using FaSSIF medium.

[OlH] Two stage dissolution with controlled dosing of FaSSGF into FaSSIF was designed and executed. The results revealed that Compound A SDDs have higher release than Compound A HC1 salt and Compound A free base at all time points. All SDDs showed supersaturation at 150 - 180 minutes and slight decrease (-1-2% release) after 330 minutes. Among the seven Compound A SDDs, the one with tartaric acid showed the highest release of 16% at 150 - 180 minutes and the final release of -14% at 330 minutes.

Introduction

[0112] Compound A HC1 SDD prepared using HPMCAS-MG show ed a chloride impurity at specific RRT 1.02 during stability testing. The objective of this Example is to a) prepare and characterize the SDDs of Compound A with free base and six other w eak nucleophilic acids b) determine if the other six SDDs provide better impurity profiles.

DSC-TGA, XRPD, SEM and PLM [0113] For the Compound A HC1 salt, XRPD data matched WO 2021/247899 and PLM and SEM showed irregular plate shape morphology.

[0114] For the SDD of Compound A HC1 salt, XRPD, PLM, and DSC data suggest that the material is amorphous. By DSC data, T_g is 136 °C. PLM and SEM showed sphere shape morphology.

Analytical Results

[0115] For the Compound A HC1 salt purity is 98.75% Area. Peak at RRT 1.03 has 0.12% Area. For the SDD of Compound A HC1 salt, assay content: 100.84%, purity is 98.68%. Peak at RRT 1.03 has 0.19% Area.

Table 1. Assay and Purity of Compound A HO and SDD by HPLC

Solubility of Compound A HC1 salt in fasted simulated state gastric fluid (FaSSGF)

[0116] Procedure: 4 mg of Compound A HC1 Salt was added to 13 mL of FaSSGF (pH = 3.0) and the mixture was stirred at room temperature. 1 mL of the suspension was withdrawn at 4 hr and 24 hr time points. The suspension was centrifuged at room temperature 16000 rpm for 10 minutes and analyzed by HPLC.

Table 2. Solubility of Compound A HC1 salt in FaSSGF at room temperature

Compound A HC1 salt to free base conversion [0117] Compound A HC1 salt was converted to free base as per the procedure given in Table 3 and Assay and Purity provided in Table 4.

Table 3. Procedures of Compound A HC1 conversion to free base

Table 4. Assay and Purity of Compound A free base by HPLC

Compound A Spray Drying

[0118] A miscibility study of Compound A free base and HPMCAS-MG with different acids was performed. Hie method for miscibility study is given in Table 5.

Table 5. Miscibility study of Compound A free base and HPMCAS-MG with different acids

Table 6. HPLC Analysis of Compound A free base Treated with Different Acids followed by Rotary Evaporation and Vacuum Drying Process

Spray Drying of 25% Compound A HC1 salt with HPMCAS-MG

[0119] Compound A HC1 salt with HPMCAS-MG was spray dried as summarized in Table 7.

Table 7. Spray Drying Process of Compound A HC1 SDD

Table 8. HPLC Analysis for Spray Dried Compound A HC1 SDD Spray Dried Dispersion of Compound A free base:HPMCAS-MG with Different Acids

[0120] Spray drying of 1 :3 (wt/wt) of Compound A:HPMCAS-MG was carried out with and without acids. Approximately 10.0 g/batch was spray dried using Buchi 290. Tire ratio between Compound A:acid was kept constant to 1: 1 (mol/mol). Process parameters w ere set to inlet temperature (89 °C), and feed rate (~15 g/min). Material w as dried under vacuum at RT and 50 °C. Each batch yielded ~ 70% recover of solids.

Procedure

• Batch size: 10 g Compound A free base, 7% solid content in 74:24:2 (wt/wt/wt) of DCM:MeOH:H₂O.

• Add specified amount of acid per sample.

• Feed rate: 40% pump rate (approximately 15 g/minutc); Inlet temperature: 89-90 °C.

• 25% of spray dried material was kept as a retain sample.

[0121] The rest of samples were isolated for secondary drying at 20 - 25 °C for ~15 h; 50 °C for ~9 h with nitrogen purging.

Table 9. Summary of Spray Drying of 1:3 (wt/wt) of (Compound A: HPMCAS-MG) with Various Acids at 10 g Scale using Buchi-290

Table 10. Impurity Profile for SDD with Different Acids

“WC = wet cake; VD = vacuum dried

Table 10 (Continued). Impurity Profile for SDD with Different Acids

*WC = wet cake; VD = vacuum dried

Single Stage Dissolution

[0122] Single stage dissolution setup: In order to compare the performance of different SDDs prepared using different acids, preliminary dissolution studies using one stage dissolution media (FaSSIF) were perfonned.

[0123] A dissolution study was carried out on Compound A HC1 SDD using the following parameters:

• USP apparatus type II, 100 rotations per minute (rpm), 37 °C, runs (n=2)

• Biorelevant FaSSIF media was prepared according to literature procedures (e.g., biorelevant.com) o FaSSIF: 41.65 g of FaSSIF buffer concentrate was added into 961.1 g of purified water followed by 2.24 g of 3F powder. The mixture was then stirred until all contents were dissolved. The medium was equilibrated for 2 hours before use and pH was taken (pH 6.5).

• Procedure (for n = 1)

1. Prepare 250 mL of FaSSIF (pH 6.5).

2. Equilibrate vessel at 37 °C.

3. Prepare SDD sample by adding a few drops of FaSSIF media from vessel to mix and wet with the SDD powder and then completely transfer the wet SDD mixture into the FaSSIF medium to initiate the dissolution testing.

4. Sample withdraw from FaSSIF stage (intestinal phase).

• Withdraw 2.0 mL at each time point.

• Time point (min): 5, 10, 15. 30, 45, 60, 75, 90, 120. 150, 180. and 240. 5. Sample preparation by centrifugation for 5 min at 25,000 rpm followed by testing clear supernatant liquid by HPLC.

Table 11. Summary Results of Compound A SDDs Single Stage Dissolution in FaSSIF Media

Single Stage Dissolution Conclusion

[0124] All seven SDD fonnulations showed similar dissolution profiles using single stage dissolution method. Two stage dissolution profiles may be able to identify which of these seven SDDs show better dissolution profiles when compared to each other.

Two Stage Dissolution of SDD in FaSSGF and FaSSIF media

[0125] A two stage dissolution study was carried out using the following parameters and the results are provided in Table 12:

• USP apparatus - type II, 100 rpm, 37 °C, runs (n=2)

• Biorelevant FaSSIF media was prepared according to literature procedures (e.g., biorelevant.com) o FaSSGF: To prepare IL of FaSSGF medium, add 36.78g of FaSSGF buffer concentrate into

961.9 g of purified water, then add 0.060 g of 3F powder to the buffer. Stir the solution until all content is dissolved. Adjust the pH with IN NaOH to pH = 3.0. o FaSSIF 2x concentrated: To prepare IL of FaSSIF medium, add 83.3g of FaSSIF buffer concentrate into 916.7 g of purified water, then add 4.48 g of 3F powder to the buffer. Stir the solution until all content is dissolved. Equilibrate the medium for 2 hours before use.

• Calibrate the peristaltic pump with water.

• Procedure (for n = 1)

1. Prepare 500 mL of FaSSGF (pH 3.0) and 250 mL of 2X FaSSIF in the adjacent vessels.

2. Equilibrate vessels for at 37 °C.

3. Prepare SDD sample by using few drops of FaSSGF (pH 3.0) media from vessel to mix and wet with the SDD powder and then completely transfer the wet SDD into the FaSSGF (pH 3.0) medium to initiate tire dissolution testing.

4. Sample withdraw from FaSSGF stage (Gastric phase) o Withdraw 2.0 mL at each time point. o Time point (min): 5, 10, 15, and 20.

5. After finishing the FaSSGF stage, start pumping the gastric phase vessel to intestinal phase vessel at 2mL/min. The pumping lasts for 125 minutes to pump total 250mL from the gastric phase vessel to intestinal phase vessel.

6. Sample withdraw from FaSSIF stage (Intestinal phase) o Withdraw 2.0 mL at each time point. o Time points (min): 5, 10, 30, 45, 60, 90, 120, 240, and 300 (intestinal phase); 35, 40, 60, 75, 90, 120, 150, 180, 270, and 330 (overall dissolution test)

7. Sample preparation by centrifugation for 5 min at 25,000 rpm followed by testing clear supernatant liquid by HPLC.

Table 12. Summary of Two Stage Dissolution Profiles

Table 12 (continued). Summary of Two Stage Dissolution Profiles

Two Stage Dissolution Conclusion

[0126] In two-stage dissolution, Compound A release from SDDs was higher compared to Compound A at all time points (FIG. 2). Among all Compound A SDDs, tartaric acid SDD and fumaric acid SDD showed the highest release of 16% at 150 - 180 minutes with an overall release of -14% at 330 minutes. Conclusion

[0127] A total of 37 g of Compound A HC1 was converted to Compound A free base, and then used in the preparation of Compound A SDD formulations. Seven SDDs of Compound A with various acids and HPMCAS-MG were prepared using a Buchi 290 spray dryer followed by secondary vacuum drying. Hie amorphous nature of the prepared SDDs were confirmed by XRPD and PLM. After manufacture, all Compound A SDDs were then analyzed by two dissolution methods. No difference was found between seven different SDDs in the single stage dissolution test using FaSSIF medium. Two stage dissolution was designed and executed using the FaSSGF followed by FaSSIF media. Results showed that Compound A SDDs have higher release than Compound A HC1 salt and Compound A free base at all time points. All SDDs showed supersaturation at 150 - 180 minutes and slight decrease (-1-2% release) at the end of 330 minutes. Among the seven Compound A SDDs, tartaric acid showed the highest release of 16% at 150 - 180 minutes and an overall release of -14% at 330 minutes.

[0128] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the application and claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. A spray-dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid: wherein Compound A is 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3- (difluoromethyl)- 1 -((1 r,4R)-4-((4-(( 3 -( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl -2 -oxo-2, 3 -dihydro- 1 H- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxamide .

2. The spray-dried formulation of claim 1, wherein the acid is sulfuric acid.

3. The spray-dried formulation of claim 1, wherein the acid is toluene sulfonic acid.

4. Tire spray-dried formulation of claim 1, wherein the acid is tartaric acid.

5. The spray-dried formulation of claim 1, wherein the acid is malic acid.

6. The spray-dried formulation of claim 1, wherein the acid is fumaric acid.

7. Tire spray-dried formulation of any one of claims 1-6, wherein the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55. HPMCAS-M, HPMCAS-L, HPMCAS-H, TPGS, and MCC.

8. The spray-dried formulation of any one of claims 1-7, wherein the pharmaceutically acceptable polymer is HPMCAS-M.

9. The spray-dried formulation of any one of claims 1-8, comprising about 1:3 wt/wt of Compound A:HPMCAS-M.

10. The spray-dried formulation of any one of claims 7-9, wherein HPMCAS-M is HPMCAS-MG.

11. Hie spray -dried formulation of any one of claims 1-10, comprising about 1: 1 mol/mol of Compound A:acid.

12. The spray-dried formulation of any one of claims 1-11, wherein said spray -dried formulation does not contain a cyclodextrin compound.

13. A unit dosage form comprising the spray-dried formulation of any one of claims 1-12.

14. A method for treating an autoimmune/autoinflammatory disease or a hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of the spray-dried formulation of any one of claims 1-12, or the unit dosage fomr of claim 13.

15. The method of claim 14. wherein the autoimmune/autoinflammatory disease is selected from a cutaneous, rheumatic, and gastrointestinal autoimmune/autoinflammatory disease.

16. The method of claim 15, wherein the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).

17. A preparation for oral administration comprising:

(a) Compound A, wherein Compound A is 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3- (difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -oxo-2, 3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide;

(b) a pharmaceutically acceptable polymer: and

(c) an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid, wherein said compound is spray dried with said pharmaceutically acceptable polymer and acid.

18. A spray -dried formulation for increasing the dissolution rate of a compound when exposed to an aqueous medium or body fluid, said spray-dried formulation comprising Compound A, a pharmaceutically acceptable polymer, and an acid selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid; wherein Compound A is 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]hcptan-5-yl)-N-(3- (difhioromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.

19. The spray-dried formulation for increasing the dissolution rate of claim 18, wherein the aqueous medium is FaSSGF and FaSSIF media.

20. The spray-dried formulation for increasing the dissolution rate of claim 18 or claim 19, wherein supersaturation of Compound A is achieved in 150 to 180 mins.

21. Tire spray -dried formulation for increasing the dissolution rate of any one of claims 18-20, wherein the release of Compound A is greater than 14% from 120 to 180 mins.

22. A process for preparing a spray-dried formulation for increasing the dissolution rate of Compound A when exposed to an aqueous medium or body fluid, wherein Compound A is 5-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3 -dihydro- IH-benzo [d] imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 - yl)methyl)cyclohexyl)- lH-pyrazol-4-yl)pyrazolo[ l,5-a]pyrimidine-3-carboxamide, comprising the steps:

(a) combine dichloromethane, methanol, and water under stirring;

(b) dissolve Compound A and HPMCAS-M to the solution of step (a) to about 7% solid content;

(c) add an acid to the solution of part (b);

(d) concentrate the solution of part (c) to dryness: and

(e) spray-drying the formulation.

23. The process of claim 22, wherein the dichloromethane, methanol, and water in step (a) is 74:24:2 wt/wt/wt.

24. Tire process of claim 22 or claim 23, wherein the Compound A and HPMCAS-M in step (b) is about 1:3 wt/wt of Compound A:HPMCAS-M.

25. The process of any one of claims 22-24, wherein the acid of step (c) is about 1: 1 mol/mol of Compound A: acid.

26. Tire process of any one of claims 22-25, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, toluene sulfonic acid, tartaric acid, malic acid, and fumaric acid.