Solid oral pharmaceutical formulations comprising a muscarinic receptor agonist

Abstract

Provided are pharmaceutical formulations and methods of treating a neurological or psychiatric disease or disorder, methods of treating behavioral problems associated with a neurological or psychiatric disease or disorder, and methods of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder in a subject in need thereof.

Description

SOLID ORAL PHARMACEUTICAL FORMULATIONS COMPRISING A MUSCARINIC RECEPTOR AGONISTBACKGROUND

[0001] Muscarinic acetylcholine receptors are G-protein coupled receptors (GPCRs) widely expressed both in the central nervous system (CNS) and the periphery. Depending on the muscarinic receptor subtype (M1-M5) and location, they mediate a variety of physiological functions. Individual subtypes differ in signaling profiles. Subtypes Ml, M3, and M5 preferentially activate the Gq / 11 class of G-proteins, while M2 and M4 preferentially activate inhibitory Gi / o G-proteins. The flexible G-protein interface of muscarinic receptors allows them to interact with several types of G-proteins with varying efficacy, potency, and kinetics. Moreover, muscarinic receptors can also couple to G-proteins from other classes.

[0002] Disruption of muscarinic signaling often contributes to pathologies in the CNS and periphery making muscarinic agonists potential tools for the treatment of a variety of pathologies. Importantly, selective modulation of individual subtypes of muscarinic receptors is necessary to avoid undesired side effects. Many muscarinic agonists targeting diseases of the CNS have failed in clinical trials mainly due to gastrointestinal and cardiovascular adverse effects attributed to the activation of peripheral M2 and M3 receptors. Compounds that exhibit selectivity for the M4 receptor relative to the M2 and M3 receptor subtypes, including czs-Compound A which has the following chemical structure:have been reported in WO 2015 / 118342 and WO 2024 / 028458.

[0003] There remains a substantial need for improved techniques and products for the oral administration of muscarinic agonists, such as Compound A (or czs-Compound A), or a pharmaceutically acceptable salt thereof, to patients in need thereof, including patients having neurological and psychiatric diseases and disorders. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0004] Provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides a maximum concentration of Compound A in plasma (Cmax) that increases in a doseproportional manner.

[0005] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 36 ng / mL to about 68 ng / mL.

[0006] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 10 ng / mL to about 19 ng / mL.

[0007] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A),or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides an area under the plasma concentration-time curve of the analyte / active substance in plasma at steady state from 0 hours to 24 hours (AUC0-24) or from 0 hours to infinity (AUCo-inf) that increases in a dose-proportional manner.

[0008] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUC0-24 of from about 193 h x ng / mL to about 357 h x ng / mL.

[0009] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUC0-24 of from about 83 h x ng / mL to about 153 h x ng / mL.

[0010] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A),or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 204 h x ng / mL to about 380 h x ng / mL.

[0011] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 97 h x ng / mL to about 179 h x ng / mL.

[0012] Also provided is a solid oral pharmaceutical formulation comprising: a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0013] Also provided is a dosage form comprising the solid oral pharmaceutical formulation described herein.

[0014] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0015] Also provided is a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising:administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0016] Also provided is a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder comprising: administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0017] A solid oral pharmaceutical formulation described herein or dosage form described herein, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof.

[0018] A solid oral pharmaceutical formulation described herein or a dosage form described herein, for use in a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder.

[0019] A solid oral pharmaceutical formulation described herein or a dosage form described herein, for use in a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder.

[0020] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIGURE 1 shows an exemplary manufacture process flow diagram for 10 mg cis- Compound A citrate monohydrate capsules.

[0022] FIGURE 2 shows an exemplary manufacture process flow diagram for 20 and 30 mg cv.s-Compound A citrate monohydrate capsules.

[0023] FIGURE 3 shows an exemplary manufacture process flow diagram for 10 mg and 20 mg cv.s-Compound A citrate monohydrate capsules.

[0024] FIGURE 4 shows the physical appearance results for the excipient compatibility study.

[0025] FIGURE 5 shows related substances by HPLC at the initial time point of the excipient compatibility study.

[0026] FIGURE 6 shows related substances by HPLC at 4 weeks at 40° C / 75% RH for the excipient compatibility study.

[0027] FIGURE 7 shows related substances by HPLC at 8 weeks at 40° C / 75% RH for the excipient compatibility study.DETAILED DESCRIPTION

[0028] In the following description, 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 invention 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 construed 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.

[0029] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain 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” or “in some embodiments” or “in a certain 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.

[0030] 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.

[0031] As used herein, “Compound A” may be referred to as ethyl 2-[4-(l -methyl- 1H- pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6-carboxylate, or ethyl 2-[4-(l-methyl- 1H -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6-carboxylate and has the following chemical structure:(Compound A).

[0032] As used herein, “Compound A citrate monohydrate” may be referred to as: ethyl 2-[4-(l -methyl- 1H -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate, ethyl 2-[4-(l-methyl-1H -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate;ethyl 2-[4-(l -methyl- 1 H-pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl 2-[4-( l -methyl- 1H -pyrazol-5-yl)piperidin- l -yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate.

[0033] In some embodiments, the stereochemistry of “Compound A” is cis, i.e., cis- Compound A has the following chemical structure:-Compound A) with a CAS number of 1803346-98-6. cis -Compound A may also be referred to as NBI- 1117568.

[0034] In some embodiments “ cis -Compound A citrate monohydrate” may be referred to as: ethyl cA-2-[4-(l-methyl-1H -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-1H -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-1H -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl cA-2-[4-(l-methyl-1H -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; and has a CAS number of 2920742-36-3.

[0035] Compound A and its pharmaceutically acceptable salts, including Compound A citrate monohydrate, may be prepared according to WO 2015 / 118342 and WO 2024 / 028458. The disclosures of both publications are incorporated herein by reference in their entirety.

[0036] Compound A and its pharmaceutically acceptable salts may form solvates, including hydrates. Solvates are formed by the incorporation into the solid-state structure (e.g. crystal structure) of the compounds and salts described herein of molecules of a non-toxic pharmaceutically acceptable solvent. Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds and salts with a solvent, or a mixture of solvents, containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-raycrystallography. The solvates can be stoichiometric or nonstoichiometric solvates. In some embodiments, the solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate.

[0037] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2%, and ± 1% of the stated value.

[0038] As used herein, “up-titration” of a therapeutic agent refers to increasing the amount of the agent administered to a patient at one or more instances for a specified period(s) to achieve a therapeutic effect while reducing the risk of dose-limiting intolerability that would likely otherwise occur if the agent were to be administered at the final dose at the beginning of the treatment.

[0039] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0040] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering off, reducing, or increasing the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.

[0041] As used herein, "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0042] As used herein, “adjunctive therapy" refers to a treatment that is used in conjunction with a primary treatment and its purpose is to assist the primary treatment. Adjunctive therapies are co-administered therapies. For example, if obsessive- compulsive disorder is being treated, the primary therapy may be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy. Likewise, if schizophrenia is being treated, the primary therapy may be, e.g., an antipsychotic agent.

[0043] As used herein, "co-administer" and "co-administration" and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be coformulated as part of the same composition, or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.

[0044] Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Its clinical features include cognitive dysfunction, memory abnormalities, progressive impairment in activities of daily living (ADL), and a host of behavioral and neuropsychiatric symptoms. While the diagnostic criteria for AD focus mostly on the related cognitive deficits, it is the behavioral and neuropsychiatric symptoms that are most troublesome for caregivers and lead to poor quality of life for patients. These symptoms include agitation, aggressive behaviors, and psychosis.

[0045] As used herein, “amelioration of the symptoms” of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0046] As used herein, “baseline” refers to the period of time just prior to initiation of therapy. The patient's condition just prior to initiation of therapy can be referred to as the patient's baseline condition.

[0047] As used herein, "AUC" refers to the area under the curve, or the integral, of the plasma concentration of an active pharmaceutical ingredient or metabolite over time following a dosing event.

[0048] As used herein " AUC0-t" is the integral under the plasma concentration curve from time “0” (dosing) to time "t".

[0049] As used herein, "AUC0-inf" is the AUC from time “0” (dosing) to time infinity.

[0050] As used herein, Cmax is a pharmacokinetic parameter denoting the maximum observed blood plasma concentration following delivery of an active pharmaceutical ingredient.

[0051] As used herein, “bipolar I disorder” (bipolar mania) is a manic-depressive illness characterized by the occurrence of at least one manic episode and may present with or without mixed or psychotic features. Most patients also exhibit one or more depressive episodes and often have had one or more major depressive episodes. Bipolar I disorder may coexist with other disorders, such as post-traumatic stress disorder (PTSD), substance use disorders, and mood disorders. Bipolar disorder is estimated to affect 2.8% of the United States Population.

[0052] As used herein, the “Clinical Global Impression - Severity” or “CGI-S” is an investigator administered, 7-point scale to assess patient’s severity of illness. See, e.g., Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.

[0053] As used herein the term "disorder" is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[0054] As used herein, a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0055] As used herein, a "dose" means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not a free base, the quantity is the molar equivalent to the corresponding amount of free base.

[0056] As used herein, the term "dose-proportional" for two compositions shall indicate that only the amount of a diluent(s) is changed to account for the change in amount of active substance, the amounts of other core excipients or capsule content being the same for the concerned strengths.

[0057] As used herein, "dosing regimen" means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient, such as from about 5 to about 70 mg once daily, e.g., about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg once daily. The additional doses of the active agent can be different from the dose taken at the first time.

[0058] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0059] As used herein, "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.

[0060] As used herein, "labeling" means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.

[0061] As used herein, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0062] As used herein, “a medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.

[0063] As used herein, "Medication Guide" means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 C.F.R. §208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product. A medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 C.F.R. §201.57, but the language need not be identical to the sections of approved labeling to which it corresponds. A medication guide is typically available for a pharmaceutical product with special risk management information.

[0064] Parkinson’s Disease (PD) is a neurodegenerative disease of the central nervous system affecting primarily the motor system. Common motor symptoms include tremors, rigidity, slowness of movement, and difficulty walking. Symptoms are progressive and, as the disease worsens, non-motor symptoms become common. These include cognitive conditions such as depression, anxiety, apathy, and dementia. The cause of PD is unknown and may involve both heritable and environmental factors. Parkinson’s Disease psychosis (PDP) is another common non-motor symptom of PD and may include visual and non-visual hallucinations and delusions. Between 20% and 40% of PD patients report experiencing hallucinations or delusions, with these symptoms being more common in more advanced cases of the disease. Hallucinations have been reported as the strongest predictor for eventual institutionalization of PD patients.

[0065] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0066] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. "Pharmacologically active" (or simply "active") as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0067] As used herein, in some embodiments, "pharmaceutically acceptable salt" refers to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Ver lag Helvetica Chimica Acta, Zurich, 2002 which is incorporated herein by reference in its entirety. The organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like. In some embodiments, "pharmaceutically acceptable salt" refers to base addition salts with an inorganic or anorganic base. Inorganic bases which may be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates. Organic bases from which may be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0068] As used herein, the “Positive and Negative Symptoms Scale” or “PANSS” is a reliable, well known, widely used, clinician administered, validated, 30-item scale designed to evaluate the severity of various symptoms of schizophrenia and is commonly employed in clinical studies involving antipsychotics. The subscales of the PANSS and the 5-factor model of the PANSS are employed to assess different symptom domains of schizophrenia. The PANSS Positive Symptom Factor Score (PSFS) is broadly used in clinical studies of schizophrenia and has demonstrated both good test-retest reliability and validity for positive symptom assessment in patients. See, e.g., Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004 Feb;161(2 Suppl):l-56 and Marder SR, Davis JM, and Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived from factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538-46.

[0069] As used herein, "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0070] As used herein, a "product" or "pharmaceutical product" means a dosage form of an active agent plus published material, and optionally packaging.

[0071] As used herein, "product insert" means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.

[0072] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA or EMEA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as,for example indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.

[0073] As used herein, "published material" means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet popup window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0074] As used herein, the term "schizophrenia or schizoaffective disorder " includes, but is not limited to, illnesses that describe abnormal social behavior and failure to understand what is real. Schizophrenia is described in terms of positive and negative (or deficit) symptoms. Positive symptoms are those that most individuals do not normally experience, but are present in people with schizophrenia. Negative symptoms are deficits of normal emotional responses or of other thought processes.Solid Oral Pharmaceutical Formulations

[0075] Compounds that exhibit selectivity for the M4 receptor relative to the M2 and M3 receptor subtypes, including cv.s-Compound A which has the following chemical structure:Compound A), have been reported in WO 2015 / 118342 and WO 2024 / 028458. WO 2024 / 028458 further reports several crystalline and / or salt forms of reports cv.s-Compound A, including HC1, fumarate, and citrate salts.

[0076] Pharmaceutically active compounds may be formulated as solid or liquid dosage forms. It is often desirable to formulate pharmaceutically active compounds as oral solid rather than liquid dosage forms. For example, conventional solid, single-unit, oral dosage forms offer the advantages of greater pharmaceutical stability, dosing accuracy, improved transportability, ease of storage and lower cost compared to oral liquid dosage forms.

[0077] However, oral liquid and oral solid formulations have different requirements for an active compound or its salt, which make selection of a particular salt form for either oral liquid or oral solid dosage forms challenging. For example, a pharmaceutically active compound or a salt of the compound, which absorbs moisture under high humidityconditions, may not be suitable for use in oral solid formulations. Likewise, a pharmaceutically active compound or a salt of the compound, which is crystalline and undergoes form change under high humidity condition, may not be suitable for use in oral solid formulations due to stability concerns. However, both aforementioned characteristics may not prevent the pharmaceutically active compound or a salt of the compound from being used in oral liquid formulations because the compound or the salt is dissolved or suspended in an aqueous media. On the other hand, for a pharmaceutically active compound or a salt to be used for oral solid formulations, it has to have certain characteristics, such as, stability under regular storage conditions, compatibility with all excipients, and reasonable brittleness for the manufacture of solid dosage forms using standard equipment.

[0078] Provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides a maximum concentration of Compound A in plasma (Cmax) that increases in a doseproportional manner. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0079] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 36 ng / mL to about 68 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0080] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 46 ng / mL to about 58 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0081] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of about 53 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0082] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 10 ng / mL to about 19 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0083] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 12 ng / mL to about 17 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0084] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of about 15 ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0085] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides an area under the plasma concentration-time curve of the analyte / active substance in plasma at steady state from 0 hours to 24 hours (AUC0-24) or from 0 hours to infinity (AUCo-inf) that increases in a dose-proportional manner. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0086] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUC0-24 of from about 193 h x ng / mL to about 357 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0087] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCO-24 of from about 220 h x ng / mL to about 330 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0088] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides anAUCo-24 of about 275 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0089] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24 of from about 83 h x ng / mL to about 153 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0090] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24 of from about 94 h x ng / mL to about 142 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0091] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24 of about 118 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0092] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, thepharmaceutical formulation provides a nAUCo-infof from about 204 h x ng / mL to about 380 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0093] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 234 h x ng / mL to about 350 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0094] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of about 292 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0095] Also provided is a solid oral pharmaceutical formulation comprising a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 97 h x ng / mL to about 179 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0096] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 110 h x ng / mL to about 166 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0097] In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of theoral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of about 138 h x ng / mL. In some embodiments, the formulation further comprises: at least one diluent; at least one binder, at least one disintegrant; and at least one lubricant.

[0098] Also provided is a solid oral pharmaceutical formulation comprising: a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0099] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 5 to about 40 mg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 10 to about 30 mg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 10, 15, 20, 25, or 30 mg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 10 mg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 20 mg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 30 mg.Formulation 1

[0100] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 5% w / w and about 15% w / w of the solid oral pharmaceutical formulation. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 8% w / w and about 12% w / w of the solid oralpharmaceutical formulation. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 9.5% w / w of the solid oral pharmaceutical formulation.

[0101] In some embodiments of Formulation 1, the solid oral pharmaceutical formulation comprises: between about 75% w / w and about 85% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0.5% w / w and about 3% w / w of the at least one lubricant.

[0102] In some embodiments of Formulation 1, the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose, isomalt, lactose, mannitol, and pregelatinized maize starch. In some embodiments, the at least one diluent is microcrystalline cellulose. In some embodiments, the at least one diluent is dibasic calcium phosphate. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate.

[0103] In some embodiments of Formulation 1, the solid oral pharmaceutical formulation comprises between about 80% w / w and about 85% w / w of the at least one diluent. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and the solid oral pharmaceutical formulation comprises about 81% w / w of the at least one diluent.

[0104] In some embodiments of Formulation 1, the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose. In some embodiments, the at least one disintegrant is croscarmellose sodium. In some embodiments, the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant. In some embodiments, the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

[0105] In some embodiments of Formulation 1, the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives. In some embodiments, the at least one binder is hydroxypropylmethyl cellulose (hypromellose). In some embodiments, the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder. In some embodiments, the at least one binder ishydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

[0106] In some embodiments of Formulation 1, the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate. In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / w of the at least one lubricant. In some embodiments, the at least one lubricant is magnesium stearate and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

[0107] In some embodiments of Formulation 1, the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 9.5% w / w of the solid oral pharmaceutical formulation; the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate and is present in an amount of about 81% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

[0108] In some embodiments, the dibasic calcium phosphate is anhydrous.

[0109] Also provided is a solid oral pharmaceutical formulation, comprising: a compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 9.5% w / w of the formulation; microcrystalline cellulose in an amount of about 67.5% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 14% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3% w / w of theformulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

[0110] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 10 mg based on the cA-Compound A free base. In some embodiments, the solid oral pharmaceutical formulation provides an AUCo-inf of cis- Compound A from about 97 h x ng / mL to about 179 h x ng / mL when the pharmaceutical formulation is administered to a subject. In some further embodiments, the AUCo-inf is from about 110 h x ng / mL to about 166 h x ng / mL. In some further embodiments, the AUCo-inf is about 138 h x ng / mL.

[0111] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 10 mg based on the cA-Compound A free base. In some embodiments, the solid oral pharmaceutical formulation provides a Cmax of cA-Compound A from about 10 ng / mL to about 19 ng / mL when the pharmaceutical formulation is administered to a subject. In some further embodiments, the Cmax is from about 12 ng / mL to about 17 ng / mL. In some further embodiments, the Cmax is about 15 ng / mL.

[0112] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cA-Compound A. In some embodiments, the citrate salt of cA-Compound A is crystalline.

[0113] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate, wherein the molar ratio between cA-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cA-Compound A citrate monohydrate is crystalline.Formulation 2

[0114] In some embodiments of Formulation 2, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 15% w / w and about 25% w / w of the solid oral pharmaceutical formulation. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 18% w / w and about 20% w / w of the solid oral pharmaceutical formulation. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 19% w / w of the solid oral pharmaceutical formulation.

[0115] In some embodiments of Formulation 2, the solid oral pharmaceutical formulation comprises:between about 65% w / w and about 75% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0. 5% w / w and about 3% w / w of the at least one lubricant.

[0116] In some embodiments of Formulation 2, the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose, isomalt, lactose, mannitol, and pregelatinized maize starch. In some embodiments, the at least one diluent is microcrystalline cellulose. In some embodiments, the at least one diluent is dibasic calcium phosphate. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate. In some embodiments, the solid oral pharmaceutical formulation comprises between about 70% w / w and about 73% w / w of the at least one diluent. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and the solid oral pharmaceutical formulation comprises about 72% w / w of the at least one diluent.

[0117] In some embodiments of Formulation 2, the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose. In some embodiments, the at least one disintegrant is croscarmellose sodium. In some embodiments, the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant. In some embodiments, the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

[0118] In some embodiments of Formulation 2, the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives. In some embodiments, the at least one binder is hydroxypropylmethyl cellulose (hypromellose). In some embodiments, the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder. In some embodiments, the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

[0119] In some embodiments of Formulation 2, the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate. In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / wof the at least one lubricant. In some embodiments, the at least one lubricant is magnesium stearate, and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

[0120] In some embodiments of Formulation 2, the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 19% by weight of the solid oral pharmaceutical formulation; the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate and is present in an amount of about 72% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropyl methyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

[0121] In some embodiments, the dibasic calcium phosphate is anhydrous.

[0122] Also provided is a solid oral pharmaceutical formulation, comprising: a compound having the structure-Compound A), or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 18.9% w / w of the formulation; microcrystalline cellulose in an amount of about 64.1% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 8% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3% w / w of the formulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

[0123] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 20 mg based on the cA-Compound A free base. In some embodiments, the solid oral pharmaceutical formulation provides an AUCo-inf of cis- Compound A from about 193 h x ng / mL to about 357 h x ng / mL when the pharmaceutical formulation is administered to a subject. In some further embodiments, the AUCo-inf is fromabout 220 h x ng / mL to about 330 h x ng / mL. In some further embodiments, the AUCo-inf is about 292 h x ng / mL.

[0124] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 20 mg based on the cA-Compound A free base. In some embodiments, the solid oral pharmaceutical formulation provides a Cmax of cA-Compound A from about 36 ng / mL to about 68 ng / mL when the pharmaceutical formulation is administered to a subject. In some further embodiments, the Cmax is from about 46 ng / mL to about 58 ng / mL. In some further embodiments, the Cmax is about 53 ng / mL.

[0125] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cA-Compound A. In some embodiments, the citrate salt of cA-Compound A is crystalline.

[0126] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate, wherein the molar ratio between cA-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cA-Compound A citrate monohydrate is crystalline.Formulation 3

[0127] In some embodiments of Formulation 3, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 25% w / w and about 35% w / w of the solid oral pharmaceutical formulation. In some embodiments of Formulation 3, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 27% w / w and about 30% w / w of the solid oral pharmaceutical formulation. In some embodiments of Formulation 3, Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 28% w / w of the solid oral pharmaceutical formulation.

[0128] In some embodiments of Formulation 3, the solid oral pharmaceutical formulation comprises: between about 55% w / w and about 70% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0. 5% w / w and about 3% w / w of the at least one lubricant.

[0129] In some embodiments of Formulation 3, the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose,isomalt, lactose, mannitol, and pregelatinized maize starch. In some embodiments, the at least one diluent is microcrystalline cellulose. In some embodiments, the at least one diluent is dibasic calcium phosphate. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate. In some embodiments, the solid oral pharmaceutical formulation comprises between about 60% w / w and about 65% w / w of the at least one diluent. In some embodiments, the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and the solid oral pharmaceutical formulation comprises about 63% w / w of the at least one diluent.

[0130] In some embodiments of Formulation 3, the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose. In some embodiments, the at least one disintegrant is croscarmellose sodium. In some embodiments, the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant. In some embodiments, the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

[0131] In some embodiments of Formulation 3, the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives. In some embodiments, the at least one binder is hydroxypropylmethyl cellulose (hypromellose). In some embodiments, the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder. In some embodiments, the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

[0132] In some embodiments of Formulation 3, the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate. In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / w of the at least one lubricant. In some embodiments, the at least one lubricant is magnesium stearate, and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

[0133] In some embodiments of Formulation 3, the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 28% by weight of the solid oral pharmaceutical formulation; the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and is present in an amount of about 63% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

[0134] In some embodiments, the dibasic calcium phosphate is anhydrous.

[0135] Also provided is a solid oral pharmaceutical formulation comprising: a compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 28.4% w / w of the formulation; microcrystalline cellulose in an amount of about 54.6% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 8% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3% w / w of the formulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

[0136] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 30 mg based on the cA-Compound A free base.

[0137] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cA-Compound A. In some embodiments, the citrate salt of cA-Compound A is crystalline.

[0138] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate, wherein the molar ratio between cA-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cA-Compound A citrate monohydrate is crystalline.Dosage Forms

[0139] Also provided is a dosage form comprising the solid oral pharmaceutical formulation described herein. In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the dosage form is in the form of a tablet.

[0140] In some embodiments, the dosage form is in the form of a capsule, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 16.1 mg of cA-Compound A citrate monohydrate, about 114.8 mg of microcrystalline cellulose, about 23.8 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.

[0141] In some embodiments, the dosage form is in the form of a capsule, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 32.1 mg of cA-Compound A citrate monohydrate, about 108.9 mg of microcrystalline cellulose, about 13.6 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.

[0142] In some embodiments, the dosage form is in the form of a capsule, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 48.3 mg of cA-Compound A citrate monohydrate, about 92.8 mg of microcrystalline cellulose, about 13.6 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.Process of Preparation

[0143] Also provided is a process for preparing a solid oral pharmaceutical formulation a process described herein, comprising: subjecting a mixture of Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant to roller compaction to produce compacted ribbons; and sizing the compacted ribbons to form granules.

[0144] In some embodiments, prior to roller compaction, a mixture of cA-Compound A, or a pharmaceutically acceptable salt thereof, and at least one diluent is subjected to blending to form a pre-blend mixture.

[0145] In some embodiments, the pre-blend mixture is subjected to de-lumping. In some embodiments, de-lumping is performed in a screening mill. In some embodiments, the screening mill is a conical screening mill.

[0146] In some embodiments, after de-lumping, the pre-blend mixture is blended with at least one binder and at least one disintegrant to form a blend mixture.

[0147] In some embodiments, de-lumping improves diffusive mixing in the blending step, resulting in improved blend uniformity.

[0148] In some embodiments, the blend mixture is lubricated with at least one lubricant prior to roller compaction to produce compacted ribbons. In some embodiments, the amount of lubricant added to the blend mixture prior to roller compaction is about 50% of the total lubricant in the final solid oral pharmaceutical formulation.

[0149] In some embodiments, the roller compactor is equipped with roll-gap control. In some embodiments, the roller compactor is operated with an average roll press force of between 5 and 11 kN / cm. In some embodiments the average roll press force is 6, 8, or 10 kN / cm.

[0150] In some embodiments, roll-gap control improves the particle size distribution of the granules obtained by sizing compacted ribbons which leads to improvements in capsule weight control for capsules filled with granules. In some embodiments, control over average roll press force improved the flow properties (for example, tapped density) of the resulting granules.

[0151] In some embodiments, the compacted ribbons are sized into granules using a sizing screen with a screen size of less than 1 mm. In some embodiments, the screen size is about 0.8 mm.

[0152] In some embodiments the granules formed by sizing the compacted ribbons are lubricated with at least one lubricant. In some embodiments, the amount of lubricant added to the granules formed by sizing the compacted ribbons is about 50% of the total lubricant in the final solid oral pharmaceutical formulation.

[0153] In some embodiments, lubricating the granules after sizing reduces granule sticking and improves compatibility with high-speed encapsulation.

[0154] In some embodiments, the granules formed by sizing compacted ribbons leads to both improved blend uniformity within granules and also improved flowability of the resulting granules and thus improved compatibility with high-speed encapsulation.

[0155] Also described herein, in some embodiments is a process for preparing a solid oral pharmaceutical formulation, comprising: subjecting a mixture of cv.s-Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant to roller compaction to produce compacted ribbons;sizing the compacted ribbons to form granules; and lubricating the granules with at least one lubricant; wherein about 50% of the total lubricant in the solid oral pharmaceutical formulation is present in the mixture of Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant; and the remaining 50% of the of the total lubricant in the solid oral pharmaceutical formulation is added to the granules.

[0156] In some embodiments, the method further comprises encapsulating the granules to form a dosage form.

[0157] In some embodiments, the method further comprises compressing the granules to form a tablet. In some embodiments, the method further comprises compressing the granules to form a minitablet.

[0158] Also provided is a granule comprising Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant, prepared by the process a process described herein.

[0159] Also provided is a solid oral pharmaceutical formulation prepared by a process described herein. In some embodiments, the solid oral pharmaceutical formulation is formulation 1, formulation 2, or formulation 3. In some embodiments, the solid oral pharmaceutical formulation is formulation 1. In some embodiments, the solid oral pharmaceutical formulation is formulation 2. In some embodiments, the solid oral pharmaceutical formulation is formulation 3.

[0160] Also provided is a dosage form that is a capsule prepared by a process described herein.

[0161] In any one of the embodiments of the process for preparing a solid oral pharmaceutical formulation, the Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A, or a pharmaceutically acceptable salt thereof.Methods of Treatment

[0162] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0163] Also provided is a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising:administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0164] Also provided is a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder comprising: administering to the subject the solid oral pharmaceutical formulation described herein or the dosage form described herein.

[0165] In some embodiments, the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, and psychosis.

[0166] In some embodiments, the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, Alzheimer’s disease psychosis, bipolar disorder, Parkinson’s disease (or synucleinopathies) psychosis, and obsessive compulsive disorder.

[0167] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

[0168] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.

[0169] In some embodiments, the subject has at least one sign or symptom of schizophrenia.

[0170] In some embodiments, the subject has at least one positive, negative, and / or cognitive sign or symptom of schizophrenia.

[0171] In some embodiments, the at least one sign or symptom is delusions, hallucinations, disorganized speech, disorganized behavior or attention, anhedonia, catatonic behavior, affective flattening, alogia, avolition, conceptual disorganization, or any combination thereof.

[0172] In some embodiments, the subject is also being administered at least one co- therapeutic agent for the treatment of schizophrenia and the neurological or psychiatric disease or disorder is adjunctive treatment of schizophrenia (ATS).

[0173] In some embodiments, the subject has a stable background antipsychotic medication dose.

[0174] In some embodiments, the subject is residually symptomatic or has at least one residual sign or symptom after first- or second-line treatment of schizophrenia.

[0175] In some embodiments, the subject is residually symptomatic or has at least one residual sign or symptom after mono- or combination therapy for schizophrenia.

[0176] In some embodiments, the subject is a human.

[0177] In some embodiments, the mono- or combination therapy is initial therapy.

[0178] In some embodiments, the at least one co-therapeutic agent is least one antipsychotic agent.

[0179] In some embodiments, the antipsychotic agent is a typical antipsychotic agent.

[0180] In some embodiments, the typical antipsychotic agent is benperidol, chlorpromazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, loxapine, molindone, pericyazine, perphenazine, pimozide, prochlorperazine, promazine, sulpiride, thiothixene, trifluoperazine, thioridazine, zuclopenthixol, or any combination thereof.

[0181] In some embodiments, the antipsychotic agent is an atypical antipsychotic agent.

[0182] In some embodiments, the atypical antipsychotic agent is clozapine, olanzapine, risperidone, sertindole, quetiapine, paliperidone, asenapine, ziprasidone, surmontil, iloperidone, aripiprazole, or any combination thereof.

[0183] In some embodiments, the neurological or psychiatric disease or disorder is psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0184] In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder.Dosing Regimen

[0185] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily doseequivalent to about 10, about 15, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0186] In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily doseequivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0187] In some embodiments, the subject is assessed for one or more adverse events during the QD dosing. The one or more adverse events may be selected from blood pressure, heart rate, and 12-lead ECGs. In some embodiments, the QD dosing may last at least 5 weeks in the absence of one or more adverse events.

[0188] In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosingregimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0189] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

[0190] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

[0191] In some embodiments, the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.

[0192] In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 10 mg of Compound A free base.

[0193] In some embodiments, the final daily dose is from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is fromabout 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is from about 8 mg to about 25 mg of Compound A free base.

[0194] In some embodiments, the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is about 10 mg of Compound A free base. In some embodiments, the final daily dose is about 15 mg of Compound A free base. In some embodiments, the final daily dose is about 20 mg of Compound A free base. In some embodiments, the final daily dose is about 25 mg of Compound A free base. In some embodiments, the final daily dose is about 30 mg of Compound A free base.

[0195] In some embodiments, the initial daily dose is administered QD. In some embodiments, the initial daily dose is administered BID. In some embodiments, the final daily dose is administered QD. In some embodiments, the final daily dose is administered BID. In some embodiments, the initial daily dose and final daily dose are administered QD.

[0196] In some embodiments, the titration period is from about 2 to about 14 days. In some embodiments, the titration period is from about 2 to about 7 days. In some embodiments, the titration period is from about 3 to about 7 days. In some embodiments, the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days. In some embodiments, the titration period is about 2 days. In some embodiments, the titration period is about 3 days. In some embodiments, the titration period is about 4 days. In some embodiments, the titration period is about 5 days. In some embodiments, the titration period is about 6 days. In some embodiments, the titration period is about 7 days.

[0197] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0198] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the dailydose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0199] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0200] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0201] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In someother further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0202] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0203] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0204] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0205] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0206] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0207] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered QD. In some other embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.

[0208] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

[0209] In some embodiments, the first titration period is from about 2 to about 14 days. In some embodiments, the first titration period is from about 2 to about 7 days. In some embodiments, the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0210] In some embodiments, the second titration period is from about 1 to about 7 days. In some embodiments, the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0211] In some embodiments, the first and second titration period combined is about 14 days. In some further embodiments, the first titration period is about 2 days, and the second titration period is about 12 days. In some further embodiments, the first titration period is about 3 days, and the second titration period is about 11 days. In some further embodiments, the first titration period is about 4 days, and the second titration period is about 10 days. In some further embodiments, the first titration period is about 5 days, and the second titration period is about 9 days. In some further embodiments, the first titration period is about 6 days, and the second titration period is about 8 days. In some further embodiments, the first titration period is about 7 days, and the second titration period is about 7 days.

[0212] In some embodiments, the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 10% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 15% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 30% of the final daily dosage. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.

[0213] In some embodiments, the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.

[0214] In some embodiments, the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 30% of the finaldaily dose. In some embodiments, the increased daily dose is an amount equivalent to about 35% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 40% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 45% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 50% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 55% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 60% of the final daily dose. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0215] In some embodiments, the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 15 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0216] In some embodiments, the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 10, about 15, about 20, about 25, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 20 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 25 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0217] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0218] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0219] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0220] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0221] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalentto about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0222] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0223] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0224] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 25 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0225] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, and wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0226] Also provided is use of a compound having the structure ofCompound A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0227] Also provided is a compound having the structure of-Compound A),or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cz.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cz.s-Compound A free base; monitoring one or more adverse events; and administering cz.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cz.s-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0228] In some embodiments, the first period is from about 1 to about 3 weeks. In some embodiments, the first period is about 1 week. In some embodiments, the first period is about 2 weeks. In some embodiments, the first period is about 3 weeks.

[0229] In some embodiments, the cz.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered as a solid oral pharmaceutical formulation.

[0230] In some embodiments, the method comprises administering cz.s-Compound A, or a pharmaceutically acceptable salt thereof, in a third period at a daily dose equivalent to about 20 mg of cz.s-Compound A free base. In a further embodiment, the cz.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered as a solid oral pharmaceutical formulation.

[0231] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0232] In some embodiments, the baseline assessment of heart rate is the heart rate recorded at 30 minutes (±20 minutes) predose on Day 1.

[0233] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0234] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0235] Also provided is a compound for use in a method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structureCompound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0236] In some embodiments, the daily dose is about 10 mg equivalent to cA-Compound A free base. In some embodiments, the daily dose is about 20 mg equivalent to cA-Compound A free base. In some embodiments, the daily dose is about 30 mg equivalent to cis- Compound A free base.

[0237] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof is administered QD.Method of Use

[0238] Provided is use of a solid oral pharmaceutical formulation as described herein for treating a neurological or psychiatric disease or disorder in a subject in need thereof.

[0239] In some embodiments, the solid oral pharmaceutical formulation provides a daily dose equivalent to about 20 mg of cA-Compound A free base. In a further embodiment, the solid oral pharmaceutical formulation is administered QD.

[0240] In some embodiments, the solid oral pharmaceutical formulation provides a daily dose equivalent to about 10 mg of cA-Compound A free base. In a further embodiment, the solid oral pharmaceutical formulation is administered QD.

[0241] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0242] In some embodiments, the solid oral pharmaceutical formulation is administered in the form of a capsule.Compounds

[0243] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is Compound A free base.

[0244] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of Compound A.

[0245] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of Compound A. In some embodiments, the citrate salt of Compound A is crystalline.

[0246] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is Compound A citrate monohydrate, wherein the molar ratio between Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the Compound A citrate monohydrate is crystalline.

[0247] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A free base.

[0248] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of cA-Compound A.

[0249] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cv.s-Compound A. In some embodiments, the citrate salt of cv.s-Compound A is crystalline.

[0250] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate, wherein the molar ratio between cv.s-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cv.s-Compound A citrate monohydrate is crystalline.

[0251] In some embodiments, the crystalline form of the citrate salt of Compound A, Compound A citrate monohydrate, or cv.s-Compound A citrate monohydrate, is characterized by at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cv.s-Compound A citrate monohydrate is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by four XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.

[0252] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLESExample 1

[0253] The cA-Compound A citrate monohydrate capsule dosage forms of 10 mg, 20 mg, and 30 mg, included, respectively, the following ingredients in Tables 1, 1A, 2, 2A, and 3.Table 1Table 1ATable 2Table 2ATable 3Table 3A

[0254] An exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg, is provided in Figure 1. A separate exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 20 mg and 30 mg, is provided in Figure 2. The differences are the initial coating of bin blender with microcrystalline cellulose, order of addition, and stepwise blending to further improve homogenous distribution of cv.s-Compound A citrate monohydrate drug substance in the blend for 20 mg and 30 mg strengths.

[0255] The manufacture of cv.s-Compound A citrate monohydrate capsules, 10 mg, 20 mg, and 30 mg used a standard dry granulation manufacturing process followed by capsule filling. For 10 mg capsule manufacture, cv.s-Compound A citrate monohydrate drug substance was mixed with the excipients to prepare a homogenous blend in three stages: the first two stages to produce a homogenous blend followed by a third, shorter lubrication blended with magnesium stearate. For 20 mg, and 30 mg capsule manufacture, approximately half of thescreened microcrystalline cellulose was charged to the bin blender and tumbled to coat the interior product contact surface. Screened components cv.s-Compound A citrate monohydrate, remaining microcrystalline cellulose, and dibasic calcium phosphate were charged to the bin blender and mixed, then de-lumped by passing through a screening mill, and mixed again. Screened components hypromellose and croscarmellose sodium were charged to the bin blender and mixed. Lastly, screened magnesium stearate was charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction.

[0256] The blend was then processed through a roller compactor to produce compacted ribbons. These ribbons were then sized through a screening mill to yield granules suitable for filling directly into a Size 3 Swedish orange hard gelatin capsule shells using either a manual PROFILL® capsule filling system (as was performed for the 10 mg product) or a fully automated encapsulation machine (as was performed for the 20 and 30 mg products). The filled capsules were then passed through deduster / metal detector and weight sorter.

[0257] Another exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg and 20 mg, described in Tables 1A and 2A, is provided in Figure 3. The process flow diagram in Figure 3 differs from that in Figure 2 in that the magnesium stearate lubricant is added in two stages. In the first stage, about half of the magnesium stearate is screened and charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction. In the second stage, the remaining magnesium stearate is screened and mixed with the sized granules that are produced by the roller compactor with inline milling.The lubricated granules have improved properties for rapid capsule filling in a dosator-based encapsulation. Additionally, pre-blending was optimized by removing redundant blending step post delumping.Example 2: Plasma Pharmacokinetics of Solid, Oral Formulation of Citrate Salt of cisCompound A

[0258] Sixteen healthy male subjects aged 18 to 55 years were randomized to receive a single dose of 10 mg or 20 mg cv.s-Compound A and CSF concentrations were determined either 2 or 6 hours postdose. Samples for pharmacokinetics analysis were also collected.

[0259] Detected concentrations of cv.s-Compound A in the CSF and plasma and systemic exposure (AUCo-inf and Cmax) increased with increasing doses (Table 4). Concentrations of cv.s-Compound were below the limit of quantification at the end of the study, with the exception of 1 outlier subject.

[0260] Concentrations of cA-Compound A in the CSF increased in an approximately doseproportional manner. The arithmetic mean ratio of CSF to plasma (CSF:plasma) was 0.667 and 0.678 at 10 and 20 mg, respectively at 2 hours post-dose; at 6 hours postdose, the arithmetic mean ratio CSF:plasma was 1.01 and 1.07, respectively, suggesting cA-Compound A had good CNS penetration and was relatively more persistent in CSF than in plasma.

[0261] After dosing with 10 or 20 mg (based on the free base) cA-Compound A citrate monohydrate, the arithmetic mean plasma CL / F was 109 and 77 mL / h, respectively, and the apparent volume of distribution was 995 and 605 L, respectively.Table 4• AUCo-inf = area under the plasma concentration-time curve from 0 hours to infinity;AUCo-24 = area under the plasma concentration-time curve from 0 to 24 hours; Cmax = maximum concentration; CV = coefficient of variation; PK = pharmacokinetic(s); t / 2= half-life; tmax = time to maximum concentration• Mean and CV values are arithmetic.• Subjects received a single oral dose of cA-Compound A. In the 10 mg dose group, 1 subject was excluded from analyses as an outlier. a The tmax values are presented as median (range).Example 3: Compatibility

[0262] The API (cA-Compound A citrate monohydrate) was mixed with an excess of excipient in order to detect a potential incompatibility. The samples were prepared by weighing the required quantities of API and excipient into a scintillation vial and blendingusing a Turbula blender. Control samples of the API and individual excipients were also prepared, see Table 5.Table 5

[0263] Sample size was dictated by the ratios of each preparation. Sample sizes were as follows:1 : 10 binary mixture API: Excipient (50 mg API: 500 mg excipient)API Control 50 mgExcipient Control 500 mg 50 mg API per capsule

[0264] API-excipient mixtures, pure API and excipients were stored in open amber glass vials

[0265] All the powder preparations started off as a variation of white to off-white powders, this remained so at the 4 week time point except for povidone which had turned into a colorless, hard gel like substance with white powder inside (see Figure 4).

[0266] Povidone, which by itself looks like a white fine powder, was used as a binder. The hygroscopic nature of povidone had driven the moisture uptake from the environment causing it to set into a gel from an initial white powder appearance. The control povidone sample wasnot observed at the time points to determine if it had set into a gel, therefore the gelling was determined if it was caused by the API or was due to the high humidity environment.

[0267] At 8 weeks the appearance of povidone had not changed from the 4 week time point. The disintegrant formed a large clump of powder which was broken down using a spatula back into a powder. Mannitol and lactose had formed smaller clumps which was to be expected as both these materials do absorb moisture from the environment. Overall, apart from povidone, the appearance of the powder preparations was within expectations with no significant change into form or color occurring.

[0268] The data from the initial and 4 week time point for most of the preparations and the capsules were comparable. Overall, from the results shown in Figures 5 and 6, minimal variation was observed in the data from excipient to excipient. Specifically, more the variation was observed for related substances at RRT 0.93 and RRT 0.95, although a slight decrease was observed in the total related substances, the individual RRT peaks were consistent within the margin of error. P815-1701h had a low related substances level compared to other excipients. This was due to full extraction not being achieved as the excipient formed a precipitated mass in the HPLC sample solution, which would have trapped the API. P815-1701g also had poor recovery as the binary sample had formed a hard gel like substance with some powder in.

[0269] The data from the initial and 8 weeks time point for most of the preparations and the capsules were comparable. The 8 weeks data for P815-1701g and P815-1701h (Figure 7) had shown similarities with the 4 weeks data (Figure 6). P815-170 li had shown variability in RRT 0.95 between the three time points. These variabilities may be due to sample preparation during the HPLC run. Variabilities of 0.1% or more of label claim were deemed to be significant changes in the level of the related substance, whilst variation <0.1% label claim were mainly due to sample preparation variabilities.

[0270] The excipient compatibility study had been successful with a broad range of materials determined to be suitable for future formulation development studies for a solid oral dosage form. Some of the blends were wet but this is most likely due to the hygroscopic nature of the excipient rather than other factors. HPLC results for the related substances showed that there is variation from excipient to excipient and from time point to time point, most of these were probably due to sample preparation as the variation is below 0.1% label claim. No new quantifiable related substances were detected and no significant change of >±0.1% was observed in any of the related substances over the 8 week period to suggest that there was a trend in the data. Povidone was excluded from the development as it forms a hardgel like material and has proven to be highly hygroscopic. HPMC and API as a binary mixture had also proven difficult to extract the API from as the sample formed a precipitated mass at the bottom of the flask.Example 4: Compression Studies

[0271] G'.s-Com pound A citrate monohydrate (15 mg) was compressed into a 3 mm diameter tablet using 100 kg (-138 MPa) force for 2 minutes.

[0272] The resulting tablet was analysed by XRPD (reflection mode, C2) on its top surface before being removed from the tablet die. The reverse side was then analysed by reflection XRPD (C2) and then the whole tablet analysed by transmission XRPD (Empyrean).

[0273] The whole tablet was then analysed by Karl Fischer Titration (KF) at 150 °C. No change in form was observed by XRPD. The KF value was found to match the initial KF value of the as received powder (3.2%). G'.s-Compound A citrate monohydrate was therefore stable to compression pressures up to 100 kg (-138 Mpa) for 2 minutes.Bruker AXS C2 GADDS (Reflection Mode)

[0274] XRPD diffractograms were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for auto-sample positioning and a Vantec-500 2-dimensional area detector. X-ray optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.

[0275] The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A 9-9 continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 29 range of 1.5° - 32.5°. The sample was exposed to the X-ray beam for 120 seconds. The software used for data collection and analysis was GADDS for Win7 / XP and Diffrac Plus EVA respectively.

[0276] Samples were prepared as 3 mm diameter compressed discs and analysed within the die, under ambient conditions as a flat plate specimen. The tablet was carefully pushed out of the die, and the reverse side of the tablet analysed on a glass slide.PANalytical Empyrean (Transmission Mode)

[0277] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Seller slits with a focusing mirror were used on the incident beam. A PIXcel3Ddetector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Seller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analysed and presented using Diffrac Plus EVA or HighScore Plus.

[0278] Samples were prepared and analysed in either a metal or Millipore 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 - 2 mg) were used as received. The Millipore plate was used to isolate and analyse solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.

[0279] The scan mode for the metal plate used the gonio scan axis, whereas a 29 scan was utilised for the Millipore plate.

[0280] The details of the standard screening data collection method were:Angular range: 2.5 to 32.0° 29Step size: 0.0130° 29Collection time: 12.75 s / step (total collection time of 2.07 min)Bruker AXS D8 Advance (High Resolution, Reflectance Mode)

[0281] XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a 9-29 goniometer fitted with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit followed by a 0.2 mm antiscatter slit and knife edge. The diffracted beam passed through an 8.0 mm receiving slit with 2.5° Seller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.

[0282] Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.

[0283] The details of the standard data collection method were:• Angular range: 2 to 42° 29• Step size: 0.05° 29• Collection time: 0.5 s / step (total collection time: 6.40 min)Solution State NMR spectroscopy

[0284] 1H NMR spectra were collected at 25 °C on a Bruker 400 MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Samples were prepared in DMSO-de solvent. Automated experiments were acquired using ICON-NMR configuration within Topspin software, using standard Bruker-loaded experiments. Off-line analysis was performed using ACD Spectrus Processor.Water Determination by Karl Fischer Titration (KF)

[0285] The water content of each sample was measured on a Metrohm 874 Oven Sample Processor at 150 °C with 851 Titrano Coulometer using Hydranal Coulomat AG oven reagent and nitrogen purge. Weighed solid samples were introduced into a sealed sample vial. The entire tablet (~15 mg) was used in the analysis. Data collection and analysis were performed using Tiamo software.

[0286] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0287] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

What is claimed is:

1. A solid oral pharmaceutical formulation comprising a compound having the structure(Compound A) or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides a maximum concentration of Compound A in plasma (Cmax) that increases in a doseproportional manner.

2. The solid oral pharmaceutical formulation of claim 1, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 36 ng / mL to about 68 ng / mL.

3. The solid oral pharmaceutical formulation of claim 2, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 46 ng / mL to about 58 ng / mL.

4. The solid oral pharmaceutical formulation of claim 3, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of about 53 ng / mL.

5. The solid oral pharmaceutical formulation of claim 1, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 10 ng / mL to about 19 ng / mL.

6. The solid oral pharmaceutical formulation of claim 5, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of from about 12 ng / mL to about 17 ng / mL.

7. The solid oral pharmaceutical formulation of claim 6, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the freebase), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides a Cmax of about 15 ng / mL.

8. A solid oral pharmaceutical formulation comprising a compound having the structure(Compound A) or a pharmaceutically acceptable salt thereof, wherein upon administration of the pharmaceutical formulation to a subject, the pharmaceutical formulation provides an area under the plasma concentration-time curve of the analyte / active substance in plasma at steady state from 0 hours to 24 hours (AUC0-24) or from 0 hours to infinity (AUCo-inf) that increases in a dose-proportional manner.

9. The solid oral pharmaceutical formulation of claim 8, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUC0-24 of from about 193 h x ng / mL to about 357 h x ng / mL.

10. The solid oral pharmaceutical formulation of claim 9, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24x of from about 220 h x ng / mL to about 330 h x ng / mL.

11. The solid oral pharmaceutical formulation of claim 10, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24 of about 275 h x ng / mL.

12. The solid oral pharmaceutical formulation of claim 8, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUC0-24 of from about 83 h x ng / mL to about 153 h x ng / mL.

13. The solid oral pharmaceutical formulation of claim 12, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject,the pharmaceutical formulation provides an AUC0-24 of from about 94 h x ng / mL to about 142 h x ng / mL.

14. The solid oral pharmaceutical formulation of claim 13, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-24 of about 118 ng / mL.

15. The solid oral pharmaceutical formulation of claim 8, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 204 h x ng / mL to about 380 h x ng / mL.

16. The solid oral pharmaceutical formulation of claim 15, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 234 h x ng / mL to about 350 h x ng / mL.

17. The solid oral pharmaceutical formulation of claim 16, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 20 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of about 292 h x ng / mL.

18. The solid oral pharmaceutical formulation of claim 8, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 97 ng / mL to about 179 h x ng / mL.

19. The solid oral pharmaceutical formulation of claim 18, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of from about 110 ng / mL to about 166 h x ng / mL.

20. The solid oral pharmaceutical formulation of claim 19, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 10 mg (based on the free base), and wherein upon administration of the oral pharmaceutical formulation to a subject, the pharmaceutical formulation provides an AUCo-inf of about 138 h x ng / mL.

21. The solid oral pharmaceutical formulation of any one of the preceding claims, wherein the formulation further comprises: at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

22. A solid oral pharmaceutical formulation comprising: a compound having the structure(Compound A) or a pharmaceutically acceptable salt thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

23. The solid oral pharmaceutical formulation of any one of claims 1 to 22, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 5% w / w and about 15% w / w of the solid oral pharmaceutical formulation.

24. The solid oral pharmaceutical formulation of claim 23, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 8% w / w and about 12% w / w of the solid oral pharmaceutical formulation.

25. The solid oral pharmaceutical formulation of claim 24, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 9.5% w / w of the solid oral pharmaceutical formulation.

26. The solid oral pharmaceutical formulation of any one of claims 21 to 25, wherein the solid oral pharmaceutical formulation comprises: between about 75% w / w and about 85% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0.5% w / w and about 3% w / w of the at least one lubricant.

27. The solid oral pharmaceutical formulation of claim 26, wherein the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose, isomalt, lactose, mannitol, and pregelatinized maize starch.

28. The solid oral pharmaceutical formulation of claim 27, wherein the at least one diluent is microcrystalline cellulose.

29. The solid oral pharmaceutical formulation of claim 27, wherein the at least one diluent is dibasic calcium phosphate.

30. The solid oral pharmaceutical formulation of claim 27, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate.

31. The solid oral pharmaceutical formulation of any one of claims 26 to 30, wherein the solid oral pharmaceutical formulation comprises between about 80% w / w and about 85% w / w of the at least one diluent.

32. The solid oral pharmaceutical formulation of claim 31, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and the solid oral pharmaceutical formulation comprises about 81% w / w of the at least one diluent.

33. The solid oral pharmaceutical formulation of claim 26, wherein the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose.

34. The solid oral pharmaceutical formulation of claim 33, wherein the at least one disintegrant is croscarmellose sodium.

35. The solid oral pharmaceutical formulation of any one of claims 26 to 34, wherein the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant.

36. The solid oral pharmaceutical formulation of claim 35, wherein the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

37. The solid oral pharmaceutical formulation of any one of claims 26 to 36, wherein the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives.

38. The solid oral pharmaceutical formulation of claim 37, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose).

39. The solid oral pharmaceutical formulation of any one of claims 26 to 38, wherein the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder.

40. The solid oral pharmaceutical formulation of claim 39, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

41. The solid oral pharmaceutical formulation of claim 26, wherein the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate.

42. The solid oral pharmaceutical formulation of claim 41, wherein the at least one lubricant is magnesium stearate.

43. The solid oral pharmaceutical formulation of any one of claims 26 to 42, wherein the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / w of the at least one lubricant.

44. The solid oral pharmaceutical formulation of claim 43, wherein the at least one lubricant is magnesium stearate, and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

45. The solid oral pharmaceutical formulation of claim 26, wherein the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 9.5% w / w of the solid oral pharmaceutical formulation; the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate and is present in an amount of about 81% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

46. The solid oral pharmaceutical formulation of any one of claims 1 to 22, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 15% w / w and about 25% w / w of the solid oral pharmaceutical formulation.

47. The solid oral pharmaceutical formulation of claim 46, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 18% w / w and about 20% w / w of the solid oral pharmaceutical formulation.

48. The solid oral pharmaceutical formulation of claim 47, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 19% w / w of the solid oral pharmaceutical formulation.

49. The solid oral pharmaceutical formulation of any one of claims 46 to 48, wherein the solid oral pharmaceutical formulation comprises: between about 65% w / w and about 75% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0. 5% w / w and about 3% w / w of the at least one lubricant.

50. The solid oral pharmaceutical formulation of claim 49, wherein the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose, isomalt, lactose, mannitol, and pregelatinized maize starch.

51. The solid oral pharmaceutical formulation of claim 50, wherein the at least one diluent is microcrystalline cellulose.

52. The solid oral pharmaceutical formulation of claim 50, wherein the at least one diluent is dibasic calcium phosphate.

53. The solid oral pharmaceutical formulation of claim 50, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate.

54. The solid oral pharmaceutical formulation of any one of claims 49 to 53, wherein the solid oral pharmaceutical formulation comprises between about 70% w / w and about 73% w / w of the at least one diluent.

55. The solid oral pharmaceutical formulation of claim 56, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate and the solid oral pharmaceutical formulation comprises about 72% w / w of the at least one diluent.

56. The solid oral pharmaceutical formulation of any one of claims 46 to 55, wherein the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose.

57. The solid oral pharmaceutical formulation of claim 56, wherein the at least one disintegrant is croscarmellose sodium.

58. The solid oral pharmaceutical formulation of any one of claims 46 to 57, wherein the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant.

59. The solid oral pharmaceutical formulation of claim 58, wherein the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

60. The solid oral pharmaceutical formulation of any one of claims 46 to 59, wherein the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives.

61. The solid oral pharmaceutical formulation of claim 60, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose).

62. The solid oral pharmaceutical formulation of any one of claims 46 to 61, wherein the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder.

63. The solid oral pharmaceutical formulation of claim 62, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

64. The solid oral pharmaceutical formulation of any one of claims 46 to 63, wherein the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate.

65. The solid oral pharmaceutical formulation of claim 64, wherein the at least one lubricant is magnesium stearate.

66. The solid oral pharmaceutical formulation of any one of claims 46 to 65, wherein the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / w of the at least one lubricant.

67. The solid oral pharmaceutical formulation of claim 66, wherein the at least one lubricant is magnesium stearate and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

68. The solid oral pharmaceutical formulation of claim 46, wherein the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 19% by weight of the solid oral pharmaceutical formulation;the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and is present in an amount of about 72% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

69. The solid oral pharmaceutical formulation of any one of claims 1 to 22, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 25% w / w and about 35% w / w of the solid oral pharmaceutical formulation.

70. The solid oral pharmaceutical formulation of claim 69, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of between about 27% w / w and about 30% w / w of the solid oral pharmaceutical formulation.

71. The solid oral pharmaceutical formulation of claim 69 or 70, wherein Compound A, or a pharmaceutically acceptable salt thereof, is present in the formulation at a level (based on the free base) of about 28% w / w of the solid oral pharmaceutical formulation.

72. The solid oral pharmaceutical formulation of any one of claims 69 to 71, wherein the solid oral pharmaceutical formulation comprises: between about 55% w / w and about 70% w / w of the at least one diluent; between about 1% w / w and about 5% w / w of the at least one binder; between about 3% w / w and about 8% w / w of the at least one disintegrant; and between about 0. 5% w / w and about 3% w / w of the at least one lubricant.

73. The solid oral pharmaceutical formulation of claim 72, wherein the at least one diluent is chosen from microcrystalline cellulose, dibasic calcium phosphate, silicified microcrystalline cellulose, isomalt, lactose, mannitol, and pregelatinized maize starch.

74. The solid oral pharmaceutical formulation of claim 73, wherein the at least one diluent is microcrystalline cellulose.

75. The solid oral pharmaceutical formulation of claim 73, wherein the at least one diluent is dibasic calcium phosphate.

76. The solid oral pharmaceutical formulation of claim 73, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate.

77. The solid oral pharmaceutical formulation of any one of claims 72 to 76, wherein the solid oral pharmaceutical formulation comprises between about 60% w / w and about 65% w / w of the at least one diluent.

78. The solid oral pharmaceutical formulation of claim 77, wherein the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and the solid oral pharmaceutical formulation comprises about 63% w / w of the at least one diluent.

79. The solid oral pharmaceutical formulation of any one of claims 72 to 78, wherein the at least one disintegrant is chosen from croscarmellose sodium, sodium starch glycolate (Type A or B), crospovidone, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl cellulose.

80. The solid oral pharmaceutical formulation of claim 79, wherein the at least one disintegrant is croscarmellose sodium.

81. The solid oral pharmaceutical formulation of any one of claims 72 to 80, wherein the solid oral pharmaceutical formulation comprises between about 4% w / w and about 7% w / w of the at least one disintegrant.

82. The solid oral pharmaceutical formulation of claim 81, wherein the at least one disintegrant is croscarmellose sodium and the solid oral pharmaceutical formulation comprises about 5% w / w of the at least one disintegrant.

83. The solid oral pharmaceutical formulation of any one of claims 72 to 82, wherein the at least one binder is chosen from hydroxypropylmethyl cellulose (hypromellose), polyvinylpyrrolidone, starch, sucrose, mannitol, polyethylene glycol, cellulose and cellulose derivatives.

84. The solid oral pharmaceutical formulation of claim 83, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose).

85. The solid oral pharmaceutical formulation of any one of claims 72 to 84, wherein the solid oral pharmaceutical formulation comprises between about 2% w / w and about 4% w / w of the at least one binder.

86. The solid oral pharmaceutical formulation of claim 85, wherein the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and the solid oral pharmaceutical formulation comprises about 3% w / w of the at least one binder.

87. The solid oral pharmaceutical formulation of any one of claims 72 to 86, wherein the at least one lubricant is chosen from magnesium stearate, stearic acid, talc, glyceryl behenate, and sodium lauryl sulfate.

88. The solid oral pharmaceutical formulation of claim 87, wherein the at least one lubricant is magnesium stearate.

89. The solid oral pharmaceutical formulation of any one of claims 72 to 88, wherein the solid oral pharmaceutical formulation comprises between about 0.5% w / w and about 2% w / w of the at least one lubricant.

90. The solid oral pharmaceutical formulation of claim 89, wherein the at least one lubricant is magnesium stearate, and the solid oral pharmaceutical formulation comprises about 1% w / w of the at least one lubricant.

91. The solid oral pharmaceutical formulation of claim 72, wherein the solid oral pharmaceutical formulation comprises:Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 28% by weight of the solid oral pharmaceutical formulation; the at least one diluent is microcrystalline cellulose and dibasic calcium phosphate, and is present in an amount of about 63% w / w of the solid oral pharmaceutical formulation; the at least one disintegrant is croscarmellose sodium and is present in an amount of about 5% w / w of the solid oral pharmaceutical formulation; the at least one binder is hydroxypropylmethyl cellulose (hypromellose) and is present in an amount of about 3% w / w of the solid oral pharmaceutical formulation; and the at least one lubricant is magnesium stearate and is present in an amount of about 1% w / w of the solid oral pharmaceutical formulation.

92. The solid oral pharmaceutical formulation of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is Compound A free base.

93. The solid oral pharmaceutical formulation of any one of claims 1-91, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of Compound A.

94. The solid oral pharmaceutical formulation of claim 93, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of Compound A.

95. The solid oral pharmaceutical formulation of claim 94, wherein the citrate salt of Compound A is crystalline.

96. The solid oral pharmaceutical formulation of claim 94, wherein the citrate salt of Compound A is Compound A citrate monohydrate, and wherein the molar ratio between Compound A, citric acid, and water is about 1 : 1 : 1.

97. The solid oral pharmaceutical formulation of claim 96, wherein Compound A citrate monohydrate is crystalline.

98. The solid oral pharmaceutical formulation of any one of claims 1 to 91, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A free base.

99. The solid oral pharmaceutical formulation of any one of claims 1 to 91, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of cv.s-Compound A.

100. The solid oral pharmaceutical formulation of claim 99, wherein Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cv.s-Compound A.

101. The solid oral pharmaceutical formulation of claim 99, wherein the citrate salt of cis- Compound A is crystalline.

102. The solid oral pharmaceutical formulation of claim 100, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate, and wherein the molar ratio between cv.s-Compound A, citric acid, and water is about 1 : 1 : 1.

103. The solid oral pharmaceutical formulation of claim 102, wherein cA-Compound A citrate monohydrate is crystalline.

104. The solid oral pharmaceutical formulation of claim 101 or 103, wherein the citrate salt of cA-Compound A or cA-Compound A citrate monohydrate has at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.

105. A dosage form comprising the solid oral pharmaceutical formulation of any one of the preceding claims.

106. The dosage form of claim 105, that is in the form of a capsule.

107. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106.

108. A solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof.

109. A method of treating behavioral problems associated with a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106.

110. A solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106, for use in a method of treating behavioral problems associated with a neurological or psychiatric disease or disorder.

111. A method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder comprising: administering to the subject the solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106.

112. A solid oral pharmaceutical formulation of any one of claims 1 to 104 or the dosage form of claim 105 or 106, for use in a method of improving behavioral and / or psychological symptoms of a neurological or psychiatric disease or disorder.

113. The method or pharmaceutical formulation of any one of claims 107 to 112, wherein the neurological or psychiatric disease or disorder is chosen from schizophrenia or schizoaffective disorder, adjunctive treatment of schizophrenia, dementia, Alzheimer’s disease psychosis, bipolar disorder, Parkinson’s disease (or synucleinopathies) psychosis, and obsessive compulsive disorder.

114. The method or pharmaceutical formation of claim 113, wherein the neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

115. The method or pharmaceutical formation of claim 114, wherein the subject has at least one sign or symptom of schizophrenia.

116. The method or pharmaceutical formation of claim 115, wherein the subject has at least one positive, negative, and / or cognitive sign or symptom of schizophrenia.

117. The method or pharmaceutical formation of claim 115 or 116, wherein the at least one sign or symptom is delusions, hallucinations, disorganized speech, disorganized behavior or attention, anhedonia, catatonic behavior, affective flattening, alogia, avolition, conceptual disorganization, or any combination thereof.

118. The method or pharmaceutical formation of any one of claims 107 to 112, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen.

119. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

120. The method or pharmaceutical formation of claim 119, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at adaily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

121. The method or pharmaceutical formation of any one of claims 118 to 120, wherein the dosing regimen comprises once daily (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof.

122. The method or pharmaceutical formation of any one of claims 118 to 120, wherein the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof.

123. The method or pharmaceutical formation of any one of claims 118 to 122, wherein the dosing regimen does not include any titration period.

124. The method or pharmaceutical formation of any one of claims 118 to 122, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

125. The method or pharmaceutical formation of claim 124, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

126. The method or pharmaceutical formation of claim 125, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base.

127. The method or pharmaceutical formation of any one of claims 124 to 126, wherein the final daily dose is from about 5 mg to about 70 mg of Compound A free base.

128. The method or pharmaceutical formation of claim 127, wherein the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

129. The method or pharmaceutical formation of any one of claims 124 to 128, wherein the initial daily dose is administered QD.

130. The method or pharmaceutical formation of any one of claims 124 to 128, wherein the initial daily dose is administered BID.

131. The method or pharmaceutical formation of any one of claims 124 to 130, wherein the final daily dose is administered QD.

132. The method or pharmaceutical formation of any one of claims 124 to 130, wherein the final daily dose is administered BID.

133. The method or pharmaceutical formation of any one of claims 124 to 128, wherein the initial daily dose and final daily dose are administered QD.

134. The method or pharmaceutical formation of any one of claims 124 to 133, wherein the titration period is from about 2 to about 14 days.

135. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

136. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

137. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

138. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

139. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg ofCompound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

140. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

141. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

142. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

143. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

144. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

145. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof,according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

146. The method or pharmaceutical formation of claim 145, wherein the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose.

147. The method or pharmaceutical formation of claim 145 or 146, wherein the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base.

148. The method or pharmaceutical formation of any one of claims 145 to 147, wherein the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose.

149. The method or pharmaceutical formation of any one of claims 145 to 148, wherein the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base.

150. The method or pharmaceutical formation of any one of claims 145 to 149, wherein the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base.

151. The method or pharmaceutical formation of any one of claims 145 to 150, wherein the doses are administered BID.

152. The method or pharmaceutical formation of any one of claims 145 to 150, wherein the doses are administered QD.

153. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 15 mg of Compound A free base.

154. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mgof Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

155. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 25 mg of Compound A free base.

156. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

157. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

158. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

159. The method or pharmaceutical formation of claim 118, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

160. The method or pharmaceutical formation of any one of claims 153 to 159, wherein the doses are administered BID.

161. The method or pharmaceutical formation of any one of claims 153 to 159, wherein the doses are administered QD.

162. A process for preparing a solid oral pharmaceutical formulation of any one of claims1 to 104, comprising: subjecting a mixture of Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant to roller compaction to produce compacted ribbons; sizing the compacted ribbons to form granules; and lubricating the granules with at least one lubricant; wherein about 50% of the total lubricant in the solid oral pharmaceutical formulation is present in the mixture of Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant; and the remaining 50% of the total lubricant in the solid oral pharmaceutical formulation is added to the grannules.

163. The process of claim 163, wherein the average roll press force is between 5 and 11 kN / cm.

164. The process of claim 162, further comprising encapsulating the granules to form a dosage form.

165. A granule comprising Compound A, or a pharmaceutically acceptable salt thereof, at least one diluent, at least one binder, at least one disintegrant, and at least one lubricant, prepared by the process of claim 162.

166. A solid oral pharmaceutical formulation prepared by the process of claim 162.

167. A dosage form that is a capsule prepared by the process of claim 163.

168. The solid oral pharmaceutical formulation of claim 22, comprising cz.s-Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 9.5% w / w of the formulation; microcrystalline cellulose in an amount of about 67.5% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 14% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3% w / w of the formulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

169. The solid oral pharmaceutical formulation of claim 168, wherein the solid oral pharmaceutical formulation is administered in the form of a capsule.

170. The solid oral pharmaceutical formulation of claim 169, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 16.1 mg of cz.s-Compound A citrate monohydrate, about 114.8 mg of microcrystalline cellulose, about 23.8 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.

171. The solid oral pharmaceutical formulation of claim 22, comprising cz.s-Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 18.9% w / w of the formulation; microcrystalline cellulose in an amount of about 64.1% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 8% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3% w / w of the formulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

172. The solid oral pharmaceutical formulation of claim 171, wherein the solid oral pharmaceutical formulation is administered in the form of a capsule.

173. The solid oral pharmaceutical formulation of claim 172, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 32.1 mg of cz.s-Compound A citrate monohydrate, about 108.9 mg of microcrystalline cellulose, about 13.6 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.

174. The solid oral pharmaceutical formulation of claim 22, comprising cz.s-Compound A, or a pharmaceutically acceptable salt thereof, at a level (based on the free base) of about 28.4% w / w of the formulation; microcrystalline cellulose in an amount of about 54.6% w / w of the formulation; anhydrous dibasic calcium phosphate in an amount of about 8% w / w of the formulation; hydroxypropylmethyl cellulose (hypromellose) in an amount of about 3%w / w of the formulation; croscarmellose sodium in an amount of about 5% w / w of the formulation; and magnesium stearate in an amount of about 1% w / w of the formulation.

175. The solid oral pharmaceutical formulation of claim 174, wherein the solid oral pharmaceutical formulation is administered in the form of a capsule.

176. The solid oral pharmaceutical formulation of claim 175, wherein the total fill weight of the capsule is about 170 mg / unit, comprising about 48.3 mg of cv.s-Compound A citrate monohydrate, about 92.8 mg of microcrystalline cellulose, about 13.6 mg of anhydrous dibasic calcium phosphate, about 8.5 mg of croscarmellose sodium, about 5.1 mg of hydroxypropylmethyl cellulose, and about 1.7 mg of magnesium Stearate.

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