Novel salts and crystals

Abstract

The present disclosure provides novel stable crystalline salt forms of lumateperone, methods for making and using same, and pharmaceutical compositions containing them.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a PCT international application claiming priority to and the benefit of U.S. Provisional Application No. 63 / 393,911, filed June 30, 2022, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present disclosure relates to certain novel salts and crystalline forms of lumateperone, a substituted heterocyclic fused γ-carboline, its preparation, pharmaceutical compositions thereof, and methods for the preparation of compounds that inhibit, for example, 5-HT 2A The present invention relates to their use in the treatment of diseases or abnormal conditions involving or mediated by the receptor, serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways. [Background technology]

[0002] Lumateperone, a substituted heterocyclic fused gamma-carboline compound, has the chemical name 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone and binds to serotonin receptors (5-HT 2A ), dopamine receptor (D1 and / or D2) and serotonin transporter (SERT) ligands, and is useful for treating various central nervous system disorders. Also known as ITI-007, it has the following structure: [ka] It has.

[0003] Lumateperone inhibits serotonin-2A (5-HT 2A) receptors and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins. This compound is primarily known to be effective in treating the positive and negative symptoms of schizophrenia, depression (particularly acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorder), and dementia (including Alzheimer's disease and related conditions). At the dopamine D2 receptor, this compound possesses dual properties, acting as both a postsynaptic antagonist and a presynaptic partial agonist of the D2 receptor. It also stimulates phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a mesolimbic-specific manner. This regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, along with serotonergic, glutamatergic, and dopaminergic interactions, is thought to contribute to the efficacy of antipsychotic drugs against the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition and provides antidepressant activity for the treatment of schizoaffective disorder, comorbid depression, and / or as a standalone treatment for major depressive disorder, bipolar depression, and treatment-resistant depression. Lumateperone is also effective in treating bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism, and other CNS disorders. These characteristics may improve the quality of life of patients with schizophrenia, enhance their social functioning, and enable them to integrate more fully into their families and workplaces.

[0004] Lumateperone showed different dose-dependent effects, with 5-HT 2A It selectively targets the D2 receptor and, at high doses, interacts gradually with the D2 receptor. As a result, at low doses, it is useful for treating sleep, aggression, and agitation. At high doses, it can treat acute exacerbations and residual schizophrenia, bipolar disorder, and mood disorders.

[0005] Lumateperone is a potent (Ki=0.5nM) 5-HT 2AIt is a receptor antagonist with in vivo presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki = 32 nM), high D1 receptor affinity (Ki = 52 nM), and activity as a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator consistent with inhibition of the serotonin transporter (SERT) (Ki = 26-62 nM using various assays for SERT activity), but negligible binding to receptors associated with the cognitive and metabolic side effects of antipsychotics (e.g., H1 histaminergic, 5-HT2C, and muscarinic).

[0006] Lumateperone tosylate (Caplyta®) is currently approved in the United States for the treatment of schizophrenia and bipolar depression. It is currently in clinical trials and development for additional indications, including major depressive disorder (MDD).

[0007] Lumateperone has also recently been shown to be particularly effective in treating acute depression and acute anxiety due to its rapid onset of action compared to existing antidepressants. This is thought to be due to signaling via a neurotransmitter system other than the traditional monoamine signaling system. Lumateperone provides dopamine D1 receptor-dependent enhancement of NMDA and AMPA currents, along with activation of the mTOR (e.g., mTORC1) signaling pathway.

[0008] Formulating lumateperone as a drug is challenging. In its free base form, ITI-007 is an oily, sticky solid with poor aqueous solubility. Making a salt of the compound has proven extremely difficult. A hydrochloride form of lumateperone, easily prepared during the synthesis of the free base, was disclosed in WO 2000 / 0770020; however, this particular salt was not crystalline, and such hydrochloride salts were found to be hygroscopic and unstable. A stable, crystalline toluenesulfonic acid addition salt (monotosylate) of lumateperone was eventually identified and described, for example, in WO 2009 / 114181. Additional salts and polymorphs of lumateperone have since been described, including the bistosylate, besylate, naphthalenesulfonate, and naphthalenedisulfonate salts. See, for example, WO2018 / 031535, WO2019 / 102240, WO2020 / 182988, WO2020 / 112941 and IN2017 / 41021763.

[0009] Typically, a pharmaceutically acceptable salt form of a drug should have high aqueous solubility, but this is not necessarily the most desirable form. For example, drugs for oral, transmucosal, and intravenous delivery should have high aqueous solubility, but salt forms with low aqueous solubility are also required, especially for delivery from long-acting injectable depots (e.g., sustained delivery over weeks or months). In this context, low aqueous solubility of a drug results in the slow dissolution of the drug from an insoluble, pharmacologically inactive depot form to a pharmacologically active, soluble form. However, such a delivery mechanism requires high chemical and physical stability to prevent the drug from decomposing in vivo into chemical products or polymorphs with unpredictable pharmacological or pharmacokinetic properties.

[0010] Therefore, there is a need for a chemically and physically stable, preferably crystalline, solid, pharmaceutically acceptable salt form of lumateperone with low aqueous solubility. Summary of the Invention

[0011] Extensive salt screening was conducted to find a novel, chemically and physically stable, preferably crystalline, solid, pharmaceutically acceptable salt form of lumateperone with low aqueous solubility. Based on the known tosylate and besylate salts, it was thought that other aromatic sulfonate salts of lumateperone might be suitable. However, lumateperone does not readily form salts with other common, pharmaceutically acceptable acids. See, for example, US2019 / 0112309, US2020 / 247805, and US2020 / 015700. These references disclose attempts to create new crystalline salt forms of lumateperone, but with very low success rates. For example, US2019 / 112309 and US2020 / 247805 disclose the results of a series of salt screening experiments conducted using 90 counterions, six solvents, and four crystallization methods. A total of 626 combinations of counterions, solvents, and methods were tested, resulting in the reproducible formation of only four stable crystalline salts (oxalate, cyclamate, 4-aminosalicylate, and three polymorphs of the hydrochloride salt). Importantly, it was not possible to predict which types of counterions would form stable crystalline salts, nor which methods would produce each stable crystalline salt. The majority of reaction conditions were found to result in either no salt formation or the formation of amorphous solid or oily liquid salts.

[0012] Here, we identified 16 novel crystalline lumateperone salt candidates through extensive screening and experimentation involving 36 different sulfonate counterions (aryl, heteroaryl, heterocycloalkyl, and alkyl sulfonates) using both 1:1 and 1:2 molar ratios and several solvents (9:1 acetonitrile / water, methanol, ethyl acetate, and toluene). Upon further scale-up and validation, eight new, reproducible, and stable crystalline salt forms of lumateperone were discovered. In particular, two novel, low-solubility salt forms of lumateperone, 4-t-butylbenzenesulfonate and 4-octylbenzenesulfonate, with aqueous solubilities of less than 2 mg / mL, were discovered. These salt forms are chemically and physically stable, crystalline, and have low aqueous solubility, making them ideally suited for novel pharmaceutical compositions for sustained or delayed release, such as long-acting injectable compositions.

[0013] Thus, the present disclosure provides novel salt forms of lumateperone, particularly novel low-water-solubility salt forms of lumateperone, that are particularly advantageous for use in the formulation of long-acting injectable formulations, as well as methods for their manufacture and use. Due to their low water solubility, these new salt forms are not expected to be suitable for conventional oral immediate-release formulations of lumateperone, such as tablets or capsules, nor are they expected to be suitable for immediate-release transmucosal formulations (e.g., sublingual tablets), immediate-release subcutaneous injectable formulations, intravenous formulations, or sustained- or delayed-release oral formulations. However, they are expected to be highly useful in a variety of sustained- or delayed-release injectable pharmaceutical formulations.

[0014] Further scope of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present disclosure, are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. [Brief explanation of the drawings]

[0015] The present disclosure will become more fully understood from the detailed description and the accompanying drawings, wherein:

[0016] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XPRD) pattern of the 4-octylbenzenesulfonate salt of lumateperone prepared according to Example 2.

[0017] [Figure 2] FIG. 2 shows the X-ray powder diffraction (XPRD) pattern of the 4-tert-butylbenzenesulfonate salt of lumateperone prepared according to Example 3.

[0018] [Figure 3] FIG. 3 shows the X-ray powder diffraction (XPRD) pattern of the 4-propylbenzenesulfonate salt of lumateperone prepared according to Example 4.

[0019] [Figure 4A] FIG. 4A shows the X-ray powder diffraction (XPRD) pattern of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 1) prepared according to Example 5A.

[0020] [Figure 4B] FIG. 4B shows the X-ray powder diffraction (XPRD) pattern of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 2) prepared according to Example 5B.

[0021] [Figure 4C] FIG. 4C shows the X-ray powder diffraction (XPRD) pattern of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 3) prepared according to Example 5C.

[0022] [Figure 5] FIG. 5 shows the X-ray powder diffraction (XPRD) pattern of the 2-naphthalenesulfonate salt of lumateperone prepared according to Example 6.

[0023] [Figure 6A] FIG. 6A shows the X-ray powder diffraction (XPRD) pattern of lumateperone besylate salt (polymorph 1) prepared according to Example 7A.

[0024] [Figure 6B] FIG. 6B shows the X-ray powder diffraction (XPRD) pattern of lumateperone besylate salt (polymorph 2) prepared according to Example 7B.

[0025] [Figure 6C] FIG. 6C shows the X-ray powder diffraction (XPRD) pattern of lumateperone besylate salt (polymorph 3) prepared according to Example 7C.

[0026] [Figure 7] FIG. 7 shows the X-ray powder diffraction (XPRD) pattern of the pentane-1-sulfonate salt of lumateperone prepared according to Example 8.

[0027] [Figure 8] FIG. 8 shows the X-ray powder diffraction (XPRD) pattern of the heptane-1-sulfonate salt of lumateperone prepared according to Example 9.

[0028] [Figure 9] FIG. 9 shows the proton-NMR spectrum of the 4-octylbenzenesulfonate salt of lumateperone prepared according to Example 2.

[0029] [Figure 10] FIG. 10 shows the proton-NMR spectrum of the 4-tert-butylbenzenesulfonate salt of lumateperone prepared according to Example 3.

[0030] [Figure 11] FIG. 11 shows the proton-NMR spectrum of the 4-propylbenzenesulfonate salt of lumateperone prepared according to Example 4.

[0031] [Figure 12A] FIG. 12A shows the proton-NMR spectrum of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 1) prepared according to Example 5A.

[0032] [Figure 12B] FIG. 12B shows the proton-NMR spectrum of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 2) prepared according to Example 5B.

[0033] [Figure 12C] FIG. 12C shows the proton-NMR spectrum of the 4-ethylbenzenesulfonate salt of lumateperone (polymorph 3) prepared according to Example 5C. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following description of the preferred embodiment is merely exemplary in nature and is in no way intended to limit the invention described in this disclosure, its application, or uses.

[0035] As used throughout, ranges are used as shorthand to describe any value within that range. Any value within the range can be selected as the endpoint of the range. Additionally, all references cited herein are incorporated by reference in their entirety. In the event of a conflict between a definition in this disclosure and a definition in a reference, the present disclosure controls.

[0036] Unless otherwise specified, all percentages and amounts expressed in this specification and elsewhere herein are understood to refer to percentages by weight. The amounts stated are based on the active weight of the material.

[0037] The present disclosure generally provides novel salt forms of lumateperone, particularly novel crystalline salt forms of lumateperone. Preferably, these novel crystalline salt forms have low aqueous solubility (e.g., at pH 7 or pH 7.4). For example, salts according to the present disclosure may have an aqueous solubility of less than 20 mg / mL, e.g., less than 15 mg / mL, or less than 10 mg / mL, or less than 5 mg / mL, or less than 3 mg / mL, or less than 2 mg / mL, or less than 1 mg / mL, or less than 0.5 mg / mL, or less than 0.1 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL.

[0038] In a first embodiment, the present disclosure provides lumateperone in the form of a 4-octylbenzenesulfonic acid addition salt (Salt 1). In a further embodiment of Salt 1, the present disclosure provides: 1.1 Salts in solid form1. 1.2 Salts 1 or 1.1 in crystalline form, for example in dry crystalline form. 1.3 Salt 1, 1.1 or 1.2, wherein the molar ratio of lumateperone to 4-octylbenzenesulfonic acid in the salt is about 1:1 (i.e., mono-4-octylbenzenesulfonate). 1.4 Salt 1, 1.1 or 1.2, wherein the molar ratio of lumateperone to 4-octylbenzenesulfonic acid in the salt is about 1:2 (i.e., bis-4-octylbenzenesulfonate). 1.5 Any of the above forms of Salt 1 that are solvates, for example, ethyl acetate or toluene solvates. 1.6 Any of the preceding forms of Salt 1, which is not a solvate. 1.7 Any of the preceding forms of salt 1 which is a hydrate. 1.8 Any of the preceding forms of salt 1 that is not a hydrate. 1.9 Any of the foregoing forms of Salt 1 formed by combining lumateperone free base and 4-octylbenzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 1.10 Any of the foregoing forms of Salt 1, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 1.11 Any of the foregoing forms of Salt 1 in a crystalline form crystallized from a mixture of 4-octylbenzenesulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of about 1:1 or about 1:2 between lumateperone free base and 4-octylbenzenesulfonic acid. 1.12 Salts crystallize from solvents after addition of an anti-solvent, for example, where the anti-solvent is water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or where the anti-solvent is heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 1.13 Any of the foregoing forms of Salt 1, wherein the salt is formed from lumateperone free base and 4-octylbenzenesulfonic acid in a 1:1 molar ratio in ethyl acetate solvent, or from lumateperone free base and 4-octylbenzenesulfonic acid in a 1:2 molar ratio in ethyl acetate solvent, or from lumateperone free base and 4-octylbenzenesulfonic acid in a 1:2 molar ratio in toluene solvent. 1.14 Salt 1.13, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-octylbenzenesulfonic acid of about 1:1. 1.15 Salt 1.13 or 1.14, wherein DSC analysis shows one endothermic event (e.g., melting) at about 156°C, or one endothermic event (e.g., melting) at about 164°C, or one endothermic event (e.g., melting) at about 135°C. 1.16 Any of the forms of salts 1.13-1.15 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 4, 5, 9, 11, 12, 15, 17, and / or 18: [Table 1] 1.17 Any of the forms of salts 1.13-1.16 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 1, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 1.18 Taking into account potential variations due to sample purity and instrumental variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the peaks are approximately 9.09, 9.19, 11.37, 11.81, 12.67, 13.24, 14.50, 15.29, 16.06, 16.30, 16.87, 18.22, 18.78, 19.43, 20.11, 20.47, 22.62, 22.67, 23.09, 23.66, 24. Any of salts 1.13 to 1.17 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 10, 24.46, 25.97, and 29.82, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 1.19 Any of the forms of salts 1.13-1.18 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 9.72, 9.61, 7.78, 7.49, 6.98, 6.68, 6.11, 5.79, 5.51, 5.43, 5.25, 4.87, 4.72, 4.57, 4.41, 4.34, 3.93, 3.92, 3.85, 3.76, 3.69, 3.64, 3.43, and 2.99, taking into account potential variations due to sample purity and instrumental variation (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 1.20 Any of salts 1.13-1.19 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 1.18 and 1.19. 1.21 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties. 1.22 Any of the foregoing forms of Salt 1, exhibiting any combination of the characteristics described in 1.1-1.21.

[0039] In a second embodiment, the present disclosure provides lumateperone in the form of a 4-tert-butylbenzenesulfonic acid addition salt (Salt 2). In a further embodiment of Salt 2, the present disclosure provides: 2.1 Salts in solid form2. 2.2 Salts 2 or 2.1 in crystalline form, for example in dry crystalline form. 2.3 Salt 2, 2.1 or 2.2, wherein the molar ratio of lumateperone to 4-tert-butylbenzenesulfonic acid in the salt is about 1:1 (i.e., mono-4-tert-butylbenzenesulfonate). 2.4 Salt 2, 2.1 or 2.2, wherein the molar ratio of lumateperone to 4-tert-butylbenzenesulfonic acid in the salt is about 1:2 (i.e., bis-4-tert-butylbenzenesulfonate). 2.5 Any of the preceding forms of salt 2 which is a solvate, for example, an ethyl acetate solvate. 2.6 Any of the above forms of salt 2, which is not a solvate. 2.7 Any of the preceding forms of salt 2, which is a hydrate. 2.8 Any of the above forms of salt 2, which is not a hydrate. 2.9 Any of the foregoing forms of Salt 2 formed by combining lumateperone free base and 4-tert-butylbenzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 2.10 Any of the foregoing forms of Salt 2, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 2.11 Any of the foregoing forms of Salt 2 in a crystalline form crystallized from a mixture of 4-tert-butylbenzenesulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or mixtures thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of lumateperone free base to 4-tert-butylbenzenesulfonic acid of about 1:2. 2.12 Salts crystallize from solvents after addition of an anti-solvent, for example, where the anti-solvent is water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or where the anti-solvent is heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 2.13 Any of the preceding forms of Salt 2, wherein the salt is formed from lumateperone free base and 4-tert-butylbenzenesulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. 2.14 Salt 2.13, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-tert-butylbenzenesulfonic acid of about 1:2. 2.15 Salt 2.13 or 2.14, wherein DSC analysis shows one endothermic event at about 68°C (e.g., desolvation) and one endothermic event at about 212°C (e.g., melting). 2.16 Any of the forms of salt 2.13-2.15 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 2, 4, 5, 6, 7, 9, 11, and / or 12: [Table 2] 2.17 Any of the forms of salts 2.13-2.16 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 2, e.g., an X-ray powder diffraction pattern corresponding to Figure 2, generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 2.18 Any of the forms of salts 2.13-2.17 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 3.22, 3.64, 6.67, 7.19, 13.90, 14.72, 15.22, 15.64, 16.05, 17.96, 18.78, 18.90, 19.59, 20.66, 22.08, 22.99, and 23.68, taking into account potential variations due to sample purity and instrumental variation (e.g., an angle shift of up to ±0.2 degrees of any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 2.19 Any of the forms of Salts 2.13-2.18 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks with d-spacing values selected from the group consisting of about 27.45, 24.25, 13.25, 12.28, 6.36, 6.01, 5.82, 5.66, 5.52, 4.94, 4.72, 4.69, 4.53, 4.30, 4.02, 3.86, and 3.75, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 2.20 Any of salts 2.13-2.19 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 2.18 and 2.19. 2.21 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties. 2.22 Any of the foregoing forms of Salt 2, exhibiting any combination of the characteristics described in 2.1-2.21.

[0040] In a third embodiment, the present disclosure provides lumateperone in the form of a 4-propylbenzenesulfonic acid addition salt (Salt 3). In a further embodiment of Salt 3, the present disclosure provides: 3.1 Salts in solid form3. 3.2 Salts 3 or 3.1 in crystalline form, for example in dry crystalline form. 3.3 Salt 3, 3.1 or 3.2, wherein the molar ratio of lumateperone to 4-propylbenzenesulfonic acid in the salt is about 1:1 (i.e., mono-4-propylbenzenesulfonate). 3.4 Salt 3, 3.1 or 3.2, wherein the molar ratio of lumateperone to 4-propylbenzenesulfonic acid in the salt is about 1:2 (i.e., bis-4-propylbenzenesulfonate). 3.5 Any of the preceding forms of salt 3, which is a solvate, for example, an ethyl acetate solvate. 3.6 Any of the preceding forms of salt 3, which is not a solvate. 3.7 Any of the preceding forms of salt 3, which is a hydrate. 3.8 Any of the preceding forms of salt 3, which is not a hydrate. 3.9 Any of the foregoing forms of Salt 3 formed by combining lumateperone free base and 4-propylbenzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 3.10 Any of the foregoing forms of Salt 3, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 3.11 Any of the foregoing forms of Salt 3 in a crystalline form crystallized from a mixture of 4-propylbenzenesulfonic acid and lumateperone free base in an organic solvent; e.g., ethyl acetate, including, e.g., ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or mixtures thereof, optionally in a molar ratio of lumateperone free base to 4-propylbenzenesulfonic acid of about 1:2. 3.12 Salts that crystallize from solvents after addition of an anti-solvent, for example, where the anti-solvent is water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or where the anti-solvent is heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 3.13 Any of the preceding forms of Salt 3, wherein the salt is formed from lumateperone free base and 4-propylbenzenesulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. 3.14 Salt 3.13, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-propylbenzenesulfonic acid of approximately 1:2. 3.15 Salt 3.13 or 3.14, in which DSC analysis shows a single endothermic event (e.g., melting) at about 159°C. 3.16 Any of the forms of salts 3.13-3.15 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 5, 9, 10, 14, and / or 18: [Table 3] 3.17 Any of the forms of salts 3.13-3.16 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 3, e.g., an X-ray powder diffraction pattern corresponding to Figure 3 generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 3.18 Taking into account potential variations due to sample purity and instrument variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the following peaks are approximately: 4.05, 8.01, 10.55, 12.62, 13.05, 13.64, 14.38, 14.80, 15.31, 16.46, 17.33, 17.75, 19.13, 19.98, 20.44, 20.75, 21.11, 21.45, 21.95, 22.28, 22.86, 23.65, 24. Any of salts 3.13 to 3.17 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 2.08, 25.61, 26.26, 26.82, 28.07, and 31.38, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 3.19 Potential variations due to sample purity and instrumental variations (e.g., maximum ±0.2% of any one or more peaks) any of the crystalline forms of salts 3.13-3.18, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 21.80, 11.03, 8.38, 7.01, 6.78, 6.48, 6.15, 5.98, 5.78, 5.38, 5.11, 4.99, 4.64, 4.44, 4.34, 4.28, 4.20, 4.14, 4.05, 3.99, 3.89, 3.76, 3.69, 3.48, 3.39, 3.32, 3.18, and 2.85, taking into account the shift in d-spacings, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 3.20 Any of salts 3.13-3.19 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 3.18 and 3.19. 3.21 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; e.g., the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties. 3.22 Any of the foregoing forms of Salt 3, exhibiting any combination of the characteristics described in 3.1-3.21.

[0041] In a fourth embodiment, the present disclosure provides lumateperone in the form of a 4-ethylbenzenesulfonic acid addition salt (Salt 4). In a further embodiment of Salt 4, the present disclosure provides: 4.1 Salts in solid form4. 4.2 Salt 4, or 4.1, in crystalline form, for example in dry crystalline form. 4.3 Salt 4, 4.1 or 4.2, wherein the molar ratio of lumateperone to 4-ethylbenzenesulfonic acid in the salt is 1:1 (i.e., mono-4-ethylbenzenesulfonate salt). 4.4 Salt 4, 4.1 or 4.2, wherein the molar ratio of lumateperone to 4-ethylbenzenesulfonic acid in the salt is 1:2 (i.e., bis-4-ethylbenzenesulfonate). 4.5 Any of the preceding forms of salt 4 which is a solvate, for example, an ethyl acetate solvate, or a toluene solvate. 4.6 Any of the preceding forms of salt 4, which is not a solvate. 4.7 Any of the preceding forms of salt 4, which is a hydrate. 4.8 Any of the preceding forms of salt 4, which is not a hydrate. 4.9 Any of the foregoing forms of salt 4 formed by combining lumateperone free base and 4-ethylbenzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 4.10 Any of the foregoing forms of Salt 4, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 4.11 Any of the foregoing forms of Salt 1 in a crystalline form crystallized from a mixture of 4-ethylbenzenesulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of about 1:1 or about 1:2 between lumateperone free base and 4-ethylbenzenesulfonic acid. 4.12 Salts crystallize from solvents after addition of an anti-solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture, the anti-solvent is water, or when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol, the anti-solvent is heptane or hexane, for example, when the organic solvent is toluene and the anti-solvent is heptane. 4.13 Salt 4 or any of 4.1-4.12, wherein the salt is formed from lumateperone free base and 4-ethylbenzenesulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. 4.14 Salt 4.13, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-ethylbenzenesulfonic acid of approximately 1:2. 4.15 Salt 4.13 or 4.14, wherein DSC analysis shows one endothermic event (e.g., melting) at about 147°C, or one endothermic event (e.g., melting) at about 156°C, or one endothermic event (e.g., melting) at about 138°C. 4.16 Any of the forms of salts 4.13-4.15 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 2, 3, 10, 11, 14, 15, and / or 16: [Table 4] 4.17 Any of the forms of salts 4.13-4.16 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 4A, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 4.18 Any of the forms of Salts 4.13-4.17 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 3.51, 3.68, 4.98, 6.92, 7.32, 10.35, 10.38, 12.49, 13.69, 14.27, 15.59, 17.50, 17.68, 18.58, 18.85, 20.13, 20.61, 20.83, 21.25, 22.02, and 27.49, taking into account potential variations due to sample purity and instrumental variation (e.g., an angle shift of up to ±0.2 degrees of any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.19 Any of the forms of Salts 4.13-4.18 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 25.14, 23.97, 17.72, 12.77, 12.07, 8.54, 8.51, 7.08, 6.46, 6.20, 5.68, 5.06, 5.01, 4.77, 4.70, 4.41, 4.31, 4.26, 4.18, 4.03, and 3.24, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.20 Any of salts 4.13-4.19 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 4.18 and 4.19. 4.21 Salt 4 or any of 4.1-4.12, wherein the salt is formed from lumateperone free base and 4-ethylbenzenesulfonic acid in a 1:2 molar ratio in toluene solvent. Salt 4.21, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-ethylbenzenesulfonic acid of approximately 1:2. 4.23 Salt 4.21 or 4.22, wherein DSC analysis shows one endothermic event (e.g., melting) at about 156°C, or one endothermic event (e.g., melting) at about 147°C, or one endothermic event (e.g., melting) at about 138°C. 4.24 Any of salts 4.21 to 4.23 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 2, 3, 8, 9, 10, 12, 13, 14, and / or 16: [Table 5] 4.25 Any of the forms of salts 4.21-4.24 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 4B, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 4.26 Taking into account potential variations due to sample purity and instrument variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the following peaks were measured: approximately 3.69, 5.03, 7.32, 10.27, 11.19, 11.70, 13.80, 14.27, 14.79, 15.63, 16.49, 17.66, 18.80, 20.22, 20.58, 20.78, 21.08, 21.41, 22.02, 22.96, 24.09, Any of salts 4.21 to 4.25 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 24.74, 25.28, 26.24, and 27.70, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.27 Any of the forms of salts 4.21-4.26 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks with d-spacing values selected from the group consisting of about 23.90, 17.54, 12.07, 8.61, 7.90, 7.56, 6.41, 6.20, 5.98, 5.66, 5.37, 5.02, 4.72, 4.39, 4.31, 4.27, 4.21, 4.15, 4.03, 3.87, 3.69, 3.60, 3.52, 3.39, and 3.22, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.28 A crystalline form of any of salts 4.21-4.27 having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 4.26 and 4.27. 4.29 Salt 4 or any of 4.1-4.12, formed from lumateperone free base and 4-ethylbenzenesulfonic acid in a 1:1 molar ratio in toluene solvent and heptane antisolvent. 4.30 Salt 4.29, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 4-ethylbenzenesulfonic acid of approximately 1:1. 4.31 Salt 4.29 or 4.30, wherein DSC analysis shows one endothermic event (e.g., melting) at about 138°C, or one endothermic event (e.g., melting) at about 156°C, or one endothermic event (e.g., melting) at about 147°C. 4.32 Any of the forms of salts 4.29-4.31 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 2, 4, 5, 6, 7, 9, 14, 16, and / or 17: [Table 6] 4.33 Any of the forms of salts 4.29-4.32 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 4C, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 4.34 Any of the forms of salts 4.29-4.33 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 2.79, 5.57, 11.38, 12.09, 13.12, 15.97, 16.59, 17.49, 18.00, 18.87, 19.41, 20.54, 21.31, 22.54, 22.80, 23.27, 24.02, 25.45, 31.61, and 34.01, taking into account potential variations due to sample purity and instrumental variations (e.g., an angle shift of up to ±0.2 degrees of any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.35 Any of salts 4.29-4.34 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 31.66, 15.86, 7.77, 7.31, 6.74, 5.55, 5.34, 5.07, 4.93, 4.70, 4.57, 4.32, 4.17, 3.94, 3.90, 3.82, 3.70, 3.50, 2.83, and 2.63, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 4.36 Any of salts 4.29-4.35 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 4.34 and 4.35. 4.37 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; e.g., the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety. 4.38 Any of the foregoing forms of Salt 4, exhibiting any combination of the characteristics described in 4.1-4.37.

[0042] In a fifth embodiment, the present disclosure provides lumateperone in the form of a 2-naphthalenesulfonic acid addition salt, wherein the salt is a solvate (Salt 5). In a further embodiment of Salt 5, the present disclosure provides: 5.1 Salts in solid form5. 5.2 Salts 5 or 5.1 in crystalline form, for example in dry crystalline form. 5.3 Salt 5, 5.1 or 5.2, wherein the molar ratio of lumateperone to 2-naphthalenesulfonic acid in the salt is 1:1 (i.e., mono-napsylate salt). 5.4 Salt 5, 5.1 or 5.2, wherein the molar ratio of lumateperone to 2-naphthalenesulfonic acid in the salt is 1:2 (i.e., bis-napsylate salt). 5.5 Any of the preceding forms wherein the salt is an ethyl acetate solvate, Salt 5. 5.6 Any of the preceding forms of salt 5, which is a hydrate. 5.7 Any of the above forms of salt 5, which is not a hydrate. 5.8 Any of the foregoing forms of salt 5 formed by combining lumateperone free base and 2-naphthalenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 5.9 Any of the foregoing forms of Salt 5, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 5.10 Any of the foregoing forms of Salt 5 in a crystalline form crystallized from a mixture of 2-naphthalenesulfonic acid and lumateperone free base in an organic solvent, e.g., ethyl acetate, including, e.g., ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or mixtures thereof, optionally in a molar ratio of lumateperone free base to 2-naphthalenesulfonic acid of about 1:2. 5.11 Salts 5.10, which crystallize from a solvent after addition of an anti-solvent, for example, where the anti-solvent is water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or where the anti-solvent is heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 5.12 Any of the preceding forms of Salt 5, wherein the salt is formed from lumateperone free base and 2-naphthalenesulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. 5.13 Salt 5.12, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to 2-naphthalenesulfonic acid of approximately 1:2. 5.14 Salt 5.12 or 5.13, wherein DSC analysis shows one endothermic event at about 108°C (e.g., desolvation) and / or one endothermic event at about 162°C (e.g., melting). 5.15 Any of the forms 5.12-5.14 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 2, 3, 4, 5, 8, 9, 11, 14, and / or 16: [Table 7] 5.16 Any of the forms of salts 5.12-5.15 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 5, e.g., an X-ray powder diffraction pattern corresponding to Figure 5 generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 5.17 Any of the forms of Salts 5.12 through 5.16 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 2.40, 7.05, 14.06, 14.91, 15.48, 17.20, 17.49, 19.02, 20.32, 20.42, 20.78, 20.84, 21.25, 23.85, 26.94, and 27.21, taking into account potential variations due to sample purity and instrumental variations (e.g., angle shifts of up to ±0.2 degrees for any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 5.18 Any of the forms of Salts 5.12-5.17 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 36.77, 12.54, 6.29, 5.94, 5.72, 5.15, 5.07, 4.66, 4.37, 4.35, 4.27, 4.26, 4.18, 3.73, 3.31, and 3.27, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 5.19 A crystalline form of any of salts 5.12-5.18 having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 5.17 and 5.18. 5.20 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties. 5.21 Any of the foregoing forms of Salt 5, exhibiting any combination of the characteristics described in 5.1-5.20.

[0043] In a sixth embodiment, the present disclosure provides lumateperone in the form of a solid crystalline salt, benzenesulfonic acid addition salt (Salt 6), wherein the salt is characterized by a DSC thermogram lacking an endothermic event between 172 and 176° C. In a further embodiment of Salt 6, the present disclosure provides: 6.1 Salt 6, in which the molar ratio of lumateperone to benzenesulfonic acid in the salt is 1:1 (i.e., mono-besylate salt). 6.2 Salt 6, in which the molar ratio of lumateperone to benzenesulfonic acid in the salt is 1:2 (i.e., bis-besylate salt). 6.3 Any of the above forms of salt 6 which is a solvate, for example, an ethyl acetate solvate, or a toluene solvate. 6.4 Any of the above forms of salt 6, which is not a solvate. 6.5 Any of the preceding forms of salt 6, which is a hydrate. 6.6 Any of the above forms of salt 6 that is not a hydrate. 6.7 Any of the foregoing forms of Salt 6 formed by combining lumateperone free base and benzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 6.8 Any of the forms of Salt 6, wherein the Salt is a homogeneous crystalline form, free or substantially free of other forms (e.g., another crystalline form or amorphous form), e.g., free or substantially free of other forms (e.g., another crystalline form or amorphous form), e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of other forms (e.g., another crystalline form or amorphous form). 6.9 Any of the foregoing forms of Salt 6, in a crystalline form crystallized from a mixture of benzenesulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of about 1:1 or about 1:2 between benzenesulfonic acid and lumateperone free base. 6.10 Salts crystallize from solvents after the addition of an anti-solvent, for example, water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 6.11 Any of salts 6 or 6.1-6.10, where the salt is formed from lumateperone free base and benzenesulfonic acid in a molar ratio of 1:1 or 1:2 in ethyl acetate solvent. 6.12 Salt 6.11, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to benzenesulfonic acid of approximately 1:1. 6.13 Salt 6.11 or 6.12, wherein DSC analysis shows one endothermic event at about 96°C (e.g., desolvation) and / or one endothermic event at about 110°C (e.g., melting). 6.14 Any of the forms of salts 6.11-6.13 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 2, 6, 7, 10, 11, 12, 13, 17, 19, 20, 24, 25, 26, and / or 28: [Table 8] 6.15 Any of the forms of salts 6.11-6.14 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 6A, e.g., an X-ray powder diffraction pattern corresponding to Figure 6A, generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shifts due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 6.16 Taking into account potential variations due to sample purity and instrument variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the following peaks are approximately: 5.81, 5.88, 8.81, 11.42, 11.73, 12.02, 12.39, 13.26, 15.78, 15.94, 16.11, 16.65, 17.00, 17.59, 17.81, 18.02, 18.28, 18.66, 19.36, 19.93, 20.20, 20.53, 21.21, 22.60, 22.98, 23.30, Any of salts 6.11 to 6.15 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 23.72, 24.09, 24.44, 25.52, 26.20, 26.33, 27.25, 27.96, and 30.13, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.17 Taking into account potential variations due to sample purity and instrument variation (e.g., a shift of up to ±0.2 d-spacings for any one or more peaks), the following values are approximate: 15.21, 15.02, 10.03, 7.74, 7.54, 7.36, 7.14, 6.67, 5.61, 5.55, 5.50, 5.32, 5.21, 5.04, 4.98, 4.92, 4.85, 4.75, 4.58, 4.45, 4.39, 4.32, 4.19, 3.93, 3.87, 3.81, 3.75, 3.69, 3.64, 3.49, 3.40, 3.50, 3.61, 3.75, 3.62, 3.53, 3.54, 3.56, 3.57, 3.59, 3.66, 3.70, 3.73, 3.74, 3.75, 3.86, 3.87, 3.88, 3.96, 3.97, 3.9 ... Any of salts 6.11 to 6.16 in crystalline form having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of 0.38, 3.27, 3.19, and 2.96, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.18 A crystalline form of any of salts 6.11-6.17 having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 6.16 and 6.17. 6.19 Salt 6 or any of 6.1-6.10, where the salt is formed from lumateperone free base and benzenesulfonic acid in a 1:1 or 1:2 molar ratio in toluene solvent. Salt 6.19, where proton-NMR analysis of the salt 6.20 indicates a molar ratio of lumateperone to benzenesulfonic acid of approximately 1:1. 6.21 Salt 6.19 or 6.20, in which DSC analysis shows a single endothermic event (e.g., melting) at about 131°C. 6.22 Any of the forms of salts 6.19-6.21 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., peaks 1, 2, 4, 5, 7, 10, 11, 12, 13, 14, 17, 19, 21, 25, 25, and / or 28: [Table 9] 6.23 Any of the forms of Salts 6.19-6.22 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 6B, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 6.24 Taking into account potential variations due to sample purity and instrument variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the peaks are approximately 4.66, 5.90, 11.43, 12.02, 12.40, 13.27, 13.89, 14.77, 15.29, 15.96, 16.11, 16.67, 17.03, 17.36, 17.85, 17.95, 18.29, 18.65, 19.37, 19.93, 20.52, 21.22, 21.85, 22.60, 22. Any of salts 6.19 to 6.23 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 98, 23.32, 23.75, 24.10, 25.12, 26.17, 27.97, and 30.13, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.25 Taking into account potential variations due to sample purity and instrumental variation (e.g., a shift of up to ±0.2 d-spacing for any one or more peaks), the following peaks were measured: approximately 18.97, 14.96, 7.73, 7.36, 7.13, 6.67, 6.37, 5.99, 5.79, 5.55, 5.50, 5.31, 5.20, 5.10, 4.97, 4.94, 4.85, 4.75, 4.58, 4.45, 4.33, 4.18, 4.07, 3.93, 3.87, 3.81, 3.74, 3.69, 3.54, 3.40 Any of salts 6.19 to 6.24 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of 3.19, 3.19, and 2.96, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.26 Any of salts 6.19-6.25 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 6.24 and 6.25. 6.27 Any of salts 6 or 6.1-6.10, where the salt is formed from lumateperone free base and benzenesulfonic acid in a 1:1 molar ratio in ethyl acetate solvent. Salt 6.27, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to benzenesulfonic acid of approximately 1:1. 6.29 Salt 6.27 or 6.28, wherein DSC analysis shows one endothermic event (e.g., melting) at about 110°C and / or one endothermic event (e.g., melting) at about 126°C. 6.30 Any of salts 6.27-6.29 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 2, 2, 3, 4, 5, 8, 14, and / or 16: [Table 10] 6.31 Any of the forms of salts 6.27-6.30 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 6C, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shift due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks). 6.32 Any of the forms of Salts 6.27-6.31 in crystalline form, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 5.24, 5.76, 14.39, 16.17, 16.71, 18.65, 19.25, 19.44, 20.70, 20.84, 21.08, 22.81, 22.91, 23.21, 23.87, 24.70, 25.07, 25.13, 26.71, 28.44, 33.76, and 37.91, taking into account potential variations due to sample purity and instrumental variations (e.g., angle shifts of up to ±0.2 degrees for any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.33 Any of Salts 6.27-6.32 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 16.85, 15.34, 6.15, 5.48, 5.30, 4.75, 4.61, 4.56, 4.29, 4.26, 4.21, 3.90, 3.88, 3.83, 3.72, 3.60, 3.55, 3.54, 3.33, 3.14, 2.65, and 2.37, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 6.34 Any of salts 6.27-6.33 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 6.32 and 6.33. 6.35 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties. 6.36 Any of the foregoing forms of salt 6, exhibiting any combination of the characteristics described in 6.1-6.35.

[0044] In a seventh embodiment, the present disclosure provides lumateperone in the form of an alkylsulfonic acid addition salt (Salt 7), for example, wherein the alkylsulfonic acid is (C 3~12 alkyl) sulfonic acid, or (C 4~12 alkyl) sulfonic acid, or (C 5~12 alkyl) sulfonic acid, or (C 3~10 alkyl) sulfonic acid, or (C 4~10 alkyl) sulfonic acid, or (C 5~10 In a further embodiment of salt 7, the present disclosure provides lumateperone salt 7, wherein the lumateperone salt is a pentane-1-sulfonate salt or a heptane-1-sulfonate salt. 7.1 Salts in solid form7. 7.2 Salts 7 or 7.1 in crystalline form, for example in dry crystalline form. 7.3 Salt 7, 7.1 or 7.2, wherein the molar ratio of lumateperone to alkylsulfonic acid in the salt is 1:1. 7.4 Salt 7, 7.1 or 7.2, wherein the molar ratio of lumateperone to alkylsulfonic acid in the salt is 1:2. 7.5 Any of the preceding forms of salt 4 which is a solvate, for example, an ethyl acetate solvate, or a toluene solvate. 7.6 Any of the above forms of salt 7, which is not a solvate. 7.7 Any of the preceding forms of salt 7, which is a hydrate. 7.8 Any of the above forms of salt 7, which is not a hydrate. 7.9 Any of the foregoing forms of salt 7 formed by combining lumateperone free base and an alkyl sulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 7.10 Any of the foregoing forms of Salt 7, a homogeneous crystalline form, free or substantially free of other forms, e.g., free or substantially free of amorphous form, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form. 7.11 Any of the foregoing forms of Salt 7 in a crystalline form crystallized from a mixture of an alkyl sulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of about 1:1 or about 1:2 between lumateperone free base and alkyl sulfonic acid. 7.12 Salts crystallize from solvents after addition of an anti-solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, the anti-solvent is water, or when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol, the anti-solvent is heptane or hexane, for example, when the organic solvent is toluene and the anti-solvent is heptane. 7.13 Salt 7 or any of 7.1-7.12, wherein the alkyl sulfonic acid is selected from propane-1-sulfonic acid, butane-1-sulfonic acid, pentane-1-sulfonic acid, hexane-1-sulfonic acid, heptane-1-sulfonic acid, octane-1-sulfonic acid, nonane-1-sulfonic acid, decane-1-sulfonic acid, undecane-1-sulfonic acid, and dodecane-1-sulfonic acid, or branched isomers thereof (e.g., 4-methylpentane-1-sulfonic acid, 4,4-dimethylpentane-1-sulfonic acid, 3,4-dimethylpentane-1-sulfonic acid, 5-methylhexane-1-sulfonic acid, 3,5-dimethylhexane-1-sulfonic acid, 3-ethylpentane-1-sulfonic acid, 3-ethylhexane-1-sulfonic acid, etc.). 7.14 Any of salts 7 or 7.1-7.13, wherein the salt has an aqueous solubility of less than 20 mg / mL, e.g., less than 15 mg / mL, or less than 10 mg / mL, or less than 5 mg / mL, or less than 3 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL, e.g., at a pH of 5-8, or at a pH of 6-8, or at a pH of 7-8, or at a pH of 7-7.5. 7.15 Any of salts 7 or 7.1-7.13, wherein the salt has an aqueous solubility of less than 2 mg / mL, or less than 1 mg / mL, or less than 0.5 mg / mL, or less than 0.1 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL, e.g., at a pH of 5-8, or at a pH of 6-8, or at a pH of 7-8, or at a pH of 7-7.5. 7.16 Any of salts 7 or 7.1-7.15, wherein the alkyl sulfonic acid is pentane-1-sulfonic acid and the salt is formed from lumateperone free base and pentane-1-sulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. 7.17 Salt 7.16, where proton-NMR analysis of the salt indicates a molar ratio of lumateperone to pentane-1-sulfonic acid of approximately 1:2. 7.18 Salt 7.16 or 7.17, in which DSC analysis shows a single endothermic event (e.g., melting) at about 141°C. 7.19 Any of the forms of salts 7.16-7.18 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 2, 5, 6, 7, 9, and / or 12: [Table 11] 7.20 Any of the forms of salts 7.16-7.19 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 7, e.g., generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account potential variations due to sample purity and instrumental variations, e.g., 2θ shifts due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 7.21 Any of the forms of Salts 7.16-7.20 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of about 2.09, 3.78, 7.49, 11.23, 14.77, 16.22, 16.56, 17.34, 17.76, 18.64, 19.66, 20.01, 20.34, 20.78, 21.35, 21.74, 22.57, 25.29, and 38.26, taking into account potential variations due to sample purity and instrumental variation (e.g., an angle shift of up to ±0.2 degrees for any one or more peaks), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 7.22 Any of the forms of Salts 7.16-7.21 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks with d-spacing values selected from the group consisting of about 42.32, 23.37, 11.80, 7.88, 5.99, 5.46, 5.35, 5.11, 4.99, 4.76, 4.51, 4.43, 4.36, 4.27, 4.16, 4.09, 3.94, 3.52, and 2.35, taking into account potential variations due to sample purity and instrumental variations (e.g., a shift in any one or more peaks of up to ±0.2 d-spacing), wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 7.23 Any of salts 7.16-7.22 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 7.19 and 7.20. 7.24 Any of salts 7 or 7.1-7.15, wherein the alkyl sulfonic acid is heptane-1-sulfonic acid and the salt is formed from lumateperone free base and heptane-1-sulfonic acid in a 1:2 molar ratio in ethyl acetate solvent. Salt 7.24, where proton-NMR analysis of the salt 7.25 indicates a molar ratio of lumateperone to heptane-1-sulfonic acid of approximately 1:2. 7.26 Salt 7.24 or 7.25, in which DSC analysis shows a single endothermic event (e.g., melting) at about 151°C. 7.27 Any of the forms of salts 7.24 to 7.26 in crystalline form, having an X-ray powder diffraction pattern corresponding to at least five, or at least six, or at least seven, or at least eight of the d-spacing and / or angle (2θ) values in the table below, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts (e.g., a shift of up to ±0.2 degrees angle or up to ±0.2 d-spacing of any one or more peaks) due to variations in X-ray wavelength, e.g., the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, and comprises at least a peak having, e.g., a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 6, 12, 13, 14, 16, 17, 20, and / or 23: [Table 12] 7.28 Any of the forms of salts 7.24-7.27 in crystalline form, having an X-ray powder diffraction pattern corresponding to Figure 8, e.g., an X-ray powder diffraction pattern corresponding to Figure 8 generated using an X-ray diffractometer equipped with a copper anode and a nickel filter, taking into account, for example, potential variations due to sample purity and instrumental variations, e.g., 2θ shifts due to variations in X-ray wavelength (e.g., a maximum angular shift of ±0.2 degrees of any one or more peaks). 7.29 Taking into account potential variations due to sample purity and instrument variation (e.g., a maximum angular shift of ±0.2 degrees for any one or more peaks), the following peaks were measured: approximately 3.49, 6.84, 7.44, 10.28, 13.69, 14.18, 14.88, 15.75, 16.32, 16.74, 17.12, 17.62, 18.04, 18.35, 19.22, 19.90, 20.18, 20.50, 21.60, 22.40, 23.22, 24.18, 24.84, Any of salts 7.24 to 7.28 in crystalline form, having an X-ray powder diffraction pattern with at least five, or at least six, or at least seven, or at least eight peaks having angle (2θ) values selected from the group consisting of 26.33, 27.56, 30.59, 31.76, 32.89, and 33.60, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 7.30 Potential variation due to sample purity and instrument variation (e.g., maximum ±0.2% of any one or more peaks) any of the crystalline salts 7.24-7.29, having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having d-spacing values selected from the group consisting of about 25.29, 12.92, 11.88, 8.60, 6.47, 6.24, 5.95, 5.62, 5.43, 5.29, 5.17, 5.03, 4.91, 4.83, 4.61, 4.46, 4.40, 4.33, 4.11, 3.97, 3.83, 3.68, 3.58, 3.38, 3.23, 2.92, 2.82, 2.72, and 2.67, taking into account shifts in d-spacings, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer equipped with a copper anode and a nickel filter. 7.31 Any of salts 7.24-7.30 in crystalline form having an X-ray powder diffraction pattern having at least five, or at least six, or at least seven, or at least eight peaks having the angle (2θ) values and / or d-spacing values shown in 7.27 and 7.28. 7.32 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety. 7.33 Any of the foregoing forms of salt 7, exhibiting any combination of the characteristics described in 7.1 to 7.32.

[0045] In an eighth embodiment, the present disclosure provides a compound substituted with one, two, or three R groups, each R independently being C 1~12

[0013] Provided is lumateperone as an acid addition salt with the alkyl group benzenesulfonic acid (Salt 8), with the proviso that the acid is not p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid, 4-propylbenzenesulfonic acid, 4-t-butylbenzenesulfonic acid, or 4-octylbenzenesulfonic acid. In further embodiments of Salt 8, the present disclosure provides: 8.1 Salt 8, wherein each group R is independently selected from a straight or branched chain 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-carbon saturated hydrocarbon group. 8.2 Salt 8.1, wherein each group R is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, s-pentyl, t-pentyl, neopentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, and n-decyl. 8.3 Salt 8, wherein the substituted benzenesulfonic acid is selected from meta-toluenesulfonic acid, ortho-toluenesulfonic acid, or dimethylbenzenesulfonic acid (e.g., 2,4-dimethylbenzenesulfonic acid, 2,5-dimethylbenzenesulfonic acid, 2,6-dimethylbenzenesulfonic acid) or trimethylbenzenesulfonic acid. 8.4 Acids that are meta-substituted C 2~12 Alkylbenzenesulfonic acid, ortho-substituted C 2~12 Alkylbenzenesulfonic acid, di-(C 2~12 alkyl)benzenesulfonic acid, or tri-C 2~12 alkylbenzene sulfonic acid, and optionally, 2~12 Salt 8, wherein each alkyl is selected from ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, or any branched alkyl isomer thereof. 8.5 Salts in solid form Any of the foregoing forms of 8. 8.6 Any of the foregoing forms of salt 8 in crystalline form, e.g., dry crystalline form. 8.7 Any of salts 8 or 8.1-8.6, wherein the salt has an aqueous solubility of less than 20 mg / mL, e.g., less than 15 mg / mL, or less than 10 mg / mL, or less than 5 mg / mL, or less than 3 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL, e.g., at a pH of 5-8, or at a pH of 6-8, or at a pH of 7-8, or at a pH of 7-7.5. 8.8 Any of salts 8 or 8.1-8.6, wherein the salt has an aqueous solubility of less than 2 mg / mL, or less than 1 mg / mL, or less than 0.5 mg / mL, or less than 0.1 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL, e.g., at a pH of 5-8, or at a pH of 6-8, or at a pH of 7-8, or at a pH of 7-7.5. 8.9 Any of salts 8 or 8.1-8.8, wherein the molar ratio of lumateperone to substituted benzenesulfonic acid in the salt is 1:1. 8.10 Any of salts 8 or 8.1-8.8, in which the molar ratio of lumateperone to substituted benzenesulfonic acid in the salt is 1:2. 8.11 Any of the preceding forms of salt 8 which is a solvate, for example an ethyl acetate or toluene solvate. 8.12 Any of the above forms of salt 8, but not a solvate. 8.13 Any of the preceding forms of salt 8, which is a hydrate. 8.14 Any of the above forms of salt 8, which is not a hydrate. 8.15 Any of the foregoing forms of salt 8 formed by combining lumateperone free base and a substituted benzenesulfonic acid in a molar ratio of 1:0.5 to 1:3, e.g., a molar ratio of 1:0.75 to 1:1.5, or a molar ratio of 1:0.75 to 1:1.25, or a molar ratio of 1:1.5 to 1:2.5, or a molar ratio of 1:1.75 to 1:2.25, or a molar ratio of 1:1.75 to 1:3, or a molar ratio of 1:1 to 1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5. 8.16 Any of the foregoing forms of Salt 8 in a crystalline form crystallized from a mixture of a substituted benzenesulfonic acid and lumateperone free base in an organic solvent, such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof; e.g., ethyl acetate or toluene, optionally in a molar ratio of about 1:1 or about 1:2 between lumateperone free base and substituted benzenesulfonic acid. 8.17 Salts crystallize from solvents after the addition of an anti-solvent, where, for example, the anti-solvent is water when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, or the anti-solvent is heptane or hexane when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol. 8.18 Lumateperone is deuterated, e.g., the deuterium:protium ratio at one or more specific positions in the molecule is significantly higher, e.g., at least 2-fold, e.g., at least 10-fold higher, than the natural isotope ratio or the isotope ratio at other positions in the molecule; e.g., either or both of the -CH2- moieties of the piperazine ring are deuterated to a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., -CHD- or -CD2- and / or wherein the methyl group on the piperazine ring is deuterated at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio elsewhere in the molecule, e.g., CD3-; for example, the deuterated lumateperone is any deuterated lumateperone described in US2019 / 0231780 or US2021 / 0008065, the contents of each of which are incorporated herein by reference in their entireties.

[0046] In another embodiment, the present disclosure provides a method (Preparation Method 1) for preparing any of the salts described herein, comprising the steps of: (a) reacting lumateperone free base with a corresponding acid together with an organic solvent (e.g., including ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof), e.g., in a molar ratio of 1:1 to 1:2, or about 1:1, or about 1:2, of the acid to lumateperone; optionally at a temperature of 0°C to 100°C; and (b) optionally subjecting the resulting mixture to a thermal cycling protocol (e.g., raising the temperature to above 50°C and then cooling to 0°C, optionally repeating this heating and cooling cyclically), or cooling the mixture from the reaction temperature to 5°C or below; and (c) optionally diluting the resulting mixture with an anti-solvent, wherein, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, the anti-solvent is water, or when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol, the anti-solvent is heptane or hexane; optionally at a temperature between 0°C and 100°C; and (d) optionally performing a second thermal cycling protocol (e.g., increasing the temperature to above 50°C and then cooling to 0°C, optionally repeating this heating and cooling cyclically), or cooling the mixture from the reaction temperature to 5°C or below; and (e) recovering the salt thereby formed, e.g., any of Salts 1 or later, 2 or later, 3 or later, 4 or later, 5 or later, 6 or later, 7 or later, 8 or later, or any other salt described herein. The present invention provides a method of manufacturing a semiconductor device, comprising:

[0047] In another embodiment of Preparation Method 1, reacting step (a) comprises dissolving or suspending lumateperone free base in an organic solvent, such as toluene or ethyl acetate, followed by adding an acid, or dissolving or suspending the acid in an organic solvent and then adding lumateperone free base, or combining dry acid and dry lumateperone free base and then adding an organic solvent. In some embodiments, the organic solvent is a mixture of two solvents, preferably two completely miscible solvents, such as water / methanol, water / ethanol, water / isopropanol, ethanol / methanol, ethanol / isopropanol, water / acetonitrile, acetonitrile / methanol, acetonitrile / ethanol, toluene / ethyl acetate, toluene / methyl ethyl ketone, ethyl acetate / methyl ethyl ketone, etc.

[0048] In some embodiments of Preparation Method 1, the crystalline salt product precipitates when the lumateperone free base, acid, and organic solvent are combined at a reaction temperature (e.g., 0° C. to 100° C., or about 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 50° C., 60° C., 70° C., or 80° C.). In some embodiments of Preparation Method 1, the crystalline salt product precipitates when the mixture of lumateperone free base, acid, and organic solvent is cooled to a temperature below the reaction temperature (e.g., about 0° C., 5° C., 10° C., or 15° C.).

[0049] In some embodiments of Process 1, the crystalline salt product precipitates when a mixture of lumateperone free base, acid, and organic solvent is subjected to a thermal cycling protocol, e.g., raising the temperature above 50°C, then cooling to 0°C, and optionally repeating this heating and cooling cycle periodically. For example, the reaction may be heated to 50°C or 60°C, held for a period of time (e.g., 15 to 300 minutes, e.g., 60 minutes), then cooled to 0°C or 5°C, held for a period of time (e.g., 15 to 300 minutes, e.g., 60 minutes), and then this heating / cooling cycle may be repeated 2, 3, 4, or 5 times. Optionally, the elevated temperature is decreased by 10°C with each cycle. For example: 20℃-50℃-0℃-40℃-0℃-30℃-0℃-20℃-0℃-10℃-0℃; or 20℃-50℃-0℃-40℃-0℃-30℃-0℃-20℃-0℃.

[0050] In some embodiments of Production Method 1, production step (a) is carried out as a batch process, and in other embodiments, production step (a) is carried out as a continuous (flow) process.

[0051] In another embodiment, the present disclosure provides a method for purifying lumateperone in free or salt form, comprising reacting a crude solution of mateperone free base with an acid described herein to form any of the salts described herein, and recovering the salt thereby formed, e.g., according to Preparation Method 1, and optionally converting the salt thereby formed back to lumateperone free base or any other salt form of lumateperone (e.g., lumateperone monotosylate).

[0052] In another embodiment, the present disclosure provides a pharmaceutical composition (Composition 1) comprising any of the salts described herein, e.g., Salt 1 or later, Salt 2 or later, Salt 3 or later, Salt 4 or later, Salt 5 or later, Salt 6 or later, Salt 7 or later, Salt 8 or later, as an active ingredient, in combination with or with a pharmaceutically acceptable diluent or carrier. In some embodiments, the pharmaceutical composition is formulated for oral delivery, e.g., as an enteric-coated tablet or capsule, optionally formulated for sustained or delayed release. In some embodiments, the pharmaceutical composition is formulated for transmucosal delivery, e.g., as an oral fast-dissolving tablet, wafer, or gel, e.g., for sublingual or buccal administration. In some embodiments, the pharmaceutical composition is formulated for transdermal delivery, e.g., as a patch, ointment, or gel, e.g., for administration through the skin to tissues below the epidermis. In some embodiments, the pharmaceutical composition is formulated for injectable delivery, e.g., as a subcutaneous, intravenous, intraperitoneal, intramuscular, or intrathecal injection, e.g., for immediate release. In some embodiments, the pharmaceutical composition is formulated for sustained or delayed infusion delivery, for example, as a subcutaneous or intramuscular long-acting injection (LAI).

[0053] Suitable carriers for these pharmaceutical formulations are known in the art and include, for example, those described in US2016 / 0031885, US2016 / 0310502, US2018 / 271862, US2021 / 0315891, US2020 / 0220280, and US2021 / 0069683, the contents of each of which are incorporated herein by reference in their entirety.

[0054] In some embodiments, the pharmaceutical composition of the present disclosure comprises the lumateperone salt of the present disclosure as a crystalline solid. In some embodiments, the pharmaceutical composition may comprise the lumateperone salt in the form of an amorphous solid dispersion. Amorphous solid dispersions of lumateperone tosylate are described in WO2020 / 123952 and US2019 / 0192511, the contents of each of which are incorporated herein by reference in their entirety. In the amorphous solid dispersion, the amorphous lumateperone salt of the present disclosure is stabilized, for example, by dispersing it in an additive that stabilizes the amorphous solid against crystallization, thereby preventing or inhibiting the transition to crystals. Suitable stabilizing additives include, but are not limited to, cellulose acetate, cellulose acetate phthalate, methacrylate / methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, and polyethylene glycol / polyvinyl acetate / polyvinyl caprolactam copolymer.In some embodiments, salt can be stabilized by dispersing in one stabilizing additive, and in other embodiments, salt can be stabilized by dispersing in two or more stabilizing additives. In some embodiments, one or more additives may be combined with the lumateperone salt in a weight ratio of lumateperone salt to additive of 25:75 to 75:25, e.g., 26:74 to 74:26, or 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55 to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to 51:49, or about 50:50.In other embodiments, one or more additives may be combined with the lumateperone salt in a weight ratio of lumateperone salt to additive of 5:95 to 50:50, e.g., 5:95 to 49:51, or 5:95 to 45:55, or 10:90 to 40:60, or 15:85 to 35:65, or 20:80 to 30:70, or 22:78 to 28:82, or 23:77 to 27:83, or 24:76 to 26:74, or about 25:75. In other embodiments, one or more additives may be combined with the lumateperone salt in a weight ratio of lumateperone salt to additive of 50:50 to 95:5, e.g., 51:49 to 95:5, or 55:45 to 95:5, or 60:40 to 90:10, or 65:45 to 85:15, or 70:30 to 80:20, or about 75:25.

[0055] In certain embodiments, the present disclosure provides a long-acting injectable pharmaceutical composition (Composition 2) comprising an acid addition salt of lumateperone having an aqueous solubility of less than 20 mg / mL. In further embodiments of Composition 2, the present disclosure provides: 2.1 Composition 2, wherein the acid addition salt of lumateperone has an aqueous solubility of less than 15 mg / mL, or less than 10 mg / mL, or less than 5 mg / mL, or less than 3 mg / mL, or less than 2 mg / mL, or less than 1 mg / mL, e.g., at a pH of 5 to 8, or a pH of 6 to 8, or a pH of 7 to 8, or a pH of 7 to 7.5. 2.2 Composition 2, wherein the acid addition salt of lumateperone has an aqueous solubility of less than 0.9 mg / mL, or less than 0.7 mg / mL, or less than 0.5 mg / mL, or less than 0.4 mg / mL, or less than 0.3 mg / mL, or less than 0.2 mg / mL, or less than 0.1 mg / mL, e.g., at a pH of 5 to 8, or a pH of 6 to 8, or a pH of 7 to 8, or a pH of 7 to 7.5. 2.3 Composition 2, 2.1, or 2.2, wherein the acid addition salt of lumateperone has an aqueous solubility of at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL, e.g., at a pH of 5 to 8, or at a pH of 6 to 8, or at a pH of 7 to 8, or at a pH of 7 to 7.5. 2.4 Any of Compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is Salt 1 or any of Salts 1.1-1.22. 2.5 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 2 or any of 2.1-2.22. 2.6 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 3 or any of 3.1-3.22. 2.7 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 4 or any of 4.1-4.38. 2.8 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 5 or any of salts 5.1-5.21. 2.9 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 6 or any of 6.1-6.36. 2.10 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 7 or any of 7.1-7.33. 2.11 Any of compositions 2 or 2.1-2.3, wherein the acid addition salt of lumateperone is salt 8 or any of salts 8.1-8.18. 2.12 Any of Compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone 4-octylbenzenesulfonate, e.g., the salt described in Example 2. 2.13 Any of Compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone 4-tert-butylbenzenesulfonate, e.g., the salt described in Example 3. 2.14 Any of compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone 4-propylbenzenesulfonate, e.g., the salt described in Example 4. 2.15 Any of compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone 4-ethylbenzenesulfonate, e.g., the salt described in Example 5. 2.16 Any of compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone 2-naphthalenesulfonate, e.g., the salt described in Example 6. 2.17 Any of compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone benzenesulfonate, e.g., the salt described in Example 7. 2.18 Any of Compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone pentane-1-sulfonate, e.g., the salt described in Example 8. 2.19 Any of Compositions 2 or 2.1-2.11, wherein the acid addition salt of lumateperone is lumateperone hexane-1-sulfonate, e.g., the salt described in Example 9. 2.20 Any of compositions 2 or 2.1-2.19, wherein the acid addition salt of lumateperone is crystalline. 2.21 Composition 2 or any of 2.1-2.19, wherein the acid addition salt of lumateperone is amorphous, e.g., the composition comprises the salt as an amorphous solid dispersion. 2.22 Composition 2 or any of 2.1-2.21, wherein the composition is formulated for intramuscular injection. 2.23 Composition 2 or any of 2.1-2.21, wherein the composition is formulated for subcutaneous injection. 2.24 Composition 2 or any of 2.1-2.23, wherein the composition further comprises at least one pharmaceutically acceptable diluent, carrier, or excipient suitable for injection. 2.25 Composition 2.24, wherein the diluent or carrier comprises water and / or a water-miscible organic solvent. 2.26 Composition 2.24, or 2.25, wherein the diluent, carrier, or additive comprises a polymer, e.g., a biocompatible and biodegradable polymer, particularly a polymer used to inhibit dissolution of an encapsulated or dispersed drug. 2.27 The polymer may be a polyester of hydroxy fatty acids (or its derivatives), a polymer of alkyl α-cyanoacrylate (e.g., poly(butyl 2-cyanoacrylate)), a polyalkylene oxylate (e.g., polytrimethylene oxylate or polytetramethylene oxylate), a polyorthoester, a polycarbonate (e.g., polyethylene carbonate or polyethylene-propylene carbonate), a polyortho-carbonate, a polyamino acid (e.g., poly-γ-L- alanine, poly-γ-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), hyaluronic acid ester, polylactide (e.g., poly-L-lactide, poly-L-lactic acid, poly-D,L-lactide, poly-D,L-lactic acid), polyglycolide (e.g., polyglycolide or polyglycolic acid), polylactide-co-glycolide copolymer (e.g., PLGA with a lactide to glycolide molar ratio of 75:25 to 50:50 or 50:50 to 90:10, e.g., PLGA Composition 2.26, wherein the polymer is selected from poly(aliphatic carboxylic acids) (e.g., polycitric acid, polymalic acid, poly-β-hydroxybutyric acid), copolyoxylates, polycaprolactone, poly(glycolic acid-caprolactone), polydioxanone, poly(acetal), poly(lactic acid-caprolactone), polyanhydrides, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, or polyglycolic acid-polyethylene glycol copolymer, and natural polymers including albumin, casein, and waxes, e.g., glycerol mono- and distearate. 2.28 Composition 2.27 wherein the polymer is a polylactide, polyglycolide, or polylactide-co-glycolide copolymer (PLGA), optionally with carboxylic acid or carboxylic ester end groups. 2.29 Composition 2.28, wherein the polylactide-co-glycolide copolymer (PLGA) has a molar ratio of lactide to glycolide of 75:25 to 50:50, or 50:50 to 90:10, e.g., PLGA 50:50, PLGA 85:15, or PLGA 90:10. 2.30 Composition 2.27, 2.28 or 2.29, wherein the PLGA copolymer has a weight average molecular weight of 5,000 to 500,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons, or 113,000 to 159,000 daltons, e.g., about 113,000 daltons or about 159,000 daltons. 2.31 Any of compositions 2.26-2.30, wherein an acid addition salt of lumateperone is dispersed, dispersed, suspended or encapsulated in a polymer to form, for example, a polymer matrix, for example, in the form of a polymer microsphere (e.g., comprising 1-90% by weight, e.g., 5-50% by weight, 10-50% by weight, 20-40% by weight, 30-50% by weight, 30-40% by weight or 35-40% by weight of the acid addition salt of lumateperone, based on the weight of the microsphere). 2.32 Composition 2.24 or 2.25, wherein the diluent, carrier, or excipient does not include any polymer used to inhibit dissolution of the encapsulated or dispersed drug, e.g., any polymer described in embodiment 2.27. 2.33 Composition 2 or any of 2.1-2.23, wherein the composition does not include any polymer used to inhibit dissolution of an encapsulated or dispersed drug, such as any polymer described in embodiment 2.27. 2.34 Composition 2 or any of 2.1-2.3, wherein the composition does not include any non-aqueous organic solvents (e.g., the composition does not include dimethylformamide, dimethylacetamide, dimethylsulfoxide, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane, dioxolane) and / or the composition does not include any liquid oils (e.g., vegetable oil, mineral oil). 2.35 Composition 2 or any of 2.1-2.3, wherein the composition comprises water (e.g., sterile water for injection) and one or more additives (e.g., water-soluble additives), such as a thickener, a buffer, a tonicity agent, a surfactant, and an antioxidant. 2.36 Composition 2.35, wherein the composition comprises one or more thickeners selected from, for example, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), other cellulose derivatives, crystalline cellulose, amorphous cellulose, polyacrylate polymers, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycols (e.g., PEG-400, PEG-600). 2.37 Composition 2.35 or 2.36, wherein the composition comprises one or more surfactants. 2.38 Composition 2.37, wherein the one or more surfactants comprise a non-ionic surfactant, e.g., selected from sorbitan esters (e.g., sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate), polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), polyoxyethylene alkyl ethers, fatty acid esters (e.g., glycerol monostearate, glycerol monolaurate), polyethoxylated fatty acids or vegetable oils (e.g., polyethoxylated castor oil), poloxamers, and fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, cetostearyl alcohol). 2.39 Composition 2.37, wherein the one or more surfactants comprise a cationic surfactant, e.g., a quaternary amine, e.g., cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride. 2.40 Composition 2.37, wherein the one or more surfactants include an anionic surfactant, for example, an alkyl sulfate, such as sodium dodecyl sulfate and sodium lauryl sulfate, an alkyl aryl ether polysulfonate, and an alkyl sulfosuccinate, such as docusate sodium. 2.41 Any of compositions 2.35-2.40, wherein the composition comprises one or more fillers selected from, e.g., mannitol, sucrose, fructose, maltose, xylitol, glucose, starch, sorbitol, magnesium aluminum silicate, and silica (e.g., colloidal silica). 2.42 Any of compositions 2.35-2.41, wherein the composition comprises one or more pH adjusters and / or buffers selected from, e.g., hydrochloric acid, citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium acetate, sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium maleate, potassium maleate, sodium lactate, potassium lactate, and TRIS (tris(hydroxymethyl)aminomethane). 2.43 Compositions 2 or any of 2.1-2.42, wherein the composition comprises one or more antioxidants selected from, e.g., butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, ascorbyl palmitate, sodium ascorbate, potassium ascorbate, sodium isoascorbate, tocopherol, dihydroguanic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sodium bisulfite, sodium metabisulfite, sodium EDTA, and sorbic acid. 2.44 Composition 2 or any of Compositions 2.1-2.43, wherein the composition comprises one or more other additives selected from gelatin, casein, lecithin, dextran, glycerol, propylene glycol, butylene glycol, gum acacia, gum tragacanth, wax (e.g., animal or vegetable waxes including beeswax and carnauba wax), cholesterol, vegetable oil (e.g., coconut oil, soybean oil, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, castor oil, palm oil, almond oil, and refined fractions thereof), ethyl oleate, isopropyl myristate, benzyl benzoate, sodium chloride, mineral oil, free fatty acids, or synthetic mono- or di-glycerides of fatty acids. 2.45 Composition 2 or any of Compositions 2.1-2.45, wherein the composition does not contain ethanol, glycerol, propylene glycol, butylene glycol, polyethylene glycol, or liquid vegetable oil as a co-solvent. 2.46 Compositions 2 or any of 2.1-2.45, wherein the composition comprises an acid addition salt of lumateperone (e.g., lumateperone 4-octylbenzenesulfonate or lumateperone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a viscosity increasing agent (e.g., sodium carboxymethylcellulose), a bulking agent (e.g., mannitol), a non-ionic surfactant (e.g., polysorbate 80), and optionally, one or more pH adjusting agents or buffering agents (e.g., NaOH or HCl, and / or sodium or potassium phosphate). 2.47 Compositions 2 or any of 2.1-2.45, wherein the composition comprises an acid addition salt of lumateperone (e.g., lumateperone 4-octylbenzenesulfonate or lumateperone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a viscosity increasing agent (e.g., sodium carboxymethylcellulose), a bulking agent (e.g., mannitol), and optionally, one or more pH adjusting agents or buffering agents (e.g., sodium or potassium phosphate, NaOH and / or HCl, and / or sodium or potassium phosphate). 2.48 Any of Compositions 2 or 2.1-2.47, wherein the injectable unit dose of the composition comprises an amount of an acid addition salt of lumateperone equivalent to 100-5000 mg, e.g., 100-500 mg, or 500-1000 mg, or 1000-1500 mg, or 1500-2000 mg, or 2000-3000 mg, or 3000-5000 mg, or 100-250 mg, or 250-500 mg, or 500-750 mg, or 750-1000 mg, or 1000-1250 mg, or 1250-1500 mg of lumateperone free base. 2.49 Compositions 2 or any of 2.1-2.48, wherein the composition comprises an acid addition salt of lumateperone in a concentration (measured by weight of the salt) of 0.1-1000 mg / mL, e.g., 1-1000 mg / mL, or 10-1000 mg / mL, or 50-1000 mg / mL, or 100-1000 mg / mL, or 250-1000 mg / mL, or 500-1000 mg / mL, or 750-1000 mg / mL, or 1-10 mg / mL, or 10-50 mg / mL, or 50-100 mg / mL, or 100-500 mg / mL. 2.50 The volume of a unit dose for injection of the composition is 0.1 to 5.0 mL, for example, 0.5 to 5.0 mL, or 1.0 to 5.0 mL, or 2.0 to 5.0 mL, or 3.0 to 5.0 mL, or 4.0 to 5.0 mL, or 0.5 to 4.0 mL, or 1.0 to 4.0 mL, or 2.0 to 4.0 mL, or 3.0 to 4.0 mL, or 0.1 to 3.0 mL, 0.5 to 3.0 mL, or 1.0 to 3.0 mL, or 1.5 to 3.0 mL, or 2.0 to 3.0 mL, or 2.5 to 3.0 mL L, or 0.1 to 2.5 mL, or 0.5 to 2.5 mL, or 1.0 to 2.5 mL, or 1.5 to 2.5 mL, or 2.0 to 2.5 mL, or 0.1 to 2.0 mL, or 0.5 to 2.0 mL, or 1.0 to 2.0 mL, or 1.5 to 2.0 mL, or 0.1 to 1.5 mL, or 0.5 to 1.5 mL, or 1.0 to 1.5 mL, or 0.1 to 1.0 mL, or 0.5 to 1.0 mL, or 0.1 to 0.5 mL of any of compositions 2 or 2.1 to 2.49. 2.51 Any of Compositions 2 or 2.1-2.50, which upon injection of the composition forms an intramuscular or subcutaneous depot that releases lumateperone (as a salt or free base) over a period of up to 180 days, e.g., 1 week to 6 months, or 1 month to 6 months, or 7 days to 14 days, or 14 days to 30 days, or 7 days to 30 days, or 1 month to 2 months, or 1 month to 3 months, or 3 months to 6 months. 2.52 Any of compositions 2 or 2.1-2.51, wherein the pH of the composition is 4-8, e.g., 5-8, or 5-7, or 6-8, or 6-7, or 7-8, or 6.5-7.5, or 7-7.5, or 7.5-8, or 7.1-7.4, or 7.2-7.4, or 7.3-7.4. 2.53 Composition 2 or any of 2.1 to 2.52, wherein the composition comprises an acid addition salt of lumateperone in an amount of 1 to 50% by weight of the composition (e.g., 10 to 40% by weight of the composition). 2.54 Composition 2 or any of 2.1-2.52, wherein the composition comprises one or more diluents, carriers, or additives in a net amount of 5 to 99% by weight of the composition (provided that the combination of ingredients does not exceed 100% by weight of the composition). 2.55 Compositions 2 or any of 2.1-2.54, wherein the composition comprises water and / or any water-miscible organic solvent or other liquid diluent or carrier in a net amount of 5 to 99% by weight of the composition. 2.56 Compositions 2 or any of 2.1 to 2.55, wherein the composition comprises water in an amount of 20 to 99% by weight of the composition (e.g., 20 to 90%). 2.57 Composition 2 or any of 2.1 to 2.56, wherein the composition comprises one or more additives in a net amount of 1 to 50% by weight of the composition. 2.58 Compositions 2 or any of 2.1-2.56, wherein the composition comprises one or more polymers (e.g., biocompatible and biodegradable polymers, particularly polymers used to inhibit dissolution of encapsulated or dispersed drugs) in a net amount of 0-50% by weight of the composition. 2.59 Composition 2 or any of 2.1 to 2.58, wherein the composition comprises one or more thickeners in a net amount of 0 to 50% by weight of the composition. 2.60 Compositions 2 or any of 2.1 to 2.59, wherein the composition comprises one or more fillers in a net amount of 0 to 50% by weight of the composition. 2.61 Compositions 2 or any of 2.1-2.60, wherein the composition comprises one or more buffering agents and / or pH adjusting agents in a net amount of 0-10% by weight of the composition. 2.62 A composition comprising: [Table 13] Composition 2, or any of 2.1 to 2.61, comprising: 2.63 Composition 2 or any of 2.1 to 2.62, wherein the composition is sterile. 2.64 Composition 2 or any of 2.1 to 2.63, wherein the composition is a homogeneous solution. 2.65 Compositions 2 or any of 2.1-2.63, wherein the composition is a suspension, e.g., a homogeneous suspension, and optionally, the acid addition salt of lumateperone is the only undissolved component. 2.66 Compositions 2 or any of 2.1-2.65, wherein the composition is prepared as a dry solid comprising an acid addition salt of lumateperone and one or more diluents, carriers, or excipients (e.g., water-soluble excipients), and prior to administration, the solid is reconstituted with sterile water for injection to form a long-acting injectable pharmaceutical composition; optionally, the dry solid is free of any liquid solvent or co-solvent (e.g., water, a water-miscible solvent, or a water-immiscible liquid). 2.67 Composition 2.66, wherein the dry solid is lyophilized. 2.68 Composition 2.66 or 2.67, wherein the dry solid is in the form of a powder, granules, pellets, or cake. 2.69 Any of compositions 2.66-2.68 in which the dry solid is packaged in a vial, sachet, or other single-dose package or container, e.g., sterile water for injection is added to the package or container, or the contents of the package or container are added to sterile water for injection, the combination is mixed, and the resulting composition is then drawn into a syringe and then injected into a patient. 2.70 Any of compositions 2.66-2.68, wherein the dry solid is packaged in a prefilled syringe (single or double chamber), e.g., sterile water for injection is drawn into the prefilled syringe, the contents are mixed, and then the resulting composition in the syringe is injected into a patient; optionally, the dry solid is packaged in a prefilled two-compartment syringe, one compartment containing the dry solid and the other compartment containing sterile water for injection, the contents are mixed by opening or releasing the barrier between the two compartments, followed by mixing the contents of the compartments and injecting the resulting composition into a patient. 2.71 Composition 2.70, wherein a homogeneous solution is formed after combining the dry solid with sterile water for injection. 2.72 Composition 2.70, wherein a suspension is formed after combining the dry solid with sterile water for injection, e.g., a uniform or homogeneous suspension. 2.73 Composition 2 or any of 2.1-2.72, wherein the composition is intended to be administered to a patient in need thereof once per week, once per two weeks, once per three weeks, once per month, once per two months, once per three months, once per four months, once per five months, or once per six months. 2.74 Compositions 2 or any of 2.1-2.73, wherein a single dose of the composition injected provides therapeutically effective plasma levels of lumateperone free base and / or therapeutically effective cerebrospinal fluid (CSF) levels of lumateperone free base for a period of 1 week to 6 months, e.g., 1 week to 1 month, or 1 month to 3 months, or 3 months to 6 months, or about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. 2.75 Composition 2 or any of 2.1 to 2.74, wherein the composition is not an emulsion.

[0056] Long-acting injectable (LAI) compositions have been known for some time and are primarily based on two concepts: (1) the use of a viscous, poorly water-soluble or insoluble polymer matrix to inhibit dissolution of the water-soluble active substance, and (2) the use of a water-insoluble prodrug of the water-soluble active substance. In the case of (1), a large amount of polymer, such as PLGA, is used to dissolve, disperse, or encapsulate the active drug product, or to form microspheres that encapsulate it. The dissolution kinetics is controlled by the degradation of the polymer, for example, by hydrolysis of the ester bond of the polymer. Such LAI compositions can be extremely difficult to formulate because they are prone to nonlinear release kinetics, such as an undesirable initial burst release of the drug. In the case of (2), the prodrug itself is pharmacologically inactive. Therefore, the release kinetics of the active substance is controlled by the rate of decomposition of the prodrug to the active drug, for example, by hydrolysis of an unstable ester or carbamate bond in the prodrug molecule. Such LAI compositions are also difficult to formulate because the prodrug often does not last beyond a short duration of action (i.e., several weeks). For example, if the prodrug is too unstable, it may provide a high initial plasma concentration but the depot may be depleted too quickly, whereas if the prodrug is too resistant to hydrolysis, it may be difficult to achieve therapeutic plasma concentrations over a sufficient period of time.

[0057] The low-solubility salts of the present disclosure offer a third alternative for LAI formulations. Due to the low aqueous solubility of these salts, the salts themselves essentially behave as pharmacologically inactive drugs. Only a very small amount of drug dissolves in the aqueous compartments of the body, where it can cross the blood-brain barrier as a free base and exert its therapeutic effect. As a result, large amounts of drug can be delivered by injection, forming an insoluble tissue depot in muscle or subcutaneous tissue. The "release" of the active drug (lumateperone free base) into tissue is related only to the rate at which the salt solubilizes. Unlike prior art lumateperone LAIs, the "release" of the active drug can occur independently of the formulation components (e.g., by avoiding the use of polymers that form a polymeric matrix that inhibits drug substance dissolution) and does not depend on molecular changes to the drug molecule (e.g., covalent bond cleavage). This allows for the formulation of much more efficient and controllable LAI products.

[0058] In another aspect, the present disclosure provides 5-HT 2Aand / or dopamine D1 / D2 receptor signaling pathways, e.g., a disease, disorder, or abnormal condition involving or mediated by the serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways, e.g., obesity, anorexia nervosa, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related condition, social phobia, dementia, dementia-related disorder, post-traumatic stress disorder, impulse control disorder, and intermittent explosive disorder. In preferred embodiments, the disclosure provides these salts for use in treating negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), treatment-resistant depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with comorbid depression, schizophrenia with comorbid anxiety and depression, or other mood disorders associated with encephalitis or neuroinflammation. Such uses of lumateperone are further described, for example, in US2011 / 0071080, US2015 / 0072964, US2015 / 0080404, US2016 / 0310502, US2021 / 0060009, US2021 / 0000822 and US2021 / 0186962, and PCT Application No. PCT / US2023 / 67204, the contents of each of which are incorporated herein by reference in their entirety.

[0059] In another aspect, the present disclosure provides 5-HT 2Aand / or dopamine D1 / D2 receptor signaling pathways, e.g., the disease, condition, or disorder is selected from obesity, anorexia nervosa, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related condition, social phobia, dementia, dementia-related disorder, post-traumatic stress disorder, impulse control disorder, and intermittent explosive disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of any of the salts described herein, e.g., Salt 1 or later, Salt 2 or later, Salt 3 or later, Salt 4 or later, Salt 5 or later, Salt 6 or later, Salt 7 or later, Salt 8 or later.

[0060] In another embodiment, the present disclosure provides 5-HT 2AIn one embodiment, the present invention provides a method for treating a disease, condition, or abnormal condition involving or mediated by the serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways, such as a disease, condition, or disorder selected from obesity, anorexia nervosa, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related condition, social phobia, dementia, dementia-related disorder, post-traumatic stress disorder, impulse control disorder, and intermittent explosive disorder. In preferred embodiments, the disclosure provides these salts for use in treating negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), treatment-resistant depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with comorbid depression, schizophrenia with comorbid anxiety and depression, or other mood disorders associated with encephalitis or neuroinflammation. Such uses of lumateperone are further described, for example, in US2011 / 0071080, US2015 / 0072964, US2015 / 0080404, US2016 / 0310502, US2021 / 0060009, US2021 / 0000822 and US2021 / 0186962, and PCT Application No. PCT / US2023 / 67204, the contents of each of which are incorporated herein by reference in their entirety.

[0061] In another embodiment, the present disclosure provides 5-HT 2Aand / or dopamine D1 / D2 receptor signaling pathways, e.g., the disease, condition, or disorder is selected from obesity, anorexia nervosa, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related condition, social phobia, dementia, dementia-related disorder, post-traumatic stress disorder, impulse control disorder, and intermittent explosive disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of Composition 1 or any of Compositions 2 or later.

[0062] In preferred embodiments, the methods and uses are for the treatment of a disease, condition or disorder selected from negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), treatment-resistant depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with comorbid depression, schizophrenia with comorbid anxiety and depression, or other mood disorders associated with encephalitis or neuroinflammation. Such methods of use of lumateperone are further described, for example, in US2011 / 0071080, US2015 / 0072964, US2015 / 0080404, US2016 / 0310502, US2021 / 0060009, US2021 / 0000822 and US2021 / 0186962, and PCT Application No. PCT / US2023 / 67204, the contents of each of which are incorporated herein by reference in their entirety.

[0063] For methods of use or treatment involving the use of long-acting injectable compositions according to Composition 2 and beyond, the method or use can include administering the composition by intramuscular or subcutaneous injection to a patient in need thereof once per week, once per two weeks, once per three weeks, once per month, once per two months, once per three months, once per four months, once per five months, or once per six months. Preferably, the method provides therapeutically effective plasma levels of lumateperone free base and / or therapeutically effective cerebrospinal fluid (CSF) levels of lumateperone free base for a period of 1 week to 6 months, e.g., 1 week to 1 month, or 1 month to 3 months, or 3 months to 6 months, or about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0064] In some embodiments, the method comprises administering an injectable unit dose of a composition comprising an amount of an acid addition salt of lumateperone equivalent to 100 to 5000 mg, e.g., 100 to 500 mg, or 500 to 1000 mg, or 1000 to 1500 mg, or 1500 to 2000 mg, or 2000 to 3000 mg, or 3000 to 5000 mg, or 100 to 250 mg, or 250 to 500 mg, or 500 to 750 mg, or 750 to 1000 mg, or 1000 to 1250 mg, or 1250 to 1500 mg of lumateperone free base.

[0065] In some embodiments, the dosage is administered as a unit dose volume of the composition, and is 0.1 to 5.0 mL, e.g., 0.5 to 5.0 mL, or 1.0 to 5.0 mL, or 2.0 to 5.0 mL, or 3.0 to 5.0 mL, or 4.0 to 5.0 mL, or 0.5 to 4.0 mL, or 1.0 to 4.0 mL, or 2.0 to 4.0 mL, or 3.0 to 4.0 mL, or 0.1 to 3.0 mL, 0.5 to 3.0 mL, or 1.0 to 3.0 mL, or 1.5 to 3.0 mL, or 2.0 to 3.0 mL, or 2.5 to 3.0 mL, or 0.1 to 2.5 mL, or 0.5 to 2.5 mL, or 1.0 to 2.5 mL, or 1.5 to 2.5 mL, or 2.0 to 2.5 mL, or 0.1 to 2.0 mL, or 0.5 to 2.0 mL, or 1.0 to 2.0 mL, or 1.5 to 2.0 mL, or 0.1 to 1.5 mL, or 0.5 to 1.5 mL, or 1.0 to 1.5 mL, or 0.1 to 1.0 mL, or 0.5 to 1.0 mL, or 0.1 to 0.5 mL.

[0066] In some embodiments, the method comprises administering a composition comprising an acid addition salt of lumateperone at a concentration (measured by weight of the salt) of 0.1 to 1000 mg / mL, e.g., 1 to 1000 mg / mL, or 10 to 1000 mg / mL, or 50 to 1000 mg / mL, or 100 to 1000 mg / mL, or 250 to 1000 mg / mL, or 500 to 1000 mg / mL, or 750 to 1000 mg / mL, or 1 to 10 mg / mL, or 10 to 50 mg / mL, or 50 to 100 mg / mL, or 100 to 500 mg / mL.

[0067] It is understood that the administered dose, administered volume and administered concentration depend on the intended duration of action of the LAI composition.Therefore, for long-acting compositions, a larger dose and volume are required, while for short-acting compositions, a smaller dose and volume may be sufficient.In some embodiments, the composition is administered by reconstituting a dry solid containing an acid addition salt of lumateperone and one or more diluents, carriers or additives (e.g., water-soluble additives) with sterile water for injection immediately before administration (injection) of the obtained long-acting injectable pharmaceutical composition.The dry solid can be provided as a powder, granules, pellets or cake, and is optionally packaged in a vial, sachet or pre-filled syringe (single or double chamber).Therefore, in the case of a single-chamber syringe, sterile water for injection is drawn into the pre-filled syringe containing the solid, the contents are mixed, and then the contents of the syringe are injected into the patient. In some embodiments, dry solid is packaged in a pre-filled two-compartment syringe, wherein one compartment comprises dry solid, and the other compartment comprises sterile water for injection.Therefore, the contents of two chambers are mixed by opening or opening the barrier between two compartments immediately before use, and the mixture of two compartments is mixed, and the long-acting injectable pharmaceutical composition obtained is administered to patient.When dry solid is packaged in vial, sachet or other single-dose packaging or container, sterile water for injection can be added to packaging or container, or the contents of packaging or container can be added to sterile water for injection.Then, the combination is mixed, and then the composition obtained is drawn into syringe, and then injected to patient.

[0068] Treatment using long-acting injectable compositions is particularly beneficial for patients who have poor compliance with taking oral medications, such as those suffering from schizophrenia, bipolar depression, dementia and other psychiatric disorders.

[0069] Methods for the synthesis of lumateperone free base are known and can be found, for example, in US2004 / 0220178, US2006 / 148808, US2010 / 0113781, and US2020 / 0102309, the contents of each of which are incorporated herein by reference in their entirety.

[0070] While particular embodiments of the present disclosure will now be described with reference to preparations, it should be understood that such embodiments are merely exemplary and merely illustrative of a few of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art given the benefit of this disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims. [Example]

[0071] The following equipment and methods are used to isolate and characterize the exemplary salt forms.

[0072] X-ray powder diffraction (XRPD): X-ray powder diffraction studies were performed using a Bruker AXS D2 PHASER (instrument #1549) in a Bragg-Brentano configuration. The X-ray source was a Cu anode at 30 kV and 10 mA. From the beam to the source, the slits used were a primary axial Soller slit of 2.5°, a fixed divergence slit of 1.0 mm (=0.61°), an 8.0 mm detector slit, and a secondary axial Soller slit of 2.5°. A Kβ filter (0.5% Ni) was used for monochromatization. The detector was a linear LYNXEYE detector with a receiving slit and a 5° detector opening. The sample stage rotated at a standard speed (5 / min) with a beam stop. All measurement conditions were recorded in the instrument control file. The software used for data collection was Diffrac. Measurement Centre v4.6. Data analysis was performed using Diffrac.Eva v4.1.1 evaluation software. No background correction or smoothing was applied to the patterns.

[0073] Bruker AXS D8 Discovery High-Throughput X-Ray Screening: X-ray powder diffraction studies were performed using a Bruker AXS D8 discover HTS (instrument #3198). A Cu anode was used at 40 kV, 40 mA; a Goebel mirror, linear light. Detector: LYNXEYE XE linear detector with a receiving slit 2.95° detector opening. Measurement conditions: scan range 2-45°, 2°, 1 sec / step, 0.005° / step. All measurement conditions were recorded in the instrument control file. Corundum powder was measured for system suitability. The software used for data collection was Diffrac.Commander v7.3.0.0. Data analysis was performed using Diffrac.Eva v4.2.1. No background correction or smoothing was applied to the patterns. S (NIST standard) was checked daily for peak position, peak shape, intensity, and linearity.

[0074] Simultaneous thermogravimetry (TGA) and differential scanning calorimetry (DSC) or TGA / DSC analysis: TGA / DSC testing was performed using a Mettler Toledo TGA / DSC-3+ STARe system (instrument #3119 / #3287) equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl, perforated). Typically, 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668. No corrections were applied to the thermograms. Indium and zinc were measured as a system suitability check. The instrument was calibrated using benzophenone, indium, lead, tin, and zinc references.

[0075] Differential Scanning Calorimetry (DSC): DSC tests were performed using a Mettler Toledo DSC1 / DSC3+ STARe system (instrument #1564 / #3168). Samples were prepared using Al crucibles (40 μl, perforated). Typically, 1–8 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min, holding at 350°C for 1 minute. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668. No corrections were applied to the thermograms. Indium and zinc were measured as a system suitability check. Indium, lead, and zinc references were used for instrument calibration.

[0076] Polarized Light Microscopy (PLM): Microscopic examinations are performed using an AxioVert 35M (instrument #1612) equipped with an AxioCamERc 5s. The microscope is equipped with four lenses: Zeiss A-Plan 5x / 0.12, Zeiss A-Plan 10x / 0.25, LD A-Plan 20x / 0.30, and Achros TIGMAT 32x / 0.40. Data collection and evaluation are performed using Carl Zeiss Zen AxioVision Blue Edition Lite 2012 v1.0.0.0 software. A small amount of sample is placed on the objective glass and carefully spread until a thin layer is obtained.

[0077] Proton nuclear magnetic resonance spectroscopy ( 1 H-NMR): NMR studies were performed using a Varian Unity Inova 400 NMR spectrometer (instrument #1857) equipped with a 5 mm ID probe.

[0078] Technobis Crystalline: Experiments are performed using a Technobis Crystalline (instrument #2537). A total of eight small reactors are available, using 8 mL glass vials. For each reactor, a vial is filled with the desired chemical and closed with the desired cap. CCD cameras are connected to reactors E to H to monitor the reaction over time. Data are collected with Crystalline version 2.17.2 and evaluated with CrystalClear version 1.0.1.614.

[0079] MYA4: Experiments are carried out using a Radleys MYA 4 reaction station (apparatus #3181) equipped with the Process Package. A total of four reactor stations are available, each available in scales of 50 mL, 100 mL, 250 mL, and 500 mL. All reactors are equipped with stirrers, thermometers, and KNF Simdos 02 / 10 liquid dosing pumps. The MYA 4 reaction station is controlled with MYA control software V1.1.1 with a custom driver for the KNF Simdos 02-10 liquid dosing pump.

[0080] Example 1: Salt crystal screening Salt screening is performed to identify new solid, stable crystalline salts of lumateperone, particularly those with low solubility. Lumateperone free base is a sticky, oily substance with extremely low aqueous solubility. Many previous studies have shown that forming solid crystalline salts of lumateperone is extremely difficult. See, for example, US2011 / 112105, US2019 / 0112309, US2020 / 247805, and US2020 / 0157100. However, stable crystalline monotosylate, bistosylate, besylate, napsylate, and napadisylate salts of lumateperone have been described, suggesting that sulfonic acid may be the preferred acid counterpart for salt formation. This study relies on a large set of mono- and di-sulfonic acid salts, most of which have bulky and / or nonpolar side chains.

[0081] In the initial screening, 36 different sulfonic acids are tested in four solvent systems: acetonitrile / water (9:1 v / v), methanol, ethyl acetate, and toluene, at molar ratios of 1:1 and / or 1:2 free base to acid. These solvents are selected based on the known solubility of lumateperone free base and the solubility of the selected acids. This initial screening is performed on a Technobis Crystal 16 instrument using thermal cycling.

[0082] Stock solutions of lumateperone free base were prepared at a concentration of 25 mg / 0.5 mL in each of the four selected solvents. The acid was weighed into an empty vial to a molar ratio of 1:1 or 1:2, followed by the addition of lumateperone free base solution. The samples were then subjected to a thermal cycling protocol: 20°C-60°C-0°C-50°C-0°C-30°C-0°C-20°C-0°C. The applied heating rate was 20°C / min, and the applied cooling rate was 0.5°C / min. Finally, each vial was checked for solid material.

[0083] The majority of vials contain either a clear solution or an oil. All vials with clear solutions are then subjected to the anti-solvent protocol. If the solvent is acetonitrile / water or methanol, 0.5 mL of water is added to the vial. If the solvent is ethyl acetate or toluene, 0.5 mL of heptane is added to the vial. The thermal cycling protocol is then repeated.

[0084] The vials containing the solid material (either after initial screening or after antisolvent treatment) are then centrifuged, the supernatant removed with a pipette, and the solid transferred to a well plate for XRPD analysis. The resulting XRPD spectrum is evaluated to determine whether it is amorphous or corresponds to a new crystalline diffraction pattern.

[0085] A total of 272 counterion / solvent / ratio combinations were tested in this initial screen, with only 35 resulting in solids, with 7 of the solids being obtained in insufficient quantities for analysis (indicating extremely low salt yields, if any salts were formed). Of the 28 solids formed in sufficient quantities for analysis, XRPD shows that 5 are amorphous and 23 are crystalline. Analysis of the crystalline solids by XRPD shows the formation of 19 distinct new XRPD patterns arising from 14 acids (out of 36 acids tested).

[0086] In a second set of preliminary experiments, each of the 14 acids that produced crystalline solids in the initial screening was tested using a different protocol. The specific acid was added to a vial to achieve a 1:1 molar ratio of acid to lumateperone free base (25 mg), followed by the addition of lumateperone free base solution (5 mg / 0.5 mL). The solvents chosen were based on the results of the initial screening: 11 experiments were performed using ethyl acetate, 5 experiments were performed using toluene, and 1 experiment each was performed using acetonitrile / water or methanol. The reaction was heated to 50°C for 2 hours and then cooled to 5°C. All experiments resulted in a clear solution or oil. Addition of antisolvent was performed on the clear solution, as described above. Of the 18 experiments, only two produced solids, both of which represented 20 distinct new XPRD patterns.

[0087] Thus, a total of 290 experiments yielded 20 new candidate crystalline lumateperone polymorphs. The candidate polymorphs were obtained using 14 of the 36 different acids. These 20 candidate salts were then analyzed by DSC and TGA, revealing that 9 were solvated and 10 were nonsolvated and anhydrous.

[0088] Scaling up and further characterization at the 100 mg scale was then attempted for each of these 20 candidate salt polymorphs using the conditions (molar ratio, solvent) that yielded the original candidate salt. Only 12 were successfully regenerated. The procedure was as follows: Acid was weighed into an empty vial to a 1:1 or 1:2 molar ratio, and 2.0 mL of the appropriate lumateperone free base stock solution was added to the vial. The mixture was stirred until a clear solution was obtained. The vials were then subjected to a thermal cycling protocol: 20°C-60°C-0°C-50°C-0°C-30°C-0°C-20°C-0°C. The applied heating rate was 10°C / min, and the applied cooling rate was 0.5°C / min. Finally, each vial was checked for solid material. If solids were present, the supernatant liquid was removed with a pipette, and the solid was dried under vacuum. The solid was then analyzed by XRPD, DSC-TGA, and proton NMR.

[0089] Twelve of the 19 experiments yielded solids with XRPD spectra identical to those found during the initial screening and were considered successful for scale-up. Five experiments did not form solids. Three experiments formed solids that were not lumateperone salts based on DSC-TGA and proton NMR. Two experiments yielded new crystalline salt forms that were clearly identified as lumateperone salts, but whose XRPD spectra did not match those obtained during the initial screening under the same conditions.

[0090] The same 100 mg scale-up was also attempted using conditions that yielded five different amorphous solids during the initial screening, with the hope that these might result in crystallization at a larger scale. One of these five attempts yielded a new crystalline XRPD pattern identified as a lumateperone salt.

[0091] In these 100 mg scale-up experiments, 12 different polymorphs derived from eight different acids were formed: three benzenesulfonate polymorphs, one 2-naphthalenesulfonate polymorph, three 4-ethylbenzenesulfonate polymorphs, one 4-propylbenzenesulfonate polymorph, one 4-tert-butylbenzenesulfonate polymorph, one 4-octylbenzenesulfonate polymorph, one pentane-1-sulfonate polymorph, and one heptane-1-sulfonate polymorph.

[0092] Importantly, the acids used in these experiments included several sulfonic acids that did not form solids or did not reproducibly form crystalline solids, yet these acids share structural similarity with the eight acids that reproducibly formed lumateperone salts. For example, the aromatic acids naphthalene-1,5-disulfonic acid and 5-isoquinolinesulfonic acid produced initial crystalline solids, but this was not reproducible at scale. In contrast, no significant solids were obtained under any of the conditions using quinoline-8-sulfonic acid, pyridine-2-sulfonic acid, or pyridine-3-sulfonic acid. Even acids that formed salts in this study, such as benzenesulfonic acid and 4-ethylbenzenesulfonic acid, only formed salts under certain conditions (forming salts in certain solvents but not others, or forming salts at a 1:1 molar ratio but not at a 1:2 molar ratio (or vice versa)). This underscores the ongoing conclusion, based on this and previous studies, that lumateperone forms solid crystalline salts with unpredictable acids in unpredictable environments and conditions. However, it also indicates that the mere fact that a particular acid did not form a reproducible crystalline salt under the conditions tested here does not preclude the possibility that such an acid may be able to form a stable, reproducible crystalline lumateperone salt given further study of alternative conditions. Thus, this is an ongoing study.

[0093] Example 2: 4-octylbenzenesulfonate Initial screening results indicated the formation of crystalline lumateperone 4-octylbenzenesulfonate using a 1:1 molar ratio in ethyl acetate or toluene solvents, and a 1:2 molar ratio in ethyl acetate or toluene solvents. Identical XRPD patterns were obtained under all four conditions. No solids were obtained using acetonitrile / water or methanol as solvents at either molar ratio. Initial DSC suggested that these were nonsolvated anhydrous crystals under each of the four conditions. DSA showed a melting event at 164.6°C, and there was no weight loss by TGA.

[0094] Since identical XPRD patterns were obtained using both solvents, a 100 mg scale-up was performed using ethyl acetate at 1:1 and 1:2 molar ratios, resulting in solids with the same XRPD pattern as the initial 25 mg screen. The DSA of the solid obtained from the 1:1 molar ratio showed a single melting event at 135.0°C, while the DSA of the solid obtained from the 1:2 molar ratio showed a single melting event at 157.6°C. Both are indicative of unsolvated anhydrous crystals.

[0095] The scale-up was again repeated on a 500 mg scale using a 1:1 molar ratio in ethyl acetate, again resulting in a solid with the same XRPD pattern as previously shown, which is shown in Figure 1 and the peak list is given in the table below: [Table 14]

[0096] DSC of this solid shows a single melting event at 156.7°C. Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1.0:0.8, thus confirming that this is a 1:1 salt. The NMR spectrum is shown in Figure 9.

[0097] Example 3: 4-tert-butylbenzenesulfonate Initial screening results indicated the formation of crystalline lumateperone 4-tert-butylbenzenesulfonate using a 1:2 molar ratio in ethyl acetate solvent. No solids were obtained using acetonitrile / water, methanol, or toluene as solvents, and the acid was not tested at a 1:1 molar ratio. Initial DSC suggested this was a nonsolvated anhydrous crystal. DSA showed a melting event at 210.9°C, and TGA showed a 1.0% weight loss (suggesting residual solvent).

[0098] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio, yielding a solid with the same XRPD pattern as the 25 mg initial screen. DSA of the solid showed one melting event at 211.7 °C and a desolvation event at 67.7 °C. The TGA mass was 1.3%, consistent with a desolvation event, indicating solvated crystals.

[0099] The XRPD pattern is shown in Figure 2 and the peak list is given in the table below: [Table 15]

[0100] Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1:2, thus confirming that this is a 1:2 salt. The NMR spectrum is shown in Figure 10.

[0101] Example 4: 4-Propylbenzenesulfonate Initial screening results indicated the formation of crystalline lumateperone 4-propylbenzenesulfonate using a 1:2 molar ratio in ethyl acetate solvent. No solids were obtained using acetonitrile / water, methanol, or toluene as solvents, and the acid was not tested at a 1:1 molar ratio. Initial DSC suggested this was a nonsolvated anhydrous crystal. DSA showed a melting event at 158.3°C, and there was no weight loss by TGA.

[0102] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio, yielding a solid with the same XRPD pattern as the 25 mg initial screen. DSA of the solid showed a single melting event at 160.2 °C. The TGA mass was 0.7%, consistent with residual solvent, indicating unsolvated anhydrous crystals.

[0103] The XRPD pattern is shown in Figure 3 and the peak list is given in the table below: [Table 16]

[0104] Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1:2, thus confirming that this is a 1:2 salt. The NMR spectrum is shown in Figure 11.

[0105] Example 5: 4-Ethylbenzenesulfonate Initial screening results indicated the formation of crystalline lumateperone 4-ethylbenzenesulfonate using a 1:2 molar ratio in both ethyl acetate and toluene solvents, but initial XRPD showed that these solids had two different XPRD patterns. Amorphous solids were also obtained from screening using a 1:2 molar ratio in methanol and a 1:2 molar ratio in methanol, and these two amorphous XRPD patterns were also different. No solids were obtained using acetonitrile / water as the solvent or using toluene or ethyl acetate in a 1:1 molar ratio. Initial DSC suggested that both crystalline solids were nonsolvated anhydrous crystals. DSA showed one melting event at 153.2°C for the ethyl acetate condition and one melting event at 157.6°C for the toluene condition. Weight loss in TGA was 0% for the ethyl acetate condition and 2.2% for the toluene condition.

[0106] Alternative reaction conditions (50 mg scale, 50 °C for 2 hours) also yielded a third crystalline 4-ethylbenzenesulfonate salt candidate. This salt was obtained using both ethyl acetate and toluene solvents. The solid from the toluene condition was examined by DSC and TGA. DSC showed a single melting event at 141.5 °C, and TGA showed a mass loss of 0.6% (residual solvent).

[0107] A 100 mg scale-up was performed using each of the three initial conditions that produced crystalline solids, and in each case, solids with the same XRPD pattern as the 25 mg initial screening were obtained. Polymorph 1 was obtained using a 1:2 molar ratio in ethyl acetate solvent; polymorph 2 was obtained using a 1:2 molar ratio in toluene solvent; and polymorph 3 was obtained using a 1:1 molar ratio in toluene solvent and heptane antisolvent. DSC showed one melting event for each solid: polymorph 1, 147.0 °C (3.7% TGA weight loss); polymorph 2, 156.5 °C (no TGA weight loss); polymorph 3, 138.3 °C (1.4% TGA weight loss). The results indicate nonsolvated anhydrous crystals with some residual solvent loss.

[0108] The XRPD patterns are shown in Figures 4A, 4B and 4C, and the peak list is shown in the table below: [Table 17] [Table 18] [Table 19]

[0109] Proton NMR was performed and the lumateperone to acid molar ratio was estimated to be 1:2 for polymorphs 1 and 2, and 1:1 for polymorph 3. The NMR spectra are shown in Figures 12A, 12B, and 12C.

[0110] Example 6: 2-Naphthalenesulfonate Initial screening results indicated the formation of crystalline lumateperone 2-naphthalenesulfonate using a 1:2 molar ratio in ethyl acetate solvent. No significant solids were obtained using acetonitrile / water, methanol, or toluene as solvents at 1:1 or 1:2 molar ratios, or ethyl acetate at a 1:1 molar ratio. Initial DSC suggested this was a solvate crystal. DSA showed a desolvation event at 91.4°C with no melting event, and TGA showed a 6.0% weight loss, consistent with desolvation of the crystals.

[0111] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio, yielding a solid with the same XRPD pattern as the 25 mg initial screen. DSA of the solid showed a desolvation event at 108.5 °C and one melting event at 162.1 °C. The TGA mass was 7.4%, consistent with crystalline desolvation.

[0112] The XRPD pattern is shown in Figure 5 and the peak list is given in the table below: [Table 20]

[0113] Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1:1, thus confirming that this is a 1:1 salt.

[0114] Example 7: Benzenesulfonate Initial screening results indicated the formation of crystalline candidate salts using a 1:2 molar ratio in both ethyl acetate and toluene solvents, but initial XRPD showed that these solids had two distinct XPRD patterns. An amorphous solid was also obtained from screening using a 1:1 molar ratio in ethyl acetate. No solids were obtained using acetonitrile / water or methanol as solvents, or using toluene at a 1:1 molar ratio. Initial DSC suggested that both of these crystalline solids were solvate crystals. DSC showed desolvation events at 73.9 °C and 110.6 °C and one melting event at 172.6 °C for the ethyl acetate condition, and a desolvation event at 75.1 °C and one melting event at 174.1 °C for the toluene condition. TGA weight losses were 4.9% for the ethyl acetate condition and 3.6% for the toluene condition, both consistent with solvated crystals.

[0115] A 100 mg scale-up was performed using each of the three initial conditions that produced solids, but the original product was not reproduced. Instead, each of the three conditions, including the 25 mg scale that yielded an amorphous solid, resulted in a different crystalline salt XRPD pattern at the 100 mg scale. Polymorph 1 was obtained using a 1:2 molar ratio in ethyl acetate solvent; polymorph 2 was obtained using a 1:2 molar ratio in toluene solvent; and polymorph 3 was obtained using a 1:1 molar ratio in ethyl acetate solvent. Polymorph 1 exhibited a desolvation event at 96.0°C and a melting event at 109.5°C, with a TGA weight loss of 6.3%, consistent with a solvated crystal. Polymorph 2 exhibited one melting event at 131.3°C with no TGA weight loss, consistent with a nonsolvated anhydrous crystal. Polymorph 3 exhibited two melting events at 109.6 and 125.9°C with no TGA weight loss. This also represents a non-solvated anhydrous crystal.

[0116] The XRPD patterns are shown in Figures 6A, 6B and 6C, and the peak list is shown in the table below: [Table 21] [Table 22] [Table 23]

[0117] Proton NMR was performed and estimated to have a 1:1 molar ratio of lumateperone to acid for each of polymorphs 1, 2, and 3. The NMR spectra are shown in Figures 12A, 12B, and 12C.

[0118] Lumateperone besylate has previously been reported in WO 2020 / 112941 (Teva Pharmaceuticals, Inc.; Teva Czech Industries S.R.O.). However, the besylate reported in this application has a much higher melting event temperature of 173-174°C compared to the polymorphs 1, 2, and 3 described above. The XRPD pattern of the Teva crystal also differs from the polymorphs 1, 2, and 3 described above.

[0119] Example 8: Pentane-1-sulfonate Initial screening results indicated the formation of crystalline lumateperone pentane-1-sulfonate using a 1:2 molar ratio in ethyl acetate solvent. No solids were obtained using acetonitrile / water, methanol, or toluene in 1:1 or 1:2 molar ratios as solvents, or in ethyl acetate at a 1:1 molar ratio. Initial DSC suggested this was a nonsolvated anhydrous crystal. DSC showed no events, and TGA showed a 1.4% weight loss, consistent with residual solvent.

[0120] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio, yielding a solid with the same XRPD pattern as the 25 mg initial screen. DSA of the solid showed a single melting event at 141.3 °C. The TGA mass was 0.9%, consistent with residual solvent, indicating unsolvated anhydrous crystals.

[0121] The XRPD pattern is shown in Figure 7 and the peak list is given in the table below: [Table 24]

[0122] Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1:1.8, thus confirming that this is a 1:2 salt.

[0123] Example 9: Heptane-1-sulfonate Initial screening results indicated the formation of crystalline lumateperone heptane-1-sulfonate using a 1:2 molar ratio in ethyl acetate solvent. No solids were obtained using acetonitrile / water, methanol, or toluene in 1:1 or 1:2 molar ratios as solvents, or in ethyl acetate at a 1:1 molar ratio. Initial DSC suggested this was a nonsolvated anhydrous crystal. DSA showed a melting event at 151.8°C, and TGA showed no weight loss. However, addition of antisolvent to a 1:2 molar ratio toluene vial resulted in the formation of a solid with an XRPD pattern different from the ethyl acetate condition. DSC of this solid showed a desolvation event at 105°C, with a TGA mass loss of 1.1%.

[0124] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio, and under these conditions a solid was obtained with the same XRPD pattern as the 25 mg initial screen. DSA of the solid showed a single melting event at 150.8 °C. TGA showed a mass loss, indicative of unsolvated anhydrous crystals.

[0125] The XRPD pattern is shown in Figure 8 and the peak list is given in the table below: [Table 25]

[0126] Proton NMR was performed and the molar ratio of lumateperone to acid was estimated to be 1:1.8, thus confirming that this is a 1:2 salt.

[0127] Example 10: Determination of Water Solubility The aqueous solubility of the regenerated salt is determined by shaking a saturated solution in water. Solubility at pH 7.4 is determined by shaking a saturated solution in a phosphate buffered system. Samples are prepared by adding a known amount of water (100-200 μl) followed by slurrying with the solid for 24 hours. All samples are then filtered using a syringe filter to remove undissolved solids, after which the filtrate is diluted with methanol / acetonitrile (1:1 v / v). LC analysis of the samples is performed and a calibration curve is used for solubility determination. The results are shown in mg / mL in the table below: [Table 26]

[0128] Some of the salts prepared according to the present disclosure have surprisingly low aqueous solubility. Therefore, these low-solubility salts are particularly suitable for formulation as aqueous, long-acting injectable compositions. Subcutaneous or intramuscular injection of such compositions provides a largely insoluble depot of the active substance, lumateperone, which slowly dissolves to release lumateperone free base according to the dissolution kinetics of the salt. Formulations suitable for subcutaneous or intramuscular injection are shown in the table below. [Table 27] One or more formulations according to the table above are prepared by combining a lumateperone salt, a viscosity enhancer (e.g., sodium carboxymethylcellulose), and a bulking agent (e.g., mannitol) in water (e.g., sterile water for injection). The solid materials, individually or together, may be milled or ground to an appropriate particle size. The solids are suspended in water and the pH is adjusted as desired, e.g., to pH 6.5-7.5, e.g., 7-7.5 or 7.3-7.4. Further testing is performed to confirm the plasma and CSF pharmacokinetics of such formulations.

Claims

1. A solid crystalline salt of lumateperone having an aqueous solubility of less than 2 mg / mL at pH 7 or less than 1 mg / mL at pH 7.

4.

2. Lumateperone in the form of a salt selected from 4-octylbenzenesulfonic acid addition salt, 4-tert-butylbenzenesulfonic acid addition salt, 4-propylbenzenesulfonic acid addition salt, 4-ethylbenzenesulfonic acid addition salt, 2-naphthalenesulfonic acid addition salt, wherein the salt is a solvate, a benzenesulfonic acid addition salt that is a solid crystalline salt characterized by a DSC thermogram lacking an endothermic event at 172-176°C, and an alkylsulfonic acid addition salt (e.g., pentane-1-sulfonate or heptane-1-sulfonate).

3. substituted with one, two, or three R groups, each R independently being C 1～12 Lumateperone in the form of an acid addition salt with the alkyl group benzenesulfonic acid, with the proviso that the acid is not p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid, 4-propylbenzenesulfonic acid, 4-t-butylbenzenesulfonic acid, or 4-octylbenzenesulfonic acid.

4. The salt according to any one of claims 1 to 3 in crystalline form.

5. 5. The salt of any one of claims 1 to 4, further defined in any of the following embodiments: Salt 1 or later, Salt 2 or later, Salt 3 or later, Salt 4 or later, Salt 5 or later, Salt 6 or later, Salt 7 or later, or Salt 8 or later, as defined in this disclosure.

6. A method for producing the salt according to any one of claims 1 to 5, comprising the steps of: (a) reacting lumateperone free base with the corresponding acid together with an organic solvent (e.g., including ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or a mixture thereof), e.g., in a molar ratio of 1:1 to 1:2, or about 1:1, or about 1:2, of the acid to lumateperone; optionally at a temperature of 0°C to 100°C; and (b) optionally subjecting the resulting mixture to a thermal cycling protocol (e.g., raising the temperature to above 50°C and then cooling to 0°C, optionally repeating this heating and cooling cyclically), or cooling the mixture from the reaction temperature to 5°C or below; and (c) optionally diluting the resulting mixture with an anti-solvent, wherein, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture, the anti-solvent is water, or when the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol, the anti-solvent is heptane or hexane; optionally at a temperature of 0° C. to 100° C.; and (d) optionally, performing a second thermal cycling protocol (e.g., increasing the temperature to above 50°C and then cooling to 0°C, optionally repeating this heating and cooling cyclically), or cooling the mixture from the reaction temperature to 5°C or below; and (e) recovering the salt thereby formed, for example a salt according to any one of claims 1 to 5. A manufacturing method comprising:

7. A method for purifying lumateperone in free or salt form, comprising reacting a crude solution of mateperone free base with an acid described herein to form any of the salts described herein, recovering the salt thereby formed, e.g., according to claim 6, and optionally converting the salt thereby formed back to lumateperone free base or any other salt form of lumateperone (e.g., lumateperone monotosylate).

8. A pharmaceutical composition comprising the salt of any one of claims 1 to 5 as an active ingredient in combination or with a pharmaceutically acceptable diluent or carrier.

9. A long-acting injectable pharmaceutical composition comprising an acid addition salt of lumateperone having an aqueous solubility of less than 20 mg / mL.

10. A long-acting injectable pharmaceutical composition comprising an acid addition salt of lumateperone according to any one of claims 1 to 5.

11. 11. The composition of claim 9 or 10, wherein the composition comprises water (e.g., sterile water for injection) and one or more additives (e.g., water-soluble additives), such as a thickener, a buffer, a tonicity agent, a surfactant, and an antioxidant.

12. the one or more water-soluble additives are thickeners selected from carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), crystalline cellulose, amorphous cellulose, polyacrylate polymers, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol, and / or sorbitan esters (e.g., sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate), polyoxyethylene sorbitan 12. The composition of claim 11, comprising a surfactant selected from fatty acid esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), polyoxyethylene alkyl ethers, fatty acid esters (e.g., glycerol monostearate, glycerol monolaurate), poloxamers, and fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, cetostearyl alcohol), and a filler selected from mannitol, sucrose, fructose, maltose, xylitol, glucose, starch, sorbitol, magnesium aluminum silicate, and silica (e.g., colloidal silica).

13. 14. The composition of any one of claims 11 to 13, wherein the composition comprises an acid addition salt of lumateperone (e.g., lumateperone 4-octylbenzenesulfonate or lumateperone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a viscosity increasing agent (e.g., sodium carboxymethylcellulose), a bulking agent (e.g., mannitol), a non-ionic surfactant (e.g., polysorbate 80), and optionally one or more pH adjusting agents or buffering agents (e.g., NaOH or HCl, and / or sodium or potassium phosphate).

14. 14. The composition of any one of claims 11 to 13, wherein the composition comprises an acid addition salt of lumateperone (e.g., lumateperone 4-octylbenzenesulfonate or lumateperone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a viscosity increasing agent (e.g., sodium carboxymethylcellulose), a bulking agent (e.g., mannitol), and optionally one or more pH adjusting or buffering agents (e.g., sodium or potassium phosphate, NaOH and / or HCl, and / or sodium or potassium phosphate).

15. The composition comprises the following components: 【Table 1】 The composition of any one of claims 9 to 15, comprising:

16. The composition according to any one of claims 9 to 15, wherein the composition is a suspension.

17. The composition of any one of claims 9 to 16, wherein the composition is prepared as a dry solid comprising an acid addition salt of lumateperone and one or more diluents, carriers, or excipients (e.g., water-soluble excipients), and prior to administration, the solid is reconstituted with sterile water for injection to form a long-acting injectable pharmaceutical composition.

18. 5-HT 2A receptors, serotonin transporter (SERT) and / or dopamine D 1 / D 2 18. A method for preventing or treating a human suffering from a disease or abnormal condition involving or mediated by a receptor signaling pathway, the method comprising administering to said human an effective amount of a salt according to any one of claims 1 to 5 or a composition according to any one of claims 6 to 17.

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