Novel salts and crystals

Abstract

The present disclosure provides novel, stable crystalline salt forms of lumepirone as well as methods of making and using them and pharmaceutical compositions comprising them.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a PCT international application, which claims priority and benefits to U.S. Provisional Application Serial No. 63 / 393,911 filed on July 30, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] field

[0004] The present disclosure relates to certain novel salts and crystalline forms of lumateperone (i.e., substituted heterocyclic fused γ-carbolines), methods for their preparation, pharmaceutical compositions thereof, and their uses, for example, in the treatment of diseases involving 5-HT 2A receptors, serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways or diseases or abnormal conditions mediated thereby.

[0005] background

[0006] The substituted heterocyclic fused γ-carboline compound lumiperone, which 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), is known to be a 5-hydroxytryptamine receptor (5-HT 2A ), dopamine receptors (D1 and / or D2) and 5-hydroxytryptamine transporter (SERT) ligands, and can be used to treat a variety of central nervous system disorders. It is also called ITI-007, and it has the following structure:

[0007]

[0008] Lumiperone antagonizes 5-HT2A 2A) receptors and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins. The compound is known to be primarily used to treat 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 its associated symptoms). At the dopamine D2 receptor, the compound has a dual nature and can act 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. It is believed that this regional selectivity for brain regions that are thought to mediate the efficacy of antipsychotic drugs, as well as serotonergic, glutamatergic and dopaminergic interactions, may produce antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition, thereby providing antidepressant activity for the treatment of schizoaffective disorder, comorbid depression and / or as a stand-alone treatment for major depressive disorder, bipolar depression and refractory depression. Lumiperone may also be used to treat bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social functioning, allowing them to more fully integrate into the family and workplace.

[0009] Lumiperone exhibits distinct dose-dependent effects, selectively targeting 5-HT at low doses 2A receptors, while at higher doses it gradually interacts with D2 receptors. Therefore, at lower doses, it can be used to treat sleep, aggression, and restlessness. At higher doses, it can treat acute exacerbation and residual schizophrenia, bipolar disorder, and mood disorders.

[0010] Lumiperone is a potent (Ki = 0.5 nM) 5-HT 2A It is a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator, with activity consistent with partial agonism of presynaptic D2 receptors and antagonism of postsynaptic D2 receptors in vivo (Ki=32nM), high D1 receptor affinity (Ki=52nM) and inhibition of the serotonin transporter (SERT) (Ki=26-62nM using different SERT activity assays), but negligible binding to receptors associated with cognitive and metabolic side effects of antipsychotic drugs (e.g., H1 histaminergic, 5-HT2C, and muscarinic).

[0011] Lumaperone Tosylate It is currently approved in the U.S. for the treatment of schizophrenia and bipolar depression. The drug is currently in clinical trials and is being developed for other indications, including major depressive disorder (MDD).

[0012] It has also recently been discovered that lumepirone may be particularly effective in treating acute depression and acute anxiety compared to existing antidepressants due to its rapid onset of action. This is believed to be due to its signaling through a neurotransmitter system separate from the traditional monoamine signaling system. Lumiperone provides dopamine D1 receptor-dependent NMDA and AMPA current enhancement and activates the mTOR (e.g., mTORC1) signaling pathway.

[0013] Lumeperone is difficult to formulate as a drug. In free base form, ITI-007 is an oily, viscous solid with poor water solubility. It has been demonstrated that it is exceptionally difficult to prepare salts of the compound. A hydrochloride salt form of lumeperone prepared simply during the free base synthesis process is disclosed in WO 2000 / 0770020, but this particular salt is not crystalline, and such hydrochlorides are found to be hygroscopic and exhibit poor stability. For example, a stable crystalline toluenesulfonic acid addition salt (monotoluenesulfonate) of lumeperone was ultimately identified and described in WO 2009 / 114181. Additional salts and polymorphs of lumeperone have since been described, including bistoluenesulfonates, benzenesulfonates, naphthylidenesulphonates and naphthylidenesulfonates. See, for example, WO 2018 / 031535, WO 2019 / 102240, WO 2020 / 182988, WO 2020 / 112941 and IN2017 / 41021763.

[0014] Although in general, the pharmaceutically acceptable salt form of the drug should have high water solubility, this is not always the most ideal form. For example, although oral, transmucosal and intravenous drugs should have high water solubility, it is also necessary to have a salt form with low water solubility, especially from a long-acting injectable reservoir delivery (e.g., continuous delivery over several weeks or months). In this case, the low water solubility of the drug causes the drug to slowly dissolve from its insoluble, pharmacologically inactive reservoir form into a pharmacologically active soluble form. However, such delivery mechanisms require a high degree of chemical and physical stability so that the drug will not be degraded into a chemical product or polymorph with unpredictable pharmacological or pharmacokinetic properties in vivo.

[0015] Therefore, there is a need for a chemically and physically stable, preferably crystalline, solid pharmaceutically acceptable salt form of lumepirone having low water solubility.

[0016] Overview

[0017] In an attempt to find a new chemically and physically stable, preferably crystalline, solid pharmaceutically acceptable salt form of lumepirone with low water solubility, extensive salt screening was undertaken. Based on the known toluenesulfonates and benzenesulfonates, it is believed that other aromatic sulfonates of lumepirone may be suitable. However, lumepirone is not easy to form salts with other common, pharmaceutically acceptable acids. See, for example, US2019 / 0112309, US2020 / 247805, and US2020 / 015700. These documents disclose attempts to prepare new crystalline salt forms of lumepirone with extremely low success rates. For example, US2019 / 112309 and US2020 / 247805 disclose the results of a series of salt screening experiments using 90 counterions, 6 solvents, and 4 crystallization methods. A total of 624 combinations of counterions, solvents, and methods were tested, and this resulted in the reproducible formation of only four stable crystalline salts (oxalate, cyclamates, 4-aminosalicylate, and three polymorphs of the hydrochloride salt). Importantly, it is not possible to predict which counterion will form a stable crystalline salt, nor which method will successfully produce each stable crystalline salt. It was found that the vast majority of reaction conditions either did not form a salt, or formed an amorphous solid or oily liquid salt.

[0018] Currently, 16 new candidate crystalline lumepirone salts have been identified after extensive screening and testing involving 36 different sulfonate counterions (aryl, heteroaryl, heterocycloalkyl and alkyl sulfonic acids) using 1:1 and 1:2 molar ratios and several solvents (9:1 acetonitrile / water, methanol, ethyl acetate and toluene). In the process of further expansion and confirmation, eight new, reproducible, stable, crystalline salt forms of lumepirone were discovered. In particular, two new low-solubility salt forms of lumepirone were discovered, which have water solubility below 2 mg / mL: 4-tert-butylbenzenesulfonate and 4-octylbenzenesulfonate. These salt forms are chemically and physically stable, crystalline, and have low water solubility, and they are ideally suited for use in new pharmaceutical compositions for sustained or delayed release, such as long-acting injectable compositions.

[0019] Thus, the present disclosure provides novel salt forms of lumepirone, particularly novel low water soluble salt forms of lumepirone, which are particularly advantageous for use in the preparation of long-acting injectable formulations, and methods of making and using the same. Due to their low water solubility, these novel salt forms are not expected to be suitable for conventional oral immediate release formulations of lumepirone, such as tablets or capsules, nor 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 very useful for a variety of sustained or delayed release injectable pharmaceutical formulations.

[0020] Further areas 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 the preferred embodiment of the present disclosure, are intended for illustration purposes only and are not intended to limit the scope of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present disclosure can be more fully understood from the detailed description and accompanying drawings, in which:

[0023] Figure 1 An X-ray powder diffraction (XPRD) pattern of the 4-octylbenzenesulfonate salt of lumiperone prepared according to Example 2 is depicted.

[0024] Figure 2 Depicted is an X-ray powder diffraction (XPRD) pattern of the 4-tert-butylbenzenesulfonate salt of lumiperone prepared according to Example 3.

[0025] Figure 3 Depicted is an X-ray powder diffraction (XPRD) pattern of 4-propylbenzenesulfonate salt of lumepirone prepared according to Example 4.

[0026] Figure 4A Depicted is an X-ray powder diffraction (XPRD) pattern of 4-ethylbenzenesulfonate salt of lumiperone (polymorph 1) prepared according to Example 5A.

[0027] Figure 4B Depicted is an X-ray powder diffraction (XPRD) pattern of 4-ethylbenzenesulfonate salt of lumiperone (polymorph 2) prepared according to Example 5B.

[0028] Figure 4C Depicted is an X-ray powder diffraction (XPRD) pattern of 4-ethylbenzenesulfonate salt of lumiperone (polymorph 3) prepared according to Example 5C.

[0029] Figure 5 Depicted is an X-ray powder diffraction (XPRD) pattern of the 2-naphthalenesulfonate salt of lumepirone prepared according to Example 6.

[0030] Fig. 6A Depicted is an X-ray powder diffraction (XPRD) pattern of the besylate salt of lumepirone (polymorph 1) prepared according to Example 7A.

[0031] Figure 6B Depicted is an X-ray powder diffraction (XPRD) pattern of the besylate salt of lumepirone (polymorph 2) prepared according to Example 7B.

[0032] Figure 6C Depicted is an X-ray powder diffraction (XPRD) pattern of the besylate salt of lumepirone (polymorph 3) prepared according to Example 7C.

[0033] Figure 7 Depicted is an X-ray powder diffraction (XPRD) pattern of the pentane-1-sulfonate salt of lumiperone prepared according to Example 8.

[0034] Figure 8 An X-ray powder diffraction (XPRD) pattern of the heptane-1-sulfonate salt of lumiperone prepared according to Example 9 is depicted.

[0035] Fig. 9 The proton-NMR spectrum of the 4-octylbenzenesulfonate salt of lumepirone prepared according to Example 2 is depicted.

[0036] Fig.10 The proton-NMR spectrum of the 4-tert-butylbenzenesulfonate salt of lumiperone prepared according to Example 3 is depicted.

[0037] Fig.11 The proton-NMR spectrum of the 4-propylbenzenesulfonate salt of lumepirone prepared according to Example 4 is depicted.

[0038] Fig. 12A Depicted is the proton-NMR spectrum of 4-ethylbenzenesulfonate salt polymorph 1 of lumepirone prepared according to Example 5A.

[0039] Fig. 12B Depicted is the proton-NMR spectrum of 4-ethylbenzenesulfonate salt polymorph 2 of lumepirone prepared according to Example 5B.

[0040] Fig. 12C Depicted is the proton-NMR spectrum of 4-ethylbenzenesulfonate polymorph 3 of lumepirone prepared according to Example 5C.

[0041] Detailed Description

[0042] The following description of the preferred embodiment is merely exemplary in nature and is in no way intended to limit the invention described in the present disclosure, its application, or uses.

[0043] Throughout the application, range is used as a shorthand for describing each and every value within the range. Any value within the range can be selected as the endpoint of the range. In addition, all documents cited herein are incorporated herein by reference in their entirety. If there is a conflict between the definition in the present disclosure and the definition of the cited document, the present disclosure shall prevail.

[0044] Unless otherwise specified, all percentages and amounts expressed herein and in the remainder of this specification should be understood to refer to percentages by weight. The amounts given are based on the effective weight of the material.

[0045] The present disclosure generally provides new salt forms of lumepirone, and in particular new crystalline salt forms of lumepirone. Preferably, these new crystalline salt forms have low water solubility (e.g., at pH 7 or at pH 7.4). For example, the salts of the present disclosure may have an aqueous solubility of less than 20 mg / mL, such as 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.

[0046] In a first embodiment, the present disclosure provides lumiperone in the form of a 4-octylbenzenesulfonic acid addition salt (Salt 1). In a further embodiment of Salt 1, the present disclosure provides:

[0047] 1.1. Salt 1 in solid form.

[0048] 1.2. Salt 1 or 1.1 in crystalline form, for example in dried crystalline form.

[0049] 1.3. Salt 1, 1.1 or 1.2, wherein the salt has a molar ratio of lumiperone to 4-octylbenzenesulfonic acid of about 1:1 (ie, mono-4-octylbenzenesulfonate).

[0050] 1.4. Salt 1, 1.1 or 1.2, wherein the salt has a molar ratio of lumiperone to 4-octylbenzenesulfonic acid of about 1:2 (ie, bis-4-octylbenzenesulfonate).

[0051] 1.5. Any of the above forms of Salt 1, which is a solvate, for example an ethyl acetate or toluene solvate.

[0052] 1.6. Any of the above forms of Salt 1 which is not a solvate.

[0053] 1.7. Any of the above forms of Salt 1, which is a hydrate.

[0054] 1.8. Any of the above forms of Salt 1, which is not a hydrate.

[0055] 1.9. Any of the above forms of Salt 1, formed by combining lumepirone free base and 4-octylbenzenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or a molar ratio of about 1:2, or a molar ratio of about 1:2.5.

[0056] 1.10. Any of the above forms of Salt 1, which is a uniform crystalline form, free of or substantially free of other forms, for example free of or substantially free of, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0057] 1.11. Any of the above forms of Salt 1, when crystallized from a mixture of 4-octylbenzenesulfonic acid and lumepirone free base, for example in an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate or toluene, optionally, wherein the molar ratio of lumepirone free base to 4-octylbenzenesulfonic acid is about 1:1 or about 1:2.

[0058] 1.12. Salt 1.11, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane.

[0059] 1.13. Any of the above forms of Salt 1, wherein the salt is formed from a 1:1 molar ratio of lumiperone free base and 4-octylbenzenesulfonic acid in an ethyl acetate solvent, or from a 1:2 molar ratio of lumiperone free base and 4-octylbenzenesulfonic acid in an ethyl acetate solvent, or from a 1:2 molar ratio of lumiperone free base and 4-octylbenzenesulfonic acid in a toluene solvent.

[0060] 1.14. Salt 1.13, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-octylbenzenesulfonic acid of about 1:1.

[0061] 1.15. Salt 1.13 or 1.14, wherein DSC analysis shows one endothermic event (eg, melting) at about 156°C, or one endothermic event (eg, melting) at about 164°C, or one endothermic event (eg, melting) at about 135°C.

[0062] 1.16. Any form of the salts 1.13-1.15, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-θ) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., 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., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0063] XRPD of 4-octylbenzenesulfonate crystals (Cu anode, Ni filter)

[0064]

[0065]

[0066] 1.17. Any of the salts 1.13-1.16, which has a corresponding Figure 1 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 1 X-ray powder diffraction pattern of .

[0067] 1.18. Any form of salt 1.13-1.17, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 24.10, 24.46, 25.97 and 29.82, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0068] 1.19. Any form of the salts 1.13-1.18, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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 variations (e.g., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0069] 1.20. Any form of salt 1.13-1.19 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 1.18 and 1.19.

[0070] 1.21. Any of the above forms of Salt 1, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0071] 1.22. Any of the above forms of Salt 1, which exhibits any combination of the features described in 1.1-1.21.

[0072] In a second embodiment, the present disclosure provides lumiperone in the form of a 4-tert-butylbenzenesulfonic acid addition salt (Salt 2). In a further embodiment of Salt 2, the present disclosure provides:

[0073] 2.1. Salt 2 in solid form.

[0074] 2.2. Salt 2 or 2.1 in crystalline form, such as dried crystalline form.

[0075] 2.3. Salt 2, 2.1 or 2.2, wherein the salt has about a 1:1 molar ratio of lumiperone and 4-tert-butylbenzenesulfonic acid (ie, mono-4-tert-butylbenzenesulfonate).

[0076] 2.4. Salt 2, 2.1 or 2.2, wherein the salt has a molar ratio of lumiperone to 4-tert-butylbenzenesulfonic acid (ie, bis-4-tert-butylbenzenesulfonate) of about 1:2.

[0077] 2.5. Any of the above forms of Salt 2, which is a solvate, such as an ethyl acetate solvate.

[0078] 2.6. Any of the above forms of Salt 2, which is not a solvate.

[0079] 2.7. Any of the above forms of Salt 2, which is a hydrate.

[0080] 2.8. Any of the above forms of Salt 2, which is not a hydrate.

[0081] 2.9. Any of the above forms of Salt 2, formed by combining lumepirone free base and 4-tert-butylbenzenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or a molar ratio of about 1:2, or a molar ratio of about 1:2.5.

[0082] 2.10. Any of the above forms of Salt 2, which is a uniform crystalline form, containing no or substantially no other forms, for example, containing no or substantially no, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0083] 2.11. Any of the above forms of Salt 2, when crystallized from a mixture of 4-tert-butylbenzenesulfonic acid and lumepirone free base, for example in an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate or toluene, optionally, wherein the molar ratio of lumepirone free base to 4-tert-butylbenzenesulfonic acid is about 1:2.

[0084] 2.12. Salt 2.11, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane.

[0085] 2.13. Any of the above forms of Salt 2, wherein the salt is formed from a 1:2 molar ratio of lumiperone free base and 4-tert-butylbenzenesulfonic acid in ethyl acetate solvent.

[0086] 2.14. Salt 2.13, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-tert-butylbenzenesulfonic acid of about 1:2.

[0087] 2.15. Salt 2.13 or 2.14 wherein DSC analysis shows one endothermic event at about 68°C (eg, desolvation) and one endothermic event at about 212°C (eg, melting).

[0088] 2.16. Any form of the salts 2.13-2.15, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, e.g., 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0089] XRPD of 4-tert-butylbenzenesulfonate crystals (Cu anode, Ni filter)

[0090] # horn d value Relative Strength 1 3.216 27.44733 13.00％ 2 3.640 24.25154 100.00％ 3 6.665 13.25211 12.90％ 4 7.194 12.27861 20.60％ 5 13.904 6.36395 14.90％ 6 14.724 6.01133 12.70％ 7 15.224 5.81524 14.30％ 8 15.642 5.66062 10.10％ 9 16.050 5.51782 12.60％ 10 17.955 4.93645 8.10％ 11 18.775 4.72263 41.10％ 12 18.903 4.69091 24.20％ 13 19.586 4.52885 17.00％ 14 20.657 4.29632 13.60％ 15 22.084 4.02185 7.30％ 16 22.994 3.86463 5.20％ 17 23.678 3.75456 10.20％

[0091] 2.17. Any of the salts 2.13-2.16, which has a corresponding Figure 2 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 2 X-ray powder diffraction pattern of .

[0092] 2.18. Any form of the salt 2.13-2.17 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​selected from 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 variations (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0093] 2.19. Any form of the salt 2.13-2.18, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0094] 2.20. Any form of salt 2.13-2.19 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 2.18 and 2.19.

[0095] 2.21. Any of the above forms of Salt 2, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times higher, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0096] 2.22. Any of the above forms of Salt 2, which exhibits any combination of the features described in 2.1-2.21.

[0097] In a third embodiment, the present disclosure provides lumiperone in the form of a 4-propylbenzenesulfonic acid addition salt (Salt 3). In a further embodiment of Salt 3, the present disclosure provides:

[0098] 3.1. Salt 3 in solid form.

[0099] 3.2. Salt 3 or 3.1 in crystalline form, such as dried crystalline form.

[0100] 3.3. Salt 3, 3.1 or 3.2, wherein the salt has about a 1:1 molar ratio of lumiperone and 4-propylbenzenesulfonic acid (ie, mono-4-propylbenzenesulfonate).

[0101] 3.4. Salt 3, 3.1 or 3.2, wherein the salt has a molar ratio of lumiperone to 4-propylbenzenesulfonic acid (ie, bis-4-propylbenzenesulfonate) of about 1:2.

[0102] 3.5. Any of the above forms of Salt 3, which is a solvate, such as an ethyl acetate solvate.

[0103] 3.6. Any of the above forms of Salt 3 which is not a solvate.

[0104] 3.7. Any of the above forms of Salt 3, which is a hydrate.

[0105] 3.8. Any of the above forms of Salt 3, which is not a hydrate.

[0106] 3.9. Any of the above forms of Salt 3, which is formed by combining lumepirone free base and 4-propylbenzenesulfonic acid in a 1:0.5-1:3 molar ratio, such as a 1:0.75-1:1.5 molar ratio, or a 1:0.75-1.25 molar ratio, or a 1:1.5-1:2.5 molar ratio, or a 1:1.75-1:2.25 molar ratio, or a 1:1.75-1:3 molar ratio, or a 1:1-1:2 molar ratio, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5 molar ratio.

[0107] 3.10. Any of the above forms of Salt 3, which is a uniform crystalline form, containing no or substantially no other forms, for example, containing no or substantially no, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0108] 3.11. Any of the above forms of Salt 3, when crystallized from a mixture of 4-propylbenzenesulfonic acid and lumepirone free base, for example in an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate, optionally, wherein the molar ratio of lumepirone free base to 4-propylbenzenesulfonic acid is about 1:2.

[0109] 3.12. Salt 3.11, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane.

[0110] 3.13. Any of the above forms of Salt 3, wherein the salt is formed from a 1:2 molar ratio of lumiperone free base and 4-propylbenzenesulfonic acid in ethyl acetate solvent.

[0111] 3.14. Salt 3.13, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-propylbenzenesulfonic acid of about 1:2.

[0112] 3.15. Salt 3.13 or 3.14 wherein DSC analysis shows an endothermic event (eg, melting) at about 159°C.

[0113] 3.16. Any form of the salts 3.13-3.15, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-θ) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0114] XRPD of 4-propylbenzenesulfonate crystals (Cu anode, Ni filter)

[0115]

[0116]

[0117] 3.17. Any of the salts 3.13-3.16, which has a corresponding Figure 3 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 3 X-ray powder diffraction pattern of .

[0118] 3.18. Any form of salt 3.13-3.17, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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. angular (2-θ) values ​​of 44, 20.75, 21.11, 21.45, 21.95, 22.28, 22.86, 23.65, 24.08, 25.61, 26.26, 26.82, 28.07 and 31.38, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0119] 3.19. Any form of salt 3.13-3.18, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from 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 potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0120] 3.20. Any form of salt 3.13-3.19, in a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 3.18 and 3.19.

[0121] 3.21. Any of the above forms of Salt 3, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times higher, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0122] 3.22. Any of the above forms of Salt 3, which exhibits any combination of the features described in 3.1-3.21.

[0123] In a fourth embodiment, the present disclosure provides lumiperone in the form of a 4-ethylbenzenesulfonic acid addition salt (Salt 4). In a further embodiment of Salt 4, the present disclosure provides:

[0124] 4.1. Salt 4 in solid form.

[0125] 4.2. Salt 4 or 4.1 in crystalline form, such as dried crystalline form.

[0126] 4.3. Salt 4, 4.1 or 4.2, wherein the salt has a 1:1 molar ratio of lumiperone and 4-ethylbenzenesulfonic acid (ie, mono-4-ethylbenzenesulfonate).

[0127] 4.4. Salt 4, 4.1 or 4.2, wherein the salt has a 1:2 molar ratio of lumiperone and 4-ethylbenzenesulfonic acid (ie, bis-4-ethylbenzenesulfonate).

[0128] 4.5. Any of the above forms of Salt 4, which is a solvate, such as an ethyl acetate solvate or a toluene solvate.

[0129] 4.6. Any of the above forms of Salt 4 which is not a solvate.

[0130] 4.7. Any of the above forms of Salt 4, which is a hydrate.

[0131] 4.8. Any of the above forms of Salt 4, which is not a hydrate.

[0132] 4.9. Any of the above forms of Salt 4, formed by combining lumepirone free base and 4-ethylbenzenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5.

[0133] 4.10. Any of the above forms of Salt 4, which is a uniform crystalline form, free of or substantially free of other forms, for example free of or substantially free of, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0134] 4.11. Any of the above forms of Salt 1, when crystallized from a mixture of 4-ethylbenzenesulfonic acid and lumepirone free base, for example, in an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate or toluene, optionally, wherein the molar ratio of lumepirone free base to 4-ethylbenzenesulfonic acid is about 1:1 or about 1:2.

[0135] 4.12. Salt 4.11, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane, for example, wherein the organic solvent is toluene and the antisolvent is heptane.

[0136] 4.13. Salt 4 or any of 4.1-4.12, wherein the salt is formed from a 1:2 molar ratio of lumiperone free base and 4-ethylbenzenesulfonic acid in ethyl acetate solvent.

[0137] 4.14. Salt 4.13, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-ethylbenzenesulfonic acid of about 1:2.

[0138] 4.15. Salt 4.13 or 4.14 wherein DSC analysis shows one endothermic event (eg, melting) at about 147°C or one endothermic event (eg, melting) at about 156°C or one endothermic event (eg, melting) at about 138°C.

[0139] 4.16. Any form of salt 4.13-4.15, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angular (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0140] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 1 (Cu anode, Ni filter)

[0141] # horn d value Relative Strength 1 3.511 25.14320 100.00％ 2 3.684 23.96635 55.30％ 3 4.982 17.72257 14.80％ 4 6.917 12.76937 5.60％ 5 7.321 12.06545 5.30％ 6 10.354 8.53641 2.60％ 7 10.383 8.51268 2.80％ 8 12.488 7.08228 2.60％ 9 13.689 6.46357 4.10％ 10 14.269 6.20219 9.00％ 11 15.587 5.68057 40.60％ 12 17.499 5.06386 9.70％ 13 17.682 5.01186 8.80％ 14 18.581 4.77134 13.70％ 15 18.852 4.70347 13.50％ 16 20.127 4.40823 27.20％ 17 20.609 4.30628 13.50％ 18 20.833 4.26051 12.20％ 19 21.246 4.17848 7.60％ 20 22.016 4.03418 5.30％ 21 27.486 3.24248 4.50％

[0142] 4.17. Any of the salts 4.13-4.16, which has a Figure 4A The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 4AX-ray powder diffraction pattern of .

[0143] 4.18. Any form of salt 4.13-4.17, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from 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 variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0144] 4.19. Any form of salt 4.13-4.18, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0145] 4.20. Any form of salt 4.13-4.19 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 4.18 and 4.19.

[0146] 4.21. Salt 4 or any of 4.1-4.12, wherein the salt is formed from a 1:2 molar ratio of lumiperone free base and 4-ethylbenzenesulfonic acid in toluene solvent.

[0147] 4.22. Salt 4.21 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-ethylbenzenesulfonic acid of about 1:2.

[0148] 4.23. Salt 4.21 or 4.22 wherein DSC analysis shows one endothermic event (eg, melting) at about 156°C or one endothermic event (eg, melting) at about 147°C or one endothermic event (eg, melting) at about 138°C.

[0149] 4.24. Any form of salt 4.21-4.23, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angular (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0150] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 2 (Cu anode, Ni filter)

[0151]

[0152]

[0153] 4.25. Any of the salts 4.21-4.24, which has a Figure 4B The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 4B X-ray powder diffraction pattern of .

[0154] 4.26. Any form of salt 4.21-4.25, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 2 angular (2-θ) values ​​of 0.22, 20.58, 20.78, 21.08, 21.41, 22.02, 22.96, 24.09, 24.74, 25.28, 26.24 and 27.70, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0155] 4.27. Any form of salt 4.21-4.26, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from 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, 4.7 2, 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., any one or more peaks may shift by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0156] 4.28. Any form of salt 4.21-4.27, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 4.26 and 4.27.

[0157] 4.29. Salt 4 or any of 4.1-4.12, wherein the salt is formed from a 1:1 molar ratio of lumiperone free base and 4-ethylbenzenesulfonic acid in a toluene solution and a heptane antisolvent.

[0158] 4.30. Salt 4.29 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 4-ethylbenzenesulfonic acid of about 1:1.

[0159] 4.31. Salt 4.29 or 4.30 wherein DSC analysis shows an endothermic event (eg, melting) at about 138°C, or an endothermic event (eg, melting) at about 156°C, or an endothermic event (eg, melting) at about 147°C.

[0160] 4.32. Any form of salt 4.29-4.31, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angular (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0161] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 3 (Cu anode, Ni filter)

[0162] # horn d value Relative Strength 1 2.789 31.65519 30.70％ 2 5.569 15.85574 100.00％ 3 11.382 7.76773 16.90％ 4 12.090 7.31483 19.80％ 5 13.121 6.74217 21.00％ 6 15.965 5.54681 28.90％ 7 16.585 5.34081 57.90％ 8 17.487 5.06740 24.40％ 9 17.996 4.92527 27.00％ 10 18.865 4.70026 26.20％ 11 19.406 4.57029 21.80％ 12 20.542 4.32010 11.20％ 13 21.306 4.16702 20.10％ 14 22.536 3.94215 63.20％ 15 22.796 3.89784 40.40％ 16 23.272 3.81916 36.00％ 17 24.020 3.70193 50.10％ 18 25.453 3.49666 15.10％ 19 31.614 2.82786 5.90％ 20 34.006 2.63421 3.50％

[0163] 4.33. Any of the salts 4.29-4.32, which has a Figure 4C The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 4C X-ray powder diffraction pattern of .

[0164] 4.34. Any form of salt 4.29-4.33 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 degrees angle), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0165] 4.35. Any form of salt 4.29-4.34 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0166] 4.36. Any form of salt 4.29-4.35 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 4.34 and 4.35.

[0167] 4.37. Any of the above forms of Salt 4, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times higher, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0168] 4.38. Any of the above forms of Salt 4, which exhibits any combination of the characteristics described in 4.1-4.37.

[0169] In a fifth embodiment, the present disclosure provides lumiperone in the form of a 2-naphthalenesulfonic acid addition salt, wherein the salt is a solvate (Salt 5). In another embodiment of Salt 5, the present disclosure provides:

[0170] 5.1. Salt 5 in solid form.

[0171] 5.2. Salt 5 or 5.1 in crystalline form, such as dried crystalline form.

[0172] 5.3. Salt 5, 5.1 or 5.2, wherein the salt has a 1:1 molar ratio of lumiperone and 2-naphthalenesulfonic acid (ie, mono-naphthalenesulfonate).

[0173] 5.4. Salt 5, 5.1 or 5.2, wherein the salt has a 1:2 molar ratio of lumiperone to 2-naphthalenesulfonic acid (ie, bis-naphthalenesulfonate).

[0174] 5.5. Any of the above forms of Salt 5, wherein the salt is an ethyl acetate solvate.

[0175] 5.6. Any of the above forms of Salt 5, which is a hydrate.

[0176] 5.7. Any of the above forms of Salt 5, which is not a hydrate.

[0177] 5.8. Any of the above forms of Salt 5, formed by combining lumepirone free base and 2-naphthalenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5.

[0178] 5.9. Any of the above forms of Salt 5, which is a uniform crystalline form, free of or substantially free of other forms, for example free of or substantially free of, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0179] 5.10. Any of the above forms of Salt 5, when crystallized from a mixture of 2-naphthalenesulfonic acid and lumepirone free base in, for example, an organic solvent, is in a crystalline form, the organic solvent comprising, for example, 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; for example, ethyl acetate, optionally wherein the molar ratio of lumepirone free base to 2-naphthalenesulfonic acid is about 1:2.

[0180] 5.11. Salt 5.10, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane.

[0181] 5.12. Any of the above forms of Salt 5, wherein the salt is formed from a 1:2 molar ratio of lumiperone free base and 2-naphthalenesulfonic acid in ethyl acetate solvent.

[0182] 5.13. Salt 5.12, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to 2-naphthalenesulfonic acid of about 1:2.

[0183] 5.14. Salt 5.12 or 5.13 wherein DSC analysis shows an endothermic event at about 108°C (eg, desolvation) and / or an endothermic event at about 162°C (eg, melting).

[0184] 5.15. Any form of salt 5.12-5.14, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angular (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0185] XRPD of 2-naphthalenesulfonate crystals (Cu anode, Ni filter)

[0186] # horn d value Relative Strength 1 2.401 36.77034 32.50％ 2 7.045 12.53758 16.40％ 3 14.063 6.29268 10.20％ 4 14.906 5.93853 27.30％ 5 15.477 5.72064 26.40％ 6 17.204 5.15024 25.70％ 7 17.493 5.06578 21.00％ 8 19.018 4.66279 26.30％ 9 20.323 4.36625 40.90％ 10 20.418 4.34608 39.50％ 11 20.780 4.27126 84.70％ 12 20.842 4.25855 100.00％ 13 21.247 4.17835 28.40％ 14 23.846 3.72847 21.10％ 15 26.939 3.30704 9.30％ 16 27.208 3.27490 28.90％

[0187] 5.16. Any of the salts 5.12-5.15, which has a corresponding Figure 5 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 5 X-ray powder diffraction pattern of .

[0188] 5.17. Any form of salt 5.12-5.16, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 degrees angle), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0189] 5.18. Any form of salt 5.12-5.17, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0190] 5.19. Any form of salt 5.12-5.18, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 5.17 and 5.18.

[0191] 5.20. Any of the above forms of Salt 5, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0192] 5.21. Any of the above forms of Salt 5, which exhibits any combination of the features described in 5.1-5.20.

[0193] In a sixth embodiment, the present disclosure provides lumepirone in the form of a solid crystalline benzenesulfonic acid addition salt (Salt 6), wherein the salt is crystalline and characterized by a DSC thermogram with no endothermic events at 172-176° C. In additional embodiments of Salt 6, the present disclosure provides:

[0194] 6.1. Salt 6, wherein the salt has a 1:1 molar ratio of lumiperone and benzenesulfonic acid (ie, mono-benzenesulfonate).

[0195] 6.2. Salt 6, wherein the salt has a 1:2 molar ratio of lumiperone and benzenesulfonic acid (ie, bis-benzenesulfonate).

[0196] 6.3. Any of the above forms of Salt 6, which is a solvate, such as an ethyl acetate solvate or a toluene solvate.

[0197] 6.4. Any of the above forms of Salt 6 which is not a solvate.

[0198] 6.5. Any of the above forms of Salt 6, which is a hydrate.

[0199] 6.6. Any of the above forms of Salt 6, which is not a hydrate.

[0200] 6.7. Any of the above forms of Salt 6, formed by combining lumepirone free base and benzenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5.

[0201] 6.8. Any of the above forms of Salt 6, wherein the salt is a uniform crystalline form, containing no or substantially no other forms (e.g., alternative crystalline forms or amorphous forms), for example, containing no or substantially no, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of other forms (e.g., alternative crystalline forms or amorphous forms).

[0202] 6.9. Any of the above forms of Salt 6, when crystallized from a mixture of benzenesulfonic acid and lumepirone free base in, for example, an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate or toluene, optionally wherein the molar ratio of benzenesulfonic acid to lumepirone free base is about 1:1 or about 1:2.

[0203] 6.10. Salt 6.9, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane.

[0204] 6.11. Any of Salts 6 or 6.1-6.10, wherein the salt is formed from 1:1 or 1:2 molar ratios of lumiperone free base and benzenesulfonic acid in ethyl acetate solvent.

[0205] 6.12. Salt 6.11, wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to benzenesulfonic acid of about 1:1.

[0206] 6.13. Salt 6.11 or 6.12 wherein DSC analysis shows an endothermic event at about 96°C (eg, desolvation) and / or an endothermic event at about 110°C (eg, melting).

[0207] 6.14. Any form of salt 6.11-6.13, which is a crystalline form having an X-ray powder diffraction pattern with d-spacing and / or angle (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0208] XRPD of benzenesulfonate crystalline polymorph 1 (Cu anode, Ni filter)

[0209]

[0210]

[0211] 6.15. Any of the salts 6.11-6.14, which has a corresponding Fig. 6A The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Fig. 6A X-ray powder diffraction pattern of .

[0212] 6.16. Any form of salt 6.11-6.15, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 1 9.36, 19.93, 20.20, 20.53, 21.21, 22.60, 22.98, 23.30, 23.72, 24.09, 24.44, 25.52, 26.20, 26.33, 27.25, 27.96 and 30.13, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0213] 6.17. Any form of salt 6.11-6.16, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 4.7 5, 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, 3.38, 3.27, 3.19 and 2.96 d-spacing values, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0214] 6.18. Any form of salt 6.11-6.17, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 6.16 and 6.17.

[0215] 6.19. Any of Salts 6 or 6.1-6.10, wherein the salt is formed from 1:1 or 1:2 molar ratios of lumiperone free base and benzenesulfonic acid in toluene solvent.

[0216] 6.20. Salt 6.19 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to benzenesulfonic acid of about 1:1.

[0217] 6.21. Salt 6.19 or 6.20 wherein DSC analysis shows an endothermic event (eg, melting) at about 131°C.

[0218] 6.22. Any form of salt 6.19-6.21, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising those peaks having 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, 4, 5, 7, 10, 11, 12, 13, 14, 17, 19, 21, 25, 25 and / or 28:

[0219] XRPD of benzenesulfonate crystalline polymorph 2 (Cu anode, Ni filter)

[0220]

[0221]

[0222] 6.23. A salt of any of 6.19-6.22 having a Figure 6B The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 6B X-ray powder diffraction pattern of .

[0223] 6.24. Any form of salt 6.19-6.23, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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. angular (2-θ) values ​​of 29, 18.65, 19.37, 19.93, 20.52, 21.22, 21.85, 22.60, 22.98, 23.32, 23.75, 24.10, 25.12, 26.17, 27.97 and 30.13, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0224] 6.25. Any form of salt 6.19-6.24, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 3.19 and 2.96, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0225] 6.26. Any form of salt 6.19-6.25 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 6.24 and 6.25.

[0226] 6.27. Salt 6 or any form of 6.1-6.10, wherein the salt is formed from a 1:1 molar ratio of lumiperone free base and benzenesulfonic acid in ethyl acetate solvent.

[0227] 6.28. Salt 6.27 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to benzenesulfonic acid of about 1:1.

[0228] 6.29. Salt 6.27 or 6.28 wherein DSC analysis shows an endothermic event (eg, melting) at about 110°C and / or an endothermic event (eg, melting) at about 126°C.

[0229] 6.30. Any form of salt 6.27-6.29, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0230] XRPD of benzenesulfonate crystalline polymorph 3 (Cu anode, Ni filter)

[0231] # horn d value Relative Strength 1 5.240 16.85241 89.90％ 2 5.756 15.34242 100.00％ 3 14.387 6.15169 73.40％ 4 16.165 5.47865 47.20％ 5 16.713 5.30036 45.40％ 6 18.653 4.75319 21.10％ 7 19.249 4.60734 31.00％ 8 19.441 4.56222 62.80％ 9 20.697 4.28806 50.40％ 10 20.839 4.25914 50.10％ 11 21.084 4.21030 28.80％ 12 22.806 3.89608 48.00％ 13 22.907 3.87919 46.20％ 14 23.212 3.82890 71.20％ 15 23.874 3.72418 30.60％ 16 24.695 3.60221 99.90％ 17 25.066 3.54981 30.10％ 18 25.127 3.54131 24.10％ 19 26.712 3.33459 6.90％ 20 28.440 3.13583 14.30％ 21 33.755 2.65326 6.00％ 22 37.907 2.37161 11.30％

[0232] 6.31. Any of the salts 6.27-6.30, which has a corresponding Figure 6C The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 6C X-ray powder diffraction pattern of .

[0233] 6.32. Any form of salt 6.27-6.31, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from 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., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0234] 6.33. Any form of the salt 6.27-6.32, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0235] 6.34. Any form of salt 6.27-6.33, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 6.32 and 6.33.

[0236] 6.35. Any of the above forms of Salt 6, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0237] 6.36. Any of the above forms of Salt 6, which exhibits any combination of the features described in 6.1-6.35.

[0238] In a seventh embodiment, the present disclosure provides lumiperone 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 another embodiment of Salt 7, the present disclosure provides:

[0239] 7.1. Salt 7 in solid form.

[0240] 7.2. Salt 7 or 7.1 in crystalline form, eg, dried crystalline form.

[0241] 7.3. Salt 7, 7.1 or 7.2, wherein the salt has a 1:1 molar ratio of lumiperone to the alkyl sulfonic acid.

[0242] 7.4. Salt 7, 7.1 or 7.2, wherein the salt has a 1:2 molar ratio of lumiperone to the alkyl sulfonic acid.

[0243] 7.5. Any of the above forms of Salt 4, which is a solvate, such as an ethyl acetate solvate or a toluene solvate.

[0244] 7.6. Any of the above forms of Salt 7 that is not a solvate.

[0245] 7.7. Any of the above forms of Salt 7, which is a hydrate.

[0246] 7.8. Any of the above forms of Salt 7, which is not a hydrate.

[0247] 7.9. Any of the above forms of Salt 7, formed by combining lumepirone free base and an alkyl sulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5.

[0248] 7.10. Any of the above forms of Salt 7, which is a uniform crystalline form, free of or substantially free of other forms, for example free of or substantially free of, for example, less than 10 wt.%, preferably less than about 5 wt.%, more preferably less than about 2 wt.%, still preferably less than about 1 wt.%, still preferably less than about 0.1%, and most preferably less than about 0.01 wt.% of an amorphous form.

[0249] 7.11. Any of the above forms of Salt 7, when crystallized from a mixture of an alkyl sulfonic acid and lumepirone free base, for example in an organic solvent, is in a crystalline form, wherein the organic solvent includes, for example, 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; for example, ethyl acetate or toluene, optionally wherein the molar ratio of lumepirone free base to the alkyl sulfonic acid is about 1:1 or about 1:2.

[0250] 7.12. Salt 7.11, wherein upon addition of an antisolvent, the salt crystallizes from the solvent, for example, when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the antisolvent is heptane or hexane, for example, wherein the organic solvent is toluene and the antisolvent is heptane.

[0251] 7.13. Salt 7 or any one 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 any branched chain 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.).

[0252] 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 pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0253] 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 pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0254] 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 a 1:2 molar ratio of lumiperone free base and pentane-1-sulfonic acid in ethyl acetate solvent.

[0255] 7.17. Salt 7.16 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to pentane-1-sulfonic acid of about 1:2.

[0256] 7.18. Salt 7.16 or 7.17 wherein DSC analysis shows an endothermic event (eg, melting) at about 141°C.

[0257] 7.19. Any form of salt 7.16-7.18, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angle (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0258] XRPD of pentane-1-sulfonate crystals (Cu anode, Ni filter)

[0259] # horn d value Relative Strength 1 2.086 42.32365 2.40％ 2 3.777 23.37371 100.00％ 3 7.487 11.79790 19.80％ 4 11.225 7.87635 5.70％ 5 14.766 5.99468 32.90％ 6 16.224 5.45895 20.60％ 7 16.561 5.34869 28.00％ 8 17.339 5.11045 17.80％ 9 17.757 4.99095 29.40％ 10 18.639 4.75678 14.70％ 11 19.663 4.51123 17.30％ 12 20.014 4.43290 54.80％ 13 20.344 4.36175 28.70％ 14 20.782 4.27088 16.80％ 15 21.353 4.15784 16.10％ 16 21.738 4.08517 20.60％ 17 22.567 3.93679 15.00％ 18 25.287 3.51922 17.40％ 19 38.261 2.35050 3.90％

[0260] 7.20. Any of the salts 7.16-7.19, which has a corresponding Figure 7 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 7 X-ray powder diffraction pattern of .

[0261] 7.21. Any form of salt 7.16-7.20 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​selected from 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 variations (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0262] 7.22. Any form of the salt 7.16-7.21 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having d-spacing values ​​selected from 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., any one or more peaks shifted by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer with a copper anode and a nickel filter.

[0263] 7.23. Any form of salt 7.16-7.22, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 7.19 and 7.20.

[0264] 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 a 1:2 molar ratio of lumiperone free base and heptane-1-sulfonic acid in ethyl acetate solvent.

[0265] 7.25. Salt 7.24 wherein proton-NMR analysis of the salt shows a molar ratio of lumiperone to heptane-1-sulfonic acid of about 1:2.

[0266] 7.26. Salt 7.24 or 7.25 wherein DSC analysis shows an endothermic event (eg, melting) at about 151°C.

[0267] 7.27. Any form of salt 7.24-7.26, which is a crystalline form having an X-ray powder diffraction pattern having d-spacing and / or angular (2-theta) values ​​corresponding to the following table, e.g., at least 5, or at least 6, or at least 7, or at least 8 of said values, e.g., taking into account potential variations due to sample purity and instrumental variations, such as 2-theta shifts due to variations in X-ray wavelength (e.g., any one or more peaks shifted by up to + / - 0.2 degrees angle or up to + / - 0.2 d-spacing), e.g., wherein the X-ray powder diffraction pattern is produced using an X-ray diffractometer having a copper anode and a nickel filter, e.g., comprising those peaks having 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:

[0268] XRPD of heptane-2-sulfonate crystals (Cu anode, Ni filter)

[0269]

[0270]

[0271] 7.28. Any of the salts 7.24-7.27, which has a Figure 8 The crystalline form of the X-ray powder diffraction pattern of the present invention may be determined by taking into account potential variations due to sample purity and instrumental variations, such as 2θ shifts due to changes in X-ray wavelength (e.g., any one or more peaks may shift by up to + / - 0.2 degrees angularly), such as corresponding to an X-ray diffractometer having a copper anode and a nickel filter. Figure 8 X-ray powder diffraction pattern of .

[0272] 7.29. Any form of salt 7.24-7.28, which is a specific form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from about 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, 1 9.90, 20.18, 20.50, 21.60, 22.40, 23.22, 24.18, 24.84, 26.33, 27.56, 30.59, 31.76, 32.89 and 33.60, taking into account potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 degree angle), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0273] 7.30. Any form of salt 7.24-7.29, which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having a peak selected from 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, 4.6 1, 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 potential variations due to sample purity and instrumental variations (e.g., any one or more peaks may shift by up to + / - 0.2 d-spacing), wherein the X-ray powder diffraction pattern was generated using an X-ray diffractometer with a copper anode and a nickel filter.

[0274] 7.31. Any form of salt 7.24-7.30 which is a crystalline form having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8 peaks having angle (2-θ) values ​​and / or d-spacing values ​​as provided in 7.27 and 7.28.

[0275] 7.32. Any of the above forms of Salt 7, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0276] 7.33. Any of the above forms of Salt 7, which exhibits any combination of the characteristics described in 7.1-7.32.

[0277] In an eighth embodiment, the present disclosure provides lumepirone in the form of an acid addition salt with benzenesulfonic acid substituted with 1, 2 or 3 groups R, wherein each R is independently C 1-12 Alkyl (Salt 8), provided that the acid is not p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid, 4-propylbenzenesulfonic acid, 4-tert-butylbenzenesulfonic acid or 4-octylbenzenesulfonic acid. In another embodiment of Salt 8, the present disclosure provides:

[0278] 8.1. Salt 8, wherein each R group is independently selected from a linear or branched 1-carbon, 2-carbon, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, 8-carbon, 9-carbon, 10-carbon, 11-carbon or 12-carbon saturated hydrocarbon group.

[0279] 8.2. Salts 8.1 in which the R groups are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl (t-pentyl), neopentyl, tert-amyl (t-amyl), n-hexyl, n-heptyl, n-octyl and n-decyl.

[0280] 8.3. Salt 8, wherein the substituted benzenesulfonic acid is selected from m-toluenesulfonic acid, o-toluenesulfonic acid or dimethylbenzenesulfonic acid (eg 2,4-dimethylbenzenesulfonic acid, 2,5-dimethylbenzenesulfonic acid, 2,6-dimethylbenzoic acid) or trimethylbenzenesulfonic acid.

[0281] 8.4. Salt 8, wherein the acid is a meta-substituted C 2-12 Alkylbenzenesulfonic acid, ortho-substituted C 2-12 Alkylbenzenesulfonic acid, di-(C 2-12Alkyl)benzenesulfonic acid or tri-C 2-12 Alkylbenzene sulfonic acid, optionally, wherein the C 2-12 Each of the alkyl groups 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 isomers thereof.

[0282] 8.5. Any of the above forms of Salt 8, which is in solid form.

[0283] 8.6. Any of the above forms of Salt 8, which is in crystalline form, such as a dried crystalline form.

[0284] 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 pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0285] 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, for example at pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0286] 8.9. Any of Salts 8 or 8.1-8.8, wherein the salt has a 1:1 molar ratio of lumiperone and the substituted benzenesulfonic acid.

[0287] 8.10. Any of Salts 8 or 8.1-8.8, wherein the salt has a 1:2 molar ratio of lumiperone to substituted benzenesulfonic acid.

[0288] 8.11. Any of the above forms of Salt 8 which is a solvate, for example an ethyl acetate or toluene solvate.

[0289] 8.12. Any of the above forms of Salt 8 that is not a solvate.

[0290] 8.13. Any of the above forms of Salt 8, which is a hydrate.

[0291] 8.14. Any of the above forms of Salt 8 that is not a hydrate.

[0292] 8.15. Any of the above forms of Salt 8, formed by combining lumepirone free base and a substituted benzenesulfonic acid in a molar ratio of 1:0.5-1:3, such as a molar ratio of 1:0.75-1:1.5, or a molar ratio of 1:0.75-1.25, or a molar ratio of 1:1.5-1:2.5, or a molar ratio of 1:1.75-1:2.25, or a molar ratio of 1:1.75-1:3, or a molar ratio of 1:1-1:2, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.5.

[0293] 8.16. Any of the above forms of Salt 8, when crystallized from a mixture of a substituted benzenesulfonic acid and lumepirone free base, for example in an organic solvent, is in a crystalline form, the organic solvent comprising, for example, 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; for example, ethyl acetate or toluene, optionally wherein the molar ratio of lumepirone free base to the substituted benzenesulfonic acid is about 1:1 or about 1:2.

[0294] 8.17. Salt 8.16, wherein the salt crystallizes from the solvent upon addition of an antisolvent, such as when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile, or a solvent / water mixture and the antisolvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK, or 1-butanol and the antisolvent is heptane or hexane.

[0295] 8.18. Any of the above forms of Salt 8, wherein lumiperone is deuterated, for example, wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher than the natural isotope ratio or the isotope ratio at other positions in the molecule, for example, at least 2 times, for example, at least 10 times higher; for example, any of the above forms of Salt 1, wherein either or both of the -CH2- moieties of the piperazine ring are deuterated, for example, -CHD- or -CD2-, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and / or wherein the methyl group on the piperazine ring is deuterated, for example, as CD3-, for example, at a level significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule; for example, wherein the deuterated lumiperone is such as US Any deuterated lumepirone described in US 2019 / 0231780 or US 2021 / 0008065, the contents of each of which are incorporated herein by reference in their entirety.

[0296] In another embodiment, the present disclosure provides a method for preparing any salt disclosed herein (Method 1), comprising the steps of:

[0297] (a) reacting lumepirone free base with a corresponding acid and 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), for example, wherein the molar ratio of acid to lumepirone is 1:1 to 1:2 or about 1:1 or about 1:2; optionally at a temperature of 0°C to 100°C; and

[0298] (b) optionally subjecting the resulting mixture to a thermal cycling protocol (e.g., raising the temperature to above 50° C., then cooling to 0° C., and optionally repeating the heating and cooling in a cycle) or cooling the mixture from its reaction temperature to 5° C. or below; and

[0299] (c) optionally diluting the resulting mixture with an anti-solvent, for example when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the anti-solvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and the anti-solvent is heptane or hexane; optionally at a temperature of 0°C to 100°C; and

[0300] (d) optionally performing a second thermal cycling protocol (e.g., raising the temperature to above 50°C, then cooling to 0°C, and optionally repeating the heating and cooling in a cycle) or cooling the mixture from its reaction temperature to 5°C or below; and

[0301] (e) recovering the salt thus formed, e.g., recovering any of Salt 1, etc., Salt 2, etc., Salt 3, etc., Salt 4, etc., Salt 5, etc., Salt 6, etc., Salt 7, etc., Salt 8, etc., or any other salt disclosed herein.

[0302] In another embodiment of method 1, the reaction step (a) comprises dissolving or suspending lumepirone free base in an organic solvent, such as toluene or ethyl acetate, and then adding an acid, or dissolving or suspending an acid in an organic solvent and then adding lumepirone free base, or combining dry acid and dry lumepirone 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.

[0303] In some embodiments of method 1, the crystalline salt product precipitates at the reaction temperature (e.g., 0°C-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) when combining lumepirone free base, acid, and organic solvent. In some embodiments of method 1, the crystalline salt product precipitates when the mixture of lumepirone 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).

[0304] In some embodiments of method 1, the crystalline salt product is precipitated when the mixture of lumepirone free base, acid and organic solvent is subjected to a thermal cycling protocol, such as raising the temperature to above 50°C, then cooling to 0°C and optionally repeating the heating and cooling in a cycle). For example, the reaction can be heated to 50°C or 60°C, maintained for a period of time (e.g., 15-300 minutes, such as 60 minutes), then cooled to 0°C or 5°C, maintained for a period of time (e.g., 15-300 minutes, such as 60 minutes), and then the heating / cooling can be repeated a second, third, fourth or fifth time. Optionally, each time the cycle is repeated, the high temperature is reduced by 10°C. For example: 20°C-50°C-0°C-40°C-0°C-30°C-0°C-20°C-0°C-10°C-0°C; or 20°C-50°C-0°C-40°C-0°C-30°C-0°C-20°C-0°C.

[0305] In some embodiments of method 1, method step (a) is performed as a batch process, and in other embodiments, method step (a) is performed as a continuous (flow) process.

[0306] In another embodiment, the present disclosure provides a method for purifying lumepirone in free or salt form, which method comprises reacting a crude solution of lumepirone free base with an acid as described herein to form any of the salts described herein, and recovering the salt thus formed, for example according to method 1, and optionally converting the salt thus formed back to lumepirone free base or any other salt form of lumepirone (e.g., lumepirone monotosylate).

[0307] In another embodiment, the present disclosure provides a pharmaceutical composition (composition 1), which comprises any salt disclosed herein, such as salt 1, etc., salt 2, etc., salt 3, etc., salt 4, etc., salt 5, etc., salt 6, etc., salt 7, etc., any one of salt 8, etc. as an active ingredient, combined or combined with a pharmaceutically acceptable diluent or carrier. In some embodiments, the pharmaceutical composition is formulated for oral delivery, such as as an enteric-coated tablet or capsule, optionally formulated for sustained release or delayed release. In some embodiments, the pharmaceutical composition is formulated for transmucosal delivery, such as an oral fast-dissolving tablet, a wafer, or a gel, such as for sublingual or buccal administration. In some embodiments, the pharmaceutical composition is formulated for transdermal delivery, such as a patch, an ointment, or a gel, such as for administration through the skin into the subepidermal tissue. In some embodiments, the pharmaceutical composition is formulated for injectable delivery, such as as subcutaneous, intravenous, intraperitoneal, intramuscular, or intrathecal injection, such as for rapid release. In some embodiments, the pharmaceutical composition is formulated for sustained or delayed injectable delivery, for example, as a subcutaneous or intramuscular long-acting injection (LAI).

[0308] Suitable carriers for these pharmaceutical compositions are well known in the art and include those disclosed in, for example, 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.

[0309] In some embodiments, the pharmaceutical composition of the present disclosure comprises a lumineperone salt disclosed as a crystalline solid. In some embodiments, the pharmaceutical composition may comprise a lumineperone salt in the form of an amorphous solid dispersion. Amorphous solid dispersions of lumineperone tosylate are disclosed in WO2020 / 123952 and US2019 / 0192511, the contents of each of which are incorporated herein by reference in their entirety. In an amorphous solid dispersion, the amorphous solid lumineperone salt of the present disclosure is stable against, for example, crystallization, by dispersing it in an excipient that stabilizes the amorphous solid, preventing or inhibiting its conversion into crystals. Suitable stabilizing excipients 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, polyvinyl pyrrolidone, polyvinyl pyrrolidone / vinyl acetate copolymer, and polyethylene glycol / polyvinyl acetate / polyvinyl caprolactam copolymer. In some embodiments, the salt can be stabilized by dispersing it in a single stabilizing excipient, and in other embodiments, the salt can be stabilized by dispersing it in a combination of two or more stabilizing excipients. In some embodiments, the one or more excipients may be combined with the lumepirone salt in a weight ratio of lumepirone salt to excipient of 25:75-75:25, e.g., 26:74-74:26 or 30:70-70:30 or 35:65-65:35 or 40:60-60:40 or 42:58-58:42 or 44:56-56:44 or 45:55-55:45 or 47:53-53:47 or 48:52-52:48 or 49:51-51:49 or about 50:50. In other embodiments, the one or more excipients may be combined with the lumepirone salt in a weight ratio of lumepirone salt to excipient of 5:95-50:50, e.g., 5:95-49:51 or 5:95-45:55 or 10:90-40:60 or 15:85-35:65 or 20:80-30:70 or 22:78-28:82 or 23:77-27:83 or 24:76-26:74 or about 25:75. In other embodiments, the one or more excipients may be combined with the lumepirone salt in a weight ratio of lumepirone salt to excipient of 50:50-95:5, such as 51:49-95:5 or 55:45-95:5 or 60:40-90:10 or 65:45-85:15 or 70:30-80:20 or about 75:25.

[0310] In a particular embodiment, the present disclosure provides a long-acting injectable pharmaceutical composition (Composition 2) comprising an acid addition salt of lumepirone having a water solubility of less than 20 mg / mL. In a further embodiment of Composition 2, the present disclosure provides:

[0311] 2.1. Composition 2, wherein the acid addition salt of lumepirone 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, for example at pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0312] 2.2. Composition 2, wherein the acid addition salt of lumepirone 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, for example at pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0313] 2.3. Composition 2, 2.1 or 2.2, wherein the acid addition salt of lumepirone 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 pH 5-8, or at pH 6-8, or at pH 7-8, or at pH 7-7.5.

[0314] 2.4. Composition 2 or any one of 2.1-2.3, wherein the acid addition salt of lumepirone is Salt 1 or any one of Salts 1.1-1.22.

[0315] 2.5. Composition 2 or any one of 2.1-2.3, wherein the acid addition salt of lumepirone is Salt 2 or any one of 2.1-2.22.

[0316] 2.6. Composition 2 or any one of 2.1-2.3, wherein the acid addition salt of lumepirone is Salt 3 or any one of 3.1-3.22.

[0317] 2.7. Composition 2 or any one of 2.1-2.3, wherein the acid addition salt of lumepirone is Salt 4 or any one of 4.1-4.38.

[0318] 2.8. Composition 2 or any one of 2.1-2.3 wherein the acid addition salt of lumepirone is Salt 5 or any one of 5.1-5.21.

[0319] 2.9. Composition 2 or any of 2.1-2.3 wherein the acid addition salt of lumepirone is Salt 6 or any of 6.1-6.36.

[0320] 2.10. Composition 2 or any of 2.1-2.3 wherein the acid addition salt of lumepirone is Salt 7 or any of 7.1-7.33.

[0321] 2.11. Composition 2 or any of 2.1-2.3 wherein the acid addition salt of lumepirone is Salt 8 or any of 8.1-8.18.

[0322] 2.12. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone 4-octylbenzenesulfonate, such as described in Example 2.

[0323] 2.13. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone 4-tert-butylbenzenesulfonate, such as a salt as described in Example 3.

[0324] 2.14. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone 4-propylbenzenesulfonate, eg, as described in Example 4.

[0325] 2.15. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone 4-ethylbenzenesulfonate, such as described in Example 5.

[0326] 2.16. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone 2-naphthalenesulfonate, such as a salt as described in Example 6.

[0327] 2.17. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone besylate, eg, as described in Example 7.

[0328] 2.18. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone pentane-1-sulfonate, eg, as described in Example 8.

[0329] 2.19. Composition 2 or any of 2.1-2.11 wherein the acid addition salt of lumepirone is lumepirone hex-1-sulfonate, eg, as described in Example 9.

[0330] 2.20. Composition 2 or any of 2.1-2.19 wherein the acid addition salt of lumepirone is crystalline.

[0331] 2.21. Composition 2 or any of 2.1-2.19 wherein the acid addition salt of lumepirone is amorphous, eg, wherein the composition comprises the salt as an amorphous solid dispersion.

[0332] 2.22. Composition 2 or any of 2.1-2.21 wherein the composition is formulated for intramuscular injection.

[0333] 2.23. Composition 2 or any of 2.1-2.21 wherein the composition is formulated for subcutaneous injection.

[0334] 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, and the composition is suitable for injection.

[0335] 2.25. Composition 2.24 wherein the diluent or carrier comprises water and / or a water-miscible organic solvent.

[0336] 2.26. Composition 2.24 or 2.25 wherein the diluent, carrier or excipient comprises a polymer, such as a biocompatible and biodegradable polymer, particularly a polymer that inhibits dissolution of the encapsulated or dispersed drug.

[0337] 2.27. Composition 2.26, wherein the polymer is selected from polyesters of hydroxy fatty acids (or derivatives thereof), polymers of alkyl α-cyanoacrylates (e.g., poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene-propylene carbonate), polyortho-carbonates, polyamino acids (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), hyaluronates, polylactides (e.g., poly-L-lactide, poly-L-lactic acid, poly-D,L-lactide, poly-D,L-lactic acid), polyglycolides (e.g., polyglycolide or polyglycolic acid), polylactide-co-glycolide copolymers (PLGA, e.g., having a lactide to glycolide molar ratio of 75:25-50:50 or 50:50-90:10, e.g., PLGA 50:50, PLGA 85:15 or PLGA 90:10), poly(aliphatic carboxylic acids) such as polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, copolyoxalates, polycaprolactones, poly(glycolic acid-caprolactone), polydioxanones, poly(acetals), poly(lactic acid-caprolactone), polyanhydrides, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers or polyglycolic acid-polyethylene glycol copolymers, and natural polymers including albumin, casein, and waxes such as glyceryl monostearate and glyceryl distearate.

[0338] 2.28. Composition 2.27 wherein the polymer is polylactide, polyglycolide or polylactide-co-glycolide (PLGA), optionally with carboxylic acid end groups or carboxylate end groups.

[0339] 2.29. Composition 2.28 wherein the polylactide-co-glycolide copolymer (PLGA) has a lactide to glycolide molar ratio of 75:25 to 50:50 or 50:50 to 90:10, eg, PLGA 50:50, PLGA 85:15, or PLGA 90:10.

[0340] 2.30. Composition 2.27, 2.28 or 2.29 wherein the PLGA copolymer has a weight average molecular weight of 5,000-500,000 Daltons, or 20,000-200,000 Daltons, or 24,000-38,000 Daltons, or 113,000-159,000 Daltons, such as about 113,000 Daltons or about 159,000 Daltons.

[0341] 2.31. Any of compositions 2.26-2.30, wherein the acid addition salt of lumepirone is dissolved, dispersed, suspended or encapsulated in a polymer, for example forming a polymer matrix, for example in the form of polymer microspheres (e.g., comprising 1-90 wt.% of the acid addition salt of lumepirone, for example 5-50 wt.%, 10-50 wt.%, 20-40 wt.%, 30-50 wt.%, 30-40 wt.% or 35-40 wt.% of the microparticles by weight).

[0342] 2.32. Composition 2.24 or 2.25 wherein the diluent, carrier or excipient does not contain any polymer that serves to inhibit dissolution of the encapsulated or dispersed drug, such as any of the polymers described in Embodiment 2.27.

[0343] 2.33. Composition 2 or any of 2.1-2.23 wherein the composition is free of any polymer that serves to inhibit dissolution of the encapsulated or dispersed drug, such as any of the polymers described in Embodiment 2.27.

[0344] 2.34. Composition 2 or any of 2.1-2.33, wherein the composition does not contain any non-aqueous organic solvent (e.g., wherein the composition does not contain dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane, dioxolane) and / or wherein the composition does contain any liquid oil (e.g., vegetable oil, mineral oil).

[0345] 2.35. Composition 2 or any of 2.1-2.34, wherein the composition comprises water (eg, sterile water for injection) and one or more excipients (eg, water-soluble excipients) such as thickeners, buffers, osmotic agents, surfactants, and antioxidants.

[0346] 2.36. Composition 2.35, wherein the composition comprises one or more thickening agents, for example selected from carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethyl cellulose (HPEC), other cellulose derivatives, microcrystalline cellulose, amorphous cellulose, polyacrylate polymers, polyvinyl pyrrolidone, polyvinyl alcohol and polyethylene glycol (e.g., PEG-400, PEG-600).

[0347] 2.37. Composition 2.35 or 2.36 wherein the composition comprises one or more surfactants.

[0348] 2.38. Composition 2.37, wherein the one or more surfactants include a nonionic surfactant, for example, 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., glyceryl monostearate, glyceryl monolaurate), polyethoxylated fatty acids or vegetable oils (e.g., polyethoxylated castor oil), poloxamers, and fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, cetearyl alcohol).

[0349] 2.39. Composition 2.37 wherein the one or more surfactants comprises a cationic surfactant, such as a quaternary amine, eg, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dimethyldioctadecyl ammonium chloride.

[0350] 2.40. Composition 2.37 wherein the one or more surfactants include anionic surfactants such as alkyl sulfates, eg, sodium dodecyl sulfate and sodium lauryl sulfate, alkyl aryl ether polysulfonates, and alkyl sulfosuccinates, eg, docusate sodium.

[0351] 2.41. Any of compositions 2.35-2.40 wherein the composition comprises one or more fillers, for example selected from mannitol, sucrose, fructose, maltose, xylitol, glucose, starch, sorbitol, magnesium aluminum silicate and silicon dioxide (eg, colloidal silicon dioxide).

[0352] 2.42. Any of compositions 2.35-2.41, wherein the composition comprises one or more pH-adjusting agents and / or buffers, for example selected from 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).

[0353] 2.43. Composition 2 or any of 2.1-2.42, wherein the composition comprises one or more antioxidants, for example selected from butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, ascorbyl palmitate, sodium ascorbate, potassium ascorbate, sodium isoascorbate, tocopherol, dihydroguaiaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sodium bisulfite, sodium metabisulfite, sodium EDTA and sorbic acid.

[0354] 2.44. Composition 2 or any of compositions 2.1-2.43, wherein the composition comprises one or more additional excipients selected from gelatin, casein, lecithin, dextran, glycerol, propylene glycol, butylene glycol, gum arabic, gum tragacanth, waxes (e.g., animal or vegetable waxes, including beeswax and carnauba wax), cholesterol, vegetable oils (e.g., coconut oil, soybean oil, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, castor oil, palm oil, almond oil and refined fractionated oils thereof), ethyl oleate, isopropyl myristate, benzyl benzoate, sodium chloride, mineral oil, mono- or di-glycerides of free fatty acids or synthetic fatty acids.

[0355] 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.

[0356] 2.46. Composition 2 or any of 2.1-2.45, wherein the composition comprises an acid addition salt of lumepirone (e.g., lumepirone 4-octylbenzenesulfonate or lumepirone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a thickener (e.g., sodium carboxymethylcellulose), a filler (e.g., mannitol), a nonionic surfactant (e.g., polysorbate 80), and optionally one or more pH-adjusting agents or buffers (e.g., NaOH or HCl and / or sodium phosphate or potassium phosphate).

[0357] 2.47. Composition 2 or any of 2.1-2.45, wherein the composition comprises an acid addition salt of lumepirone (e.g., lumepirone 4-octylbenzenesulfonate or lumepirone 4-tert-butylbenzenesulfonate), water (e.g., sterile water for injection), a thickener (e.g., sodium carboxymethylcellulose), a filler (e.g., mannitol), and optionally one or more pH-adjusting agents or buffers (e.g., sodium or potassium phosphate, NaOH and / or HCl, and / or sodium or potassium phosphate).

[0358] 2.48. Composition 2 or any of 2.1-2.47, wherein a unit dose of the composition for injection comprises an amount of an acid addition salt of lumepirone equivalent to 100-5000 mg of the free base of lumepirone, for example 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.

[0359] 2.49. Composition 2 or any of 2.1-2.48 wherein the composition comprises an acid addition salt of lumepirone at a concentration of 0.1-1000 mg / mL (measured by weight of the salt), 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.

[0360] 2.50. Composition 2 or any of 2.1-2.49, wherein the unit dose volume for injection of the composition is 0.1-5.0 mL, e.g., 0.5-5.0 mL or 1.0-5.0 mL or 2.0-5.0 mL or 3.0-5.0 mL or 4.0-5.0 mL or 0.5-4.0 mL or 1.0-4.0 mL or 2.0-4.0 mL or 3.0-4.0 mL or 0.1-3.0 mL, 0.5-3.0 mL or 1.0-3.0 mL or 1.5 -3.0mL or 2.0-3.0mL or 2.5-3.0mL or 0.1-2.5mL, 0.5-2.5mL or 1.0-2.5mL or 1.5-2.5mL or 2.0-2.5mL or 0.1-2.0mL or 0.5-2.0mL or 1.0-2.0mL or 1.5-2.0mL or 0.1-1.5mL or 0.5-1.5mL or 1.0-1.5mL or 0.1-1.0mL or 0.5-1.0mL or 0.1-0.5mL.

[0361] 2.51. Composition 2 or any of 2.1-2.50, wherein the composition, when injected, forms an intramuscular or subcutaneous depot that releases lumepirone (as a salt or as a free base) over a period of up to 180 days, for example, 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.

[0362] 2.52. Any of composition 2 or 2.1-2.51 wherein the composition has a pH of 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.

[0363] 2.53. Composition 2 or any of 2.1-2.52 wherein the composition comprises an acid addition salt of lumepirone in an amount of 1-50% by weight of the composition (eg, 10-40% by weight of the composition).

[0364] 2.54. Composition 2 or any of 2.1-2.52, wherein the composition comprises one or more diluents, carriers or excipients, the net content of which accounts for 5-99% by weight of the composition (provided that the combination of said components does not exceed 100% by weight of the composition).

[0365] 2.55. Composition 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, the net content of which accounts for 5-99% by weight of the composition.

[0366] 2.56. Any of Composition 2 or 2.1-2.55 wherein the composition comprises water in an amount of 20-99% (eg, 20-90%) by weight of the composition.

[0367] 2.57. Composition 2 or any of 2.1-2.56, wherein the composition comprises one or more excipients in an amount of 1-50% by weight of the composition.

[0368] 2.58. Composition 2 or any of 2.1-2.56, wherein the composition comprises one or more polymers (e.g., biocompatible and biodegradable polymers, particularly polymers for inhibiting dissolution of encapsulated or dispersed drugs) in a net content of 0-50% by weight of the composition.

[0369] 2.59. Composition 2 or any of 2.1-2.58 wherein the composition comprises one or more thickeners in an amount of 0-50% by weight of the composition.

[0370] 2.60. Composition 2 or any of 2.1-2.59 wherein the composition comprises one or more fillers in an amount of 0-50% by weight of the composition.

[0371] 2.61. Composition 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.

[0372] 2.62. Composition 2 or any one of 2.1-2.61, wherein the composition has the following components:

[0373] Components weight% Lumaperone salt (e.g., the salt of Example 2-9) 1-50% (e.g. 10-40%) Thickeners (e.g. sodium carboxymethyl cellulose) 0-20% (e.g. 1-20%) Bulking agents (such as mannitol) 0-20% (e.g. 1-20%) Buffer (eg sodium phosphate) 0.01-5% (e.g. 0.1-1%) pH-adjusting agent (e.g. NaOH) <1％ water Appropriate amount (e.g. 20-90%)

[0374] 2.63. Composition 2 or any of 2.1-2.62 wherein the composition is sterile.

[0375] 2.64. Any of Composition 2 or 2.1-2.63 wherein the composition is a homogeneous solution.

[0376] 2.65. Composition 2 or any of 2.1-2.63 wherein the composition is a suspension, such as a homogeneous suspension, optionally wherein the acid addition salt of lumepirone is the only insoluble component.

[0377] 2.66. Composition 2 or any one of 2.1-2.65, wherein the composition is prepared as a dry solid comprising an acid addition salt of lumepirone and one or more diluents, carriers or excipients (e.g., water-soluble excipients), and wherein the solid is reconstituted into a long-acting injectable pharmaceutical composition with sterile water for injection prior to administration; optionally wherein the dry solid does not contain any liquid solvent or co-solvent (e.g., water, a water-miscible solvent, or a water-immiscible liquid).

[0378] 2.67. Composition 2.66 wherein the dried solid is lyophilized.

[0379] 2.68. Composition 2.66 or 2.67 wherein the dry solid is in the form of a powder, granules, pellets or cake.

[0380] 2.69. Any of compositions 2.66-2.68, wherein the dry solid is packaged in a vial, sachet or other single-dose package or container, for example, wherein 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 the patient.

[0381] 2.70. Any of compositions 2.66-2.68, wherein the dry solid is packaged in a prefilled syringe (single or dual chamber), for example, wherein 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 the patient; optionally wherein the dry solid is packaged in a prefilled two-chamber syringe, wherein one chamber contains the dry solid and the other chamber contains sterile water for injection, and the contents are mixed by opening or releasing the barrier between the two chambers, followed by mixing the contents in the chambers and injecting the resulting composition into the patient.

[0382] 2.71. Composition 2.70, wherein a homogeneous solution is formed upon combining the dry solid and sterile water for injection.

[0383] 2.72. Composition 2.70 wherein upon combining the dry solid and sterile water for injection a suspension is formed, eg, a homogeneous or uniform suspension.

[0384] 2.73. Composition 2 or any of 2.1-2.72, wherein the composition is intended for administration to a patient in need thereof, and the administration frequency is once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months or once every six months.

[0385] 2.74. Composition 2 or any of 2.1-2.73, wherein a single dose of the injected composition provides therapeutically effective plasma levels of lumepirone free base and / or therapeutically effective cerebrospinal fluid (CSF) levels of lumepirone 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 one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months or six months.

[0386] 2.75. Any of composition 2 or 2.1-2.74 wherein the composition is not an emulsion.

[0387] It will be appreciated that long-acting injectable (LAI) compositions have been known for some time, but they are primarily based on two concepts: (1) the use of a viscous, poorly water-soluble or insoluble polymer matrix to inhibit dissolution of a water-soluble active substance; and (2) the use of a water-insoluble prodrug of a water-soluble active substance. In the case of (1), a polymer such as PLGA is used in large quantities to dissolve, disperse or encapsulate or form microspheres that encapsulate the active drug product. The dissolution kinetics are controlled by the degradation of the polymer, for example by hydrolysis of the polymer ester bonds. Such LAI compositions can be extremely difficult to formulate because they are prone to non-linear release kinetics, such as an undesirable initial burst of drug. In the case of (2), the prodrug itself is pharmacologically inactive. Therefore, the release kinetics of the active agent are controlled by the rate at which the prodrug degrades 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 generally cannot maintain action for more than a short period of time (i.e., a few weeks). For example, if the prodrug is too unstable, it will provide high initial plasma concentrations but the reservoir will be quickly depleted, whereas if the prodrug is too resistant to hydrolysis, it may be difficult to achieve therapeutic plasma concentrations over a sufficient period of time.

[0388] The low solubility salts disclosed herein provide a third option for LAI formulations. Due to the low water solubility of these salts, the salts themselves essentially behave as a pharmacologically inert agent. Only a very small amount of the drug dissolves in the body's water compartments, where as a free base it can cross the blood-brain barrier to exert its therapeutic effect. Therefore, large drug loads can be delivered by injection, thereby forming an insoluble tissue reservoir in muscle or subcutaneous tissue. The "release" of the active drug (lumepirone free base) into the tissue is only related to the rate at which the salt dissolves. Unlike the prior art lumepirone LAI, the "release" of the active drug can be independent of the formulation components (e.g., by avoiding the use of polymers that form a polymer matrix that inhibits the dissolution of the drug substance) and does not depend on molecular changes to the drug molecule (e.g., covalent bond cleavage). This allows the formulation of more effective and controllable LAI products.

[0389] In another aspect, the present disclosure provides any salt disclosed herein, such as any of Salt 1, etc., Salt 2, etc., Salt 3, etc., Salt 4, etc., Salt 5, etc., Salt 6, etc., Salt 7, etc., Salt 8, etc., for use in treating (or preparing a medicament for treating the following diseases) a disease involving 5-HT 2A Receptors, serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways or diseases, disorders or abnormal conditions mediated by them, such as diseases, disorders or disorders selected from the following: obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, disorders associated with headache, social phobia, dementia, disorders associated with dementia, post-traumatic stress disorder, impulse control disorders and intermittent explosive disorder. In a preferred embodiment, the present disclosure provides these salts for the treatment of the following diseases: negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), refractory depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with depression, schizophrenia with anxiety, and depression or other mood disorders associated with encephalitis or neuroinflammation. Such uses of lumepirone are further described in, for example, US2011 / 0071080, US2015 / 0072964, US 2015 / 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.

[0390] In another aspect, the present disclosure provides a method for preventing or treating a patient with a 5-HT-related 2A A method for treating a patient suffering from a disease or abnormal condition mediated by a receptor, a serotonin transporter (SERT) and / or a dopamine D1 / D2 receptor signaling pathway, or a disease or abnormal condition mediated by them, such as a disease, a condition or a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, a condition associated with headache, social phobia, dementia, a disorder associated with dementia, 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 salt disclosed herein, such as any of Salt 1, etc., Salt 2, etc., Salt 3, etc., Salt 4, etc., Salt 5, etc., Salt 6, etc., Salt 7, etc., Salt 8, etc.

[0391] In another embodiment, the present disclosure provides any one of Composition 1 or Composition 2, etc., for use in treating (or preparing a medicament for treating the following diseases) a disease involving 5-HT. 2AReceptors, serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways or diseases, disorders or abnormal conditions mediated by them, such as diseases, disorders or disorders selected from the following: obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, disorders associated with headache, social phobia, dementia, disorders associated with dementia, post-traumatic stress disorder, impulse control disorders and intermittent explosive disorder. In a preferred embodiment, the present disclosure provides these salts for use in treating negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), refractory depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with depression, schizophrenia with anxiety, and depression or other mood disorders associated with encephalitis or neuroinflammation. Such uses of lumepirone are further described in, for example, US2011 / 0071080, US 2015 / 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.

[0392] In another embodiment, the present disclosure provides for the prevention or treatment of a condition involving 5-HT 2A A method for treating a disease or abnormal condition mediated by a receptor, a serotonin transporter (SERT) and / or a dopamine D1 / D2 receptor signaling pathway, or a disease or abnormal condition mediated by them, such as a disease, condition or disorder selected from the following: obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related disorder, social phobia, dementia, dementia-related disorder, post-traumatic stress disorder, impulse control disorder and intermittent explosive disorder, the method comprising administering a therapeutically effective amount of any one of Composition 1 or Composition 2, etc. to a patient in need thereof.

[0393] In a preferred embodiment, the above methods and uses are used to treat a disease, disorder or disorder selected from the negative symptoms of schizophrenia (or residual symptoms of schizophrenia), major depressive disorder (MDD), refractory depression, acute depression, bipolar depression, bipolar I disorder, bipolar II disorder, acute anxiety, schizophrenia with depression, schizophrenia with anxiety, and depression or other mood disorders associated with encephalitis or neuroinflammation. Such methods of use of lumepirone are further described in the following documents, such as US2011 / 0071080, US2015 / 0072964, US2015 / 0080404, US 2016 / 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.

[0394] If the method of use or treatment involves the use of a long-acting injectable composition such as composition 2, the method or use may include administering the composition to a patient in need thereof by intramuscular or subcutaneous injection at a frequency of once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months or once every six months. Preferably, the method provides a therapeutically effective plasma level of lumepirone free base and / or a therapeutically effective cerebrospinal fluid (CSF) level of lumepirone free base for a period of 1 week to 6 months, such as 1 week to 1 month, or 1 month to 3 months, or 3 months to 6 months, or about one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months or six months.

[0395] In some embodiments, the method comprises administering a unit dose of a composition for injection comprising an amount of an acid addition salt of lumepirone equivalent to 100-5000 mg of lumepirone free base, such as 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.

[0396] In some embodiments, the dosage administered as a unit dose volume for injection of the composition is 0.1-5.0 mL, e.g., 0.5-5.0 mL or 1.0-5.0 mL or 2.0-5.0 mL or 3.0-5.0 mL or 4.0-5.0 mL or 0.5-4.0 mL or 1.0-4.0 mL or 2.0-4.0 mL or 3.0-4.0 mL or 0.1-3.0 mL, 0.5-3.0 mL or 1.0-3.0 mL or 1.5-3.0 mL or 2.0-3.0mL or 2.5-3.0mL or 0.1-2.5mL, 0.5-2.5mL or 1.0-2.5mL or 1.5-2.5mL or 2.0-2.5mL or 0.1-2.0mL or 0.5-2.0mL or 1.0-2.0mL or 1.5-2.0mL or 0.1-1.5mL or 0.5-1.5mL or 1.0-1.5mL or 0.1-1.0mL or 0.5-1.0mL or 0.1-0.5mL.

[0397] In some embodiments, the method comprises administering a composition having an acid addition salt of lumepirone at a concentration of 0.1-1000 mg / mL (determined by weight of the salt), such as 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.

[0398] It should be understood that the dose administered, the volume administered, and the concentration administered depend on the expected duration of action of the LAI composition. Therefore, long-acting compositions require higher doses and volumes, and shorter-acting compositions may be sufficient for smaller doses and volumes. Preferably, the composition is administered as an aqueous suspension. In some embodiments, the composition is administered by reconstituting a dry solid with sterile water for injection immediately before administering (injecting) the obtained long-acting injectable pharmaceutical composition, the solid comprising an acid addition salt of lumepirone and one or more diluents, carriers or excipients (e.g., water-soluble excipients). The dry solid may be provided in the form of a powder, granules, pellets, or cake, optionally packaged in a vial, pouch, or prefilled syringe (single chamber or dual chamber). Therefore, for a single-chamber syringe, sterile water for injection is drawn into a prefilled syringe containing a solid, the contents are mixed, and the contents in the syringe are then injected into the patient. In some embodiments, the dry solid is packaged in a prefilled dual-chamber syringe, wherein one chamber contains a dry solid and the other chamber contains sterile water for injection. Therefore, before use, the contents of the two chambers are mixed immediately, the components of the two chambers are mixed by opening or releasing the barrier between the two chambers, and then the resulting long-acting injectable pharmaceutical composition is injected into the patient. If the dry solid is packaged in a vial, pouch or other single-dose package or container, sterile water for injection can be added to the package or container, or the contents of the package or container are added to the sterile water for injection. The combination is then mixed, and the resulting long-acting injectable composition is then drawn into a syringe and then injected into the patient.

[0399] Treatment methods using long-acting injectable compositions may be particularly beneficial for patients who have poor oral medication compliance, such as those suffering from schizophrenia, bipolar depression, dementia, and other psychiatric disorders.

[0400] Methods for the synthesis of lumepirone free base are known and can be found in, for example, US2004 / 0220178, US2006 / 148808, US2010 / 0113781, and US2020 / 0102309, the contents of each of which are incorporated herein by reference in their entirety.

[0401] Although specific embodiments of the present disclosure are currently described with reference to preparations, it should be understood that these embodiments are presented only by way of example and illustrate only a small number of the many possible specific embodiments that can represent the application 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

[0402] The following instruments and methods were used to isolate and characterize exemplary salt forms.

[0403] X-ray powder diffraction (XRPD): X-ray powder diffraction studies were performed using a Bruker AXSD2 PHASER instrument #1549 in Bragg-Brentano configuration. The X-ray source was a copper anode at 30 kV, 10 mA. From beam to source, the slits used were a major axis Soller slit of 2.5°, a fixed divergence slit of 1.0 mm (= 0.61°), a detector slit of 8.0 mm, and a minor axis Soller slit of 2.5°. For monochromatization, a Kβ-filter (0.5% Ni) was used. The detector was a linear detector LYNXEYE with a detector opening of 5° for the receiving slit. The sample stage was standard rotation (5 / min) with a beam stop. All measurement conditions were recorded in the instrument control file. The software used for data acquisition was Diffrac.Measurement Centre v4.6. Data analysis was performed using Diffrac.Eva V4.1.1 evaluation software. Figures were not background corrected or smoothed.

[0404] Bruker AXSD8 Discovery High Throughput X-ray Screening: X-ray powder diffraction studies were performed using a Bruker AXSD8 discoverHTS instrument #3198. A copper anode at 40 kV and 40 mA was used; Mirror, line optics. Detector: Linear detector LYNXEYE XE, detector opening with receiving slit 2.95°. Measurement conditions: Scanning range 2-45°2°, 1 sec / step, 0.005° / step, and all measurement conditions are recorded in the instrument control file. As a system suitability, corundum powder was measured. The software used for data acquisition was Diffrac.Commander v7.3.0.0. Data analysis was performed using Diffrac.Eva v4.2.1. No background correction or smoothing was performed on the figures. S (NIST standard) was checked daily for peak position, peak shape, intensity and linearity.

[0405] Simultaneous Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) or TGA / DSC Analysis: TGA / DSC studies were performed using a Mettler Toledo TGA / DSC-3+STARe system with a 34-position autosampler, instrument #3119 / #3287. Samples were prepared using Al crucibles (40 μL; pierced). Typically, 5-10 mg of sample was loaded into a pre-weighed Al crucible and kept at 20°C for 5 minutes, after which it was heated from 20°C to 350°C at 10°C / min. A nitrogen purge of 40 mL / min was maintained over the sample. The software used for data acquisition and evaluation was STARe software v15.00 build 8668. The thermograms were not corrected in any way. As a system suitability check, indium and zinc were measured. For calibration of the instrument, benzophenone, indium, lead, tin and zinc were used as references.

[0406] Differential Scanning Calorimetry (DSC): DSC studies were performed using a Mettler Toledo DSC1 / DSC3+STARe system, instrument #1564 / #3168. Samples were made using Al crucibles (40 μL; pierced). Typically, 1-8 mg of sample was loaded into a pre-weighed Al crucible and kept at 20°C for 5 minutes, after which it was heated from 20°C to 350°C at 10°C / min and kept at 350°C for 1 minute. A nitrogen purge of 40 mL / min was maintained on the sample. The software used for data acquisition and evaluation was STAReSoftware v15.00 build 8668. The thermograms were not corrected in any way. Indium and zinc were measured as a system suitability check. For calibration, indium, lead and zinc were used as references.

[0407] Polarized light microscopy (PLM): Microscopic studies were performed using an AxioVert 35M equipped with an AxioCamERc5s, instrument #1612. The microscope was equipped with four lenses: Zeiss A-Plan 5× / 0.12, Zeiss A-Plan 10× / 0.25, LD A-Plan 20× / 0.30 and Achros TIGMAT 32× / 0.40. Data acquisition and evaluation were performed using Carl Zeiss ZenAxioVision Blue Edition Lite 2012v1.0.0.0 software. A small amount of sample was loaded on the objective and carefully spread until a thin layer was obtained.

[0408] Proton NMR spectroscopy ( 1 H-NMR): NMR studies were performed using a Varian Unity Inova 400 NMR spectrophotometer, instrument # 1857. The spectrophotometer was equipped with a 5 mm ID probe.

[0409] Technobis crystallization: This test was performed using a Technobis Crystalline (instrument #2537). A total of 8 small reactors were available, using 8 mL glass vials. For each reactor, the vial was filled with the desired chemical and closed with the desired lid. A CCD camera was connected to reactors E to H to monitor the reaction in time. Crystalline version 2.17.2 was used to collect data, and CrystalClear version 1.0.1.614 was used to evaluate.

[0410] MYA4: Experiments were performed using Radleys MYA 4 reactor station and process package (Instrument #3181). A total of four reactor stations were available, each of which could be used at scales of 50 mL-100 mL-250 mL and 500 mL. All reactors were equipped with a stirrer, thermometer, and KNF Simdos 02 / 10 liquid metering pump. The MYA 4 reactor station was controlled by MYA control software V1.1.1 with a custom driver for the KNF Simdos 02-10 liquid metering pump.

[0411] Example 1: Salt crystal screening

[0412] In order to identify new solid, stable crystalline salts of lumepirone, and in particular for the purpose of identifying low solubility salts, salt screening is performed. Lumeperone free base is a viscous, oily substance with extremely low water solubility. Many past studies have confirmed that it is very difficult to form solid crystalline salts of lumepirone. See, for example, US2011 / 112105, US2019 / 0112309, US2020 / 247805, US2020 / 0157100. However, stable crystalline monotoluenesulfonates, bistoluenesulfonates, benzenesulfonates, naphthalenesulfonates and naphthalene disulfonates of lumepirone have been described, which suggests that sulfonic acid can be a preferred acid counterpart for salt formation. This study relies on a large number of major monosulfonates and disulfonates with bulky and / or non-polar side chains.

[0413] In a preliminary screen, 36 different sulfonic acids were tested at a molar ratio of 1:1 and / or 1:2 free base to acid using four solvent systems: acetonitrile / water (9:1 v / v), methanol, ethyl acetate, and toluene. These solvents were selected based on the known solubility of lumepirone free base and the solubility of the selected acid. This preliminary screen was performed on a Technobis Crystal 16 instrument using thermal cycling.

[0414] A stock solution of lumepirone free base was prepared at a concentration of 25 mg / 0.5 mL in the 4 selected solvents. The acid was weighed into an empty vial to provide a molar ratio of 1:1 or 1:2, and then the lumepirone free base solution was added. The samples were then subjected to the following 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 matter.

[0415] The vast majority of vials had clear solutions or oils. All vials with clear solutions were then subjected to the antisolvent protocol. If the solvent was acetonitrile / water or methanol, 0.5 mL of water was added to the vial. If the solvent was ethyl acetate or toluene, 0.5 mL of heptane was added to the vial. The thermal cycling protocol was then repeated.

[0416] The vial containing the solid material (after primary screening or anti-solvent treatment) is then centrifuged, the supernatant is removed with a pipette, and the solid is transferred to a well plate for XRPD analysis. The resulting XRPD spectrum is evaluated to determine whether it is amorphous or whether it corresponds to a new crystal diffraction pattern.

[0417] In this initial screen, a total of 272 counterion / solvent / ratio combinations were tested and only 35 resulted as solids, however, 7 of the solids were obtained in insufficient quantities for analysis (indicating that the yield of salts, if any, was very low). Of the 28 solids that formed in sufficient quantities for analysis, 5 were amorphous and 23 were crystalline by XRPD. Analysis of the crystalline solids by XRPD showed that 19 different new XRPD patterns were formed from 14 acids (out of the 36 acids tested).

[0418] In a second set of preliminary experiments, each of the 14 acids that produced any crystalline solid in the preliminary screening was tested using an alternative. The specific acid was added to a vial to provide a 1:1 molar ratio of acid and lumepirone free base (25 mg), followed by the addition of lumepirone free base solution (5 mg / 0.5 mL). The solvents selected were based on the results of the preliminary screening, with 11 experiments using ethyl acetate, 5 using toluene, and 1 using acetonitrile / water or methanol. The reaction was heated to 50°C for 2 hours and then cooled to 5°C. All experiments produced clear solutions or oils. Antisolvent addition was performed with clear solutions as described above. Of the 18 experiments, only two experiments produced solids, both of which were the same 20th different new XPRD pattern.

[0419] Thus, from a total of 290 trials, 20 candidate new crystalline lumepirone polymorphs were obtained. The candidate polymorphs were the result of using 14 of the 36 different acids. These 20 candidate salts were then analyzed by DSC and TGA, and 9 were found to be solvated, and 10 were found to be non-solvated and anhydrous.

[0420] Then the conditions (molar ratio, solvent) that produced the original candidate salt were used to attempt to amplify and further characterize each of the 20 candidate salt polymorphs on a 100 mg scale. Only 12 were successfully reproduced. The method is as follows: the acid is weighed into an empty vial to provide a 1:1 or 1:2 molar ratio, and 2.0 mL of a suitable lumepirone free base stock solution is added to the vial. The mixture is stirred until a clear solution is obtained. Then, the vial is subjected to a thermal cycle scheme: 20°C-60°C-0°C-50°C-0°C-30°C-0°C-20°C-0°C. The heating rate applied is 10°C / minute, and the cooling rate applied is 0.5°C / minute. Finally, each vial is checked for solid matter. If solid is present, the supernatant is removed with a pipette, the solid is vacuum dried, and then the solid is analyzed by XRPD, DSC-TGA, and proton NMR.

[0421] Of the 19 runs, 12 yielded solids that showed the same XRPD spectra found during the primary screening, and thus these runs were considered successful scale-ups. Five of the runs did not form solids. Three runs formed a solid that was not found to be a lumepirone salt based on DSC-TGA and proton NMR. Two runs produced new crystalline salt forms that were clearly identified as lumepirone salts, but their XRPD spectra did not match those obtained when the primary screening was performed under the same conditions.

[0422] Using the conditions that produced five different amorphous solids during the initial screening process, the same 100 mg scale-up was also attempted, hoping that these might produce crystals on a larger scale. Of these five attempts, one produced a new crystalline XRPD pattern identified as the lumiperone salt.

[0423] These 100 mg scale-up experiments resulted in 3 benzenesulfonate crystalline polymorphs, 1 2-naphthalenesulfonate crystalline polymorph, 3 4-ethylbenzenesulfonate crystalline polymorphs, 1 4-propylbenzenesulfonate crystalline polymorph, 1 4-tert-butylbenzenesulfonate crystalline polymorph, 1 4-octylbenzenesulfonate crystalline polymorph, 1 pentane-1-sulfonate crystalline polymorph and 1 heptane-1-sulfonate crystalline polymorph, for a total of 12 different crystalline polymorphs derived from 8 different acids.

[0424] Importantly, the acids used in these experiments included several sulfonic acids that did not form any solids or did not form reproducible crystalline solids, yet these acids had structural similarities to the eight acids that successfully formed reproducible lumepirone salts. For example, the aromatic acids naphthalene-1,5-disulfonic acid and 5-isoquinolinesulfonic acid produced initial crystalline solids that were not reproducible on scale. In contrast, no clear solids were obtained using quinoline-8-sulfonic acid, pyridine-2-sulfonic acid, or pyridine-3-sulfonic acid under any conditions. Even the acids that did form salts in this study, such as benzenesulfonic acid and 4-ethylbenzenesulfonic acid, did so only under certain conditions—certain solvents, but not others; or when a 1:1 molar ratio was used, but not a 1:2 ratio; or vice versa. This underscores the ongoing conclusion based on this and previous studies that lumepirone forms solid crystalline salts with unpredictable acids in unpredictable environments and conditions. However, it also suggests that the fact that some acids did not form reproducibly crystalline salts under the conditions tested here does not exclude the possibility that such acids could form stable, reproducibly crystalline lumepirone salts under further investigation under alternative conditions. Therefore, this is an area of ​​ongoing research.

[0425] Example 2: 4-Octylbenzenesulfonate

[0426] Preliminary screening results indicated that crystalline lumepirone 4-octylbenzenesulfonate was formed using a 1:1 molar ratio in either ethyl acetate or toluene solvents, and a 1:2 molar ratio in either ethyl acetate or toluene solvents. The same XRPD pattern was obtained under all four conditions. No solid was obtained at any molar ratio using acetonitrile / water or methanol as solvents. Preliminary DSC suggested that this was a non-solvated anhydrous crystal under each of the four conditions. DSC showed a melting event at 164.6°C with no weight loss on TGA.

[0427] Since the same XPRD pattern was obtained using both solvents, a 100 mg scale-up was performed using ethyl acetate at 1:1 and 1:2 molar ratios and a solid with the same XRPD pattern as in the 25 mg preliminary screen was obtained. The DSC for the solid from the 1:1 molar ratio showed a single melting event at 135.0°C, while the DSC for the solid from the 1:2 molar ratio showed a single melting event at 157.6°C. Both indicated non-solvated anhydrous crystals.

[0428] The scale-up was repeated again at 500 mg using a 1:1 molar ratio in ethyl acetate and the solid obtained again had the same XRPD pattern as shown previously. Figure 1 and the peak list is shown in the following table:

[0429] XRPD of 4-octylbenzenesulfonate crystals (Cu anode, Ni filter)

[0430] # horn d value Relative Strength 1 9.086 9.72473 18.60％ 2 9.192 9.6129 6.40％ 3 11.369 7.77699 13.00％ 4 11.814 7.48515 47.70％ 5 12.671 6.98031 30.80％ 6 13.236 6.68362 8.30％ 7 14.496 6.1056 6.30％ 8 15.289 5.79046 8.90％ 9 16.063 5.51314 86.70％ 10 16.298 5.43443 74.80％ 11 16.867 5.25211 92.20％ 12 18.217 4.86602 33.50％ 13 18.783 4.72062 20.00％ 14 19.425 4.56604 16.80％ 15 20.114 4.41113 14.70％ 16 20.466 4.33592 22.50％ 17 22.615 3.92858 100.00％ 18 22.671 3.91903 98.90％ 19 23.085 3.8496 42.20％ 20 23.663 3.75691 12.10％ 21 24.099 3.68996 17.40％ 22 24.456 3.63683 17.00％ 23 25.965 3.42881 2.50％ 24 29.822 2.99358 3.50％

[0431] DSC on the solid showed a single melting event at 156.7°C. Proton NMR was performed and showed an estimated molar ratio of 1.0:0.8 for lumiperone and acid, thus confirming that it was a 1:1 salt. The NMR spectrum was as follows Fig. 9 as shown in .

[0432] Example 3: 4-tert-Butylbenzenesulfonate

[0433] Preliminary screening results indicated that crystalline lumepirone 4-tert-butylbenzenesulfonate was formed in ethyl acetate solvent using a 1:2 molar ratio. No solids were obtained using acetonitrile / water, methanol or toluene as solvents, and this acid was not tested at a 1:1 molar ratio. Preliminary DSC suggested that this was a non-solvated anhydrous crystal. DSC showed a melting event at 210.9°C and a 1.0% weight loss was shown on TGA (suggesting the presence of residual solvent).

[0434] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio and gave a solid with the same XRPD pattern as the 25 mg primary screen. DSC on the solid showed a single melting event at 211.7°C and a desolvation event at 67.7°C. The TGA mass loss was 1.3%, consistent with a desolvation event. This indicated the presence of solvated crystals.

[0435] XRPD pictures Figure 2 and the peak list is shown in the following table:

[0436] XRPD of 4-tert-butylbenzenesulfonate crystals (Cu anode, Ni filter)

[0437] # horn d value Relative Strength 1 3.216 27.44733 13.00％ 2 3.640 24.25154 100.00％ 3 6.665 13.25211 12.90％ 4 7.194 12.27861 20.60％ 5 13.904 6.36395 14.90％ 6 14.724 6.01133 12.70％ 7 15.224 5.81524 14.30％ 8 15.642 5.66062 10.10％ 9 16.050 5.51782 12.60％ 10 17.955 4.93645 8.10％ 11 18.775 4.72263 41.10％ 12 18.903 4.69091 24.20％ 13 19.586 4.52885 17.00％ 14 20.657 4.29632 13.60％ 15 22.084 4.02185 7.30％ 16 22.994 3.86463 5.20％ 17 23.678 3.75456 10.20％

[0438] Proton NMR was performed and showed an estimated molar ratio of 1:2 of lumepirone and acid, thus confirming that it was a 1:2 salt. Fig.10 as shown in .

[0439] Example 4: 4-Propylbenzenesulfonate

[0440] Preliminary screening results indicated that crystalline Lumiperone 4-propylbenzenesulfonate was formed using a 1:2 molar ratio in ethyl acetate solution. No solids were obtained using acetonitrile / water, methanol or toluene as solvents, and this acid was not tested at a 1:1 molar ratio. Preliminary DSC suggested that this was a non-solvated anhydrous crystal. DSC showed a melting event at 158.3°C and no weight loss on TGA.

[0441] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio and gave a solid with the same XRPD pattern as the 25 mg initial screening. DSC of the solid showed a single melting event at 160.2°C. The TGA mass loss was 0.7%, consistent with residual solvent. This indicated a non-solvated anhydrous crystal.

[0442] XRPD pictures Figure 3 and the peak list is shown in the following table:

[0443] XRPD of 4-propylbenzenesulfonate crystals (Cu anode, Ni filter)

[0444]

[0445]

[0446] Proton NMR was performed and showed an estimated molar ratio of 1:2 of lumepirone and acid, thus confirming that it was a 1:2 salt. Fig.11 as shown in .

[0447] Example 5: 4-Ethylbenzenesulfonate

[0448] Preliminary screening results showed that crystalline lumepirone 4-ethylbenzenesulfonate was formed in both ethyl acetate and toluene solvents using a 1:2 molar ratio, but preliminary XRPD showed that these solids had two different XPRD patterns. In addition, amorphous solids were obtained from screening using a 1:2 molar ratio in methanol and a 1:2 molar ratio in methanol, and the two amorphous XRPD patterns were also different. No solids were obtained using acetonitrile / water as solvent, or using toluene or ethyl acetate at a 1:1 molar ratio. Preliminary DSC revealed that both crystalline solids were non-solvated anhydrous crystals. DSC showed a single melting event at 153.2°C under ethyl acetate conditions, and a monolayer melting event at 157.6°C under toluene conditions. The weight loss on TGA was zero under ethyl acetate conditions and 2.2% under toluene conditions.

[0449] The above alternative reaction conditions (50 mg scale, 50 ° C for 2 hours) also produced a third crystalline 4-ethylbenzenesulfonate candidate salt. This salt was obtained using both ethyl acetate solvent and toluene solvent. The solid from the toluene condition was tested in DSC and TGA. DSC showed a single melting event at 141.5 ° C, and the mass loss on TGA was 0.6% (residual solvent).

[0450] A 100 mg scale-up was performed using each of the three preliminary conditions that produced crystalline solids, and in each case a solid with the same XRPD pattern as in the 25 mg preliminary screen was 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 a single 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 indicated non-solvated anhydrous crystals with some residual solvent loss.

[0451] XRPD pictures Figure 4A , 4B and 4C and the peak list is shown in the following table:

[0452] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 1 (Cu anode, Ni filter)

[0453] # horn d value Relative Strength 1 3.511 25.14320 100.00％ 2 3.684 23.96635 55.30％ 3 4.982 17.72257 14.80％ 4 6.917 12.76937 5.60％ 5 7.321 12.06545 5.30％ 6 10.354 8.53641 2.60％ 7 10.383 8.51268 2.80％ 8 12.488 7.08228 2.60％ 9 13.689 6.46357 4.10％ 10 14.269 6.20219 9.00％ 11 15.587 5.68057 40.60％ 12 17.499 5.06386 9.70％ 13 17.682 5.01186 8.80％ 14 18.581 4.77134 13.70％ 15 18.852 4.70347 13.50％ 16 20.127 4.40823 27.20％ 17 20.609 4.30628 13.50％ 18 20.833 4.26051 12.20％ 19 21.246 4.17848 7.60％ 20 22.016 4.03418 5.30％ 21 27.486 3.24248 4.50％

[0454] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 2 (Cu anode, Ni filter)

[0455]

[0456]

[0457] XRPD of 4-ethylbenzenesulfonate crystalline polymorph 3 (Cu anode, Ni filter)

[0458]

[0459]

[0460] Proton NMR was performed and showed an estimated molar ratio of 1:2 of lumepirone and acid for polymorphs 1 and 2 and a 1:1 ratio for polymorph 3. The NMR spectra were Fig. 12A , 12B and as shown in 12C.

[0461] Example 6: 2-Naphthalenesulfonate

[0462] Preliminary screening results showed that crystalline Lumiperone 2-naphthalenesulfonate was formed using a 1:2 molar ratio in ethyl acetate solvent. No obvious solids were obtained using acetonitrile / water, methanol or toluene as solvents at a 1:1 or 1:2 molar ratio, and no obvious solids were obtained in ethyl acetate at a 1:1 molar ratio. Preliminary DSC suggested that this was a solvated crystal. DSC showed a desolvation event at 91.4°C and no melting events, and TGA showed a 6.0% weight loss, consistent with desolvation of the crystals.

[0463] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio and gave a solid with the same XRPD pattern as the 25 mg primary screen. DSC of the solid showed a desolvation event at 108.5°C and a single melting event at 162.1°C. The TGA mass loss was 7.4%, consistent with desolvation of the crystals.

[0464] XRPD pictures Figure 5 and the peak list is shown in the following table:

[0465] XRPD of 2-naphthalenesulfonate crystals (Cu anode, Ni filter)

[0466] # horn d value Relative Strength 1 2.401 36.77034 32.50％ 2 7.045 12.53758 16.40％ 3 14.063 6.29268 10.20％ 4 14.906 5.93853 27.30％ 5 15.477 5.72064 26.40％ 6 17.204 5.15024 25.70％ 7 17.493 5.06578 21.00％ 8 19.018 4.66279 26.30％ 9 20.323 4.36625 40.90％ 10 20.418 4.34608 39.50％ 11 20.780 4.27126 84.70％ 12 20.842 4.25855 100.00％ 13 21.247 4.17835 28.40％ 14 23.846 3.72847 21.10％ 15 26.939 3.30704 9.30％ 16 27.208 3.27490 28.90％

[0467] Proton NMR was performed and showed the estimated molar ratio of lumepirone and acid to be 1 :1, thus confirming that this was a 1 :1 salt.

[0468] Example 7: Benzenesulfonate

[0469] Preliminary screening results showed that crystalline candidate salts were formed in both ethyl acetate and toluene solvents using a 1:2 molar ratio, but preliminary XRPD showed that these solids had two different XPRD patterns. In addition, an amorphous solid was obtained from the 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. Preliminary DSC revealed that both crystalline solids were solvated crystals. DSC showed desolvation events at 73.9°C and 110.6°C, and a single melting event at 172.6°C under ethyl acetate conditions, and a desolvation event at 75.1°C and a single melting event at 174.1°C under toluene conditions. The weight loss on TGA was 4.9% under ethyl acetate conditions and 3.6% under toluene conditions, both of which are consistent with solvated crystals.

[0470] A 100 mg scale-up was performed using each of the three preliminary conditions that produced solids, but none reproduced the original product. Instead, each of the three conditions—including the condition that provided an amorphous solid at the 25 mg scale—produced a different XRPD pattern of the crystalline salt 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 had a desolvation event at 96.0°C and a melting event at 109.5°C with a TGA weight loss of 6.3%. This is consistent with solvated crystals. Polymorph 2 showed a single melting event at 131.3°C and no TGA weight loss, consistent with non-solvated anhydrous crystals. Polymorph 3 showed two melting events at 109.6 and 125.9°C with no TGA weight loss. This is also indicative of non-solvated anhydrous crystals.

[0471] XRPD pictures Fig. 6A , 6B and 6C and the peak list is shown in the following table:

[0472] XRPD of benzenesulfonate crystalline polymorph 1 (Cu anode, Ni filter)

[0473]

[0474]

[0475] XRPD of benzenesulfonate crystalline polymorph 2 (Cu anode, Ni filter)

[0476]

[0477]

[0478] XRPD of benzenesulfonate crystalline polymorph 3 (Cu anode, Ni filter)

[0479] # horn d value Relative Strength 1 5.240 16.85241 89.90％ 2 5.756 15.34242 100.00％ 3 14.387 6.15169 73.40％ 4 16.165 5.47865 47.20％ 5 16.713 5.30036 45.40％ 6 18.653 4.75319 21.10％ 7 19.249 4.60734 31.00％ 8 19.441 4.56222 62.80％ 9 20.697 4.28806 50.40％ 10 20.839 4.25914 50.10％ 11 21.084 4.21030 28.80％ 12 22.806 3.89608 48.00％ 13 22.907 3.87919 46.20％ 14 23.212 3.82890 71.20％ 15 23.874 3.72418 30.60％ 16 24.695 3.60221 99.90％ 17 25.066 3.54981 30.10％ 18 25.127 3.54131 24.10％ 19 26.712 3.33459 6.90％ 20 28.440 3.13583 14.30％ 21 33.755 2.65326 6.00％ 22 37.907 2.37161 11.30％

[0480] Proton NMR was performed and showed that the estimated molar ratio of lumepirone and acid was 1:1 for each of polymorphs 1, 2 and 3. The NMR spectra were Fig. 12A , 12B and as shown in 12C.

[0481] Lumiperone besylate was previously reported in WO 2020 / 112941 (Teva Pharmaceuticals, Inc; Teva Czech Industries SRO). However, the besylate reported in this application undergoes a melting event at a higher temperature of 173-174°C compared to the above polymorphs 1, 2, and 3. The XRPD pattern of the Teva crystals is also not similar to the above polymorphs 1, 2, and 3.

[0482] Example 8: Pentan-1-sulfonate

[0483] Preliminary screening results indicated that crystalline lumiperone pentane-1-sulfonate was formed using a 1:2 molar ratio in ethyl acetate solvent. No solid was obtained using acetonitrile / water, methanol or toluene as solvents at a 1:1 or 1:2 molar ratio, or in ethyl acetate at a 1:1 molar ratio. Preliminary DSC suggested that this was a non-solvated anhydrous crystal. DSC showed no events, and TGA showed a 1.4% weight loss, consistent with residual solvent.

[0484] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio and a solid with the same XRPD pattern as the 25 mg initial screening was obtained. DSC of the solid showed a single melting event at 141.3 °C. The TGA mass loss was 0.9%, consistent with residual solvent. This indicated a non-solvated anhydrous crystal.

[0485] XRPD pictures Figure 7 and the peak list is shown in the following table:

[0486] XRPD of pentane-1-sulfonate crystals (Cu anode, Ni filter)

[0487] # horn d value Relative Strength 1 2.086 42.32365 2.40％ 2 3.777 23.37371 100.00％ 3 7.487 11.79790 19.80％ 4 11.225 7.87635 5.70％ 5 14.766 5.99468 32.90％ 6 16.224 5.45895 20.60％ 7 16.561 5.34869 28.00％ 8 17.339 5.11045 17.80％ 9 17.757 4.99095 29.40％ 10 18.639 4.75678 14.70％ 11 19.663 4.51123 17.30％ 12 20.014 4.43290 54.80％ 13 20.344 4.36175 28.70％ 14 20.782 4.27088 16.80％ 15 21.353 4.15784 16.10％ 16 21.738 4.08517 20.60％ 17 22.567 3.93679 15.00％ 18 25.287 3.51922 17.40％ 19 38.261 2.35050 3.90％

[0488] Proton NMR was performed and showed the estimated molar ratio of lumepirone and acid to be 1:1.8, thus confirming that this was a 1:2 salt.

[0489] Example 9: Heptane-1-sulfonate

[0490] Preliminary screening results indicated that crystalline Lumiperone heptane-1-sulfonate was formed using a 1:2 molar ratio in ethyl acetate solvent. No solids were obtained using acetonitrile / water, methanol, or toluene as solvents at a 1:1 or 1:2 molar ratio, or at a 1:1 molar ratio in ethyl acetate. Preliminary DSC suggested that this was a non-solvated anhydrous crystal. DSC showed a melting event at 151.8°C and TGA showed no weight loss. However, the addition of an antisolvent to the 1:2 molar ratio toluene vial formed a solid whose XRPD pattern was different from the ethyl acetate conditions. This DSC of the solid showed a desolvation event at 105°C and a TGA mass loss of 1.1%.

[0491] A 100 mg scale-up was performed using ethyl acetate at a 1:2 molar ratio and a solid with the same XRPD pattern as the 25 mg preliminary screening under these conditions was obtained. DSC of the solid showed a single melting event at 150.8°C. TGA showed no mass loss. This indicated a non-solvated anhydrous crystal.

[0492] XRPD pictures Figure 8 and the peak list is shown in the following table:

[0493] XRPD of heptane-2-sulfonate crystals (Cu anode, Ni filter)

[0494] # horn d value Relative Strength 1 3.491 25.29231 100.00％ 2 6.836 12.92058 5.90％ 3 7.435 11.88044 5.10％ 4 10.282 8.59661 2.50％ 5 13.686 6.46513 3.40％ 6 14.175 6.24316 11.20％ 7 14.883 5.94771 3.60％ 8 15.750 5.62216 7.30％ 9 16.320 5.42709 6.00％ 10 16.737 5.29276 7.80％ 11 17.121 5.17487 9.00％ 12 17.617 5.03024 14.20％ 13 18.042 4.91282 12.60％ 14 18.345 4.83224 10.20％ 15 19.220 4.61410 5.80％ 16 19.904 4.45723 26.70％ 17 20.184 4.39595 32.60％ 18 20.498 4.32935 7.80％ 19 21.602 4.11051 2.30％ 20 22.401 3.96562 9.70％ 21 23.223 3.82713 6.80％ 22 24.178 3.67808 4.80％ 23 24.844 3.58092 16.70％ 24 26.327 3.38255 2.30％ 25 27.563 3.23360 2.70％ 26 30.590 2.92015 2.50％ 27 31.762 2.81500 1.60％ 28 32.886 2.72129 2.20％ 29 33.600 2.66507 2.20％

[0495] Proton NMR was performed and showed the estimated molar ratio of lumepirone and acid to be 1:1.8, thus confirming that this was a 1:2 salt.

[0496] Example 10: Water solubility determination

[0497] The water solubility of the successfully reproduced salt is measured by the saturated solution of shaking in water.The solubility under pH 7.4 is measured by the saturated solution of shaking in the phosphate buffer system.The samples are prepared by adding a known amount of water (100-200 μL) and then slurrying with solid for 24 hours.All samples are then filtered using a syringe filter to remove undissolved solids, and the filtrate is then diluted with methanol / acetonitrile (1:1 v / v).The samples are subjected to LC analysis, and the solubility is determined using a calibration line.The results are shown in the following table, in mg / mL:

[0498] Salt water solubility pH 7.4 Solubility Example 2 0.006 0.24 Example 3 0.77 0.07 Example 4 1.62 0.17 Example 5, Polymorph 1 4.75 2.03 Example 5, Polymorph 2 3.73 1.64 Example 5, Polymorph 3 3.35 0.52 Example 6 11.84 5.18 Example 7, Polymorph 1 29.66 13.90 Example 7, Polymorph 2 14.15 11.06 Example 7, Polymorph 3 15.84 2.14 Example 8 18.77 7.76 Example 9 4.30 1.14 Lumiperone monotosylate 1.97 0.72

[0499] Several of the salts prepared according to the present disclosure are shown to have surprisingly low water solubility. Therefore, these low solubility salts are particularly suitable for formulation into aqueous long-acting injectable compositions. Subcutaneous or intramuscular injection of such compositions can provide a large insoluble reservoir of the active agent lumepirone, which will slowly dissolve to release lumepirone free base based on the dissolution kinetics of the salt. The following table provides suitable formulations for subcutaneous or intramuscular injection.

[0500] Components weight% Lumaperone salt (e.g., the salt of Example 2-9) 1-50％ Thickeners (e.g. sodium carboxymethyl cellulose) 0-20％ Bulking agents (such as mannitol) 0-20％ Buffer (eg sodium phosphate) 0.01-5％ pH-adjusting agent (e.g. NaOH) <1％ water Appropriate amount (e.g. 20-90%)

[0501] One or more formulations of the above table are prepared by combining a lumepirone salt, a thickener (e.g., sodium carboxymethylcellulose) and a filler (e.g., mannitol) in water (e.g., sterile water for injection). The solid materials may be ground or milled individually or together to an appropriate particle size. The solid is suspended in water and the pH is adjusted as desired, e.g., to 6.5 to 7.5, e.g., 7 to 7.5, or 7.3 to 7.4. Further studies are conducted to confirm the pharmacokinetics of plasma and CSF of such formulations.

Claims

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

4.

2. Lumiperone in salt form, the salt being 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; solid crystalline benzenesulfonic acid addition salt, characterized in that A DSC thermogram without an endothermic event at 172-176°C; and an alkyl sulfonic acid addition salt (eg, pentane-1-sulfonate or heptane-1-sulfonate).

3. Lumiperone in the form of an acid addition salt with benzenesulfonic acid substituted by 1, 2 or 3 groups R, wherein each R is independently C 1-12 alkyl, provided that the acid is not p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid, 4-propylbenzenesulfonic acid, 4-tert-butylbenzenesulfonic acid or 4-octylbenzenesulfonic acid.

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

5. The salt of any one of claims 1-4, further defined in any of the embodiments of Salt 1, etc., Salt 2, etc., Salt 3, etc., Salt 4, etc., Salt 5, etc., Salt 6, etc., Salt 7, etc., or Salt 8, etc. as defined in the present disclosure.

6. A process for preparing a salt according to any preceding claim, comprising the steps of: (a) reacting lumepirone free base with a corresponding acid and 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), for example, wherein the molar ratio of the acid to lumepirone is 1:1-1:2, or about 1:1, or about 1:2; optionally at a temperature of 0°C to 100°C; and (b) optionally subjecting the resulting mixture to a thermal cycling protocol (e.g., heating to above 50°C, then cooling to 0°C, and optionally repeating the heating and cooling in a cycle) or cooling the mixture from its reaction temperature to 5°C or below; and (c) optionally diluting the resulting mixture with an anti-solvent, for example when the organic solvent is methanol, ethanol, 1-butanol, acetonitrile or a solvent / water mixture and the anti-solvent is water, or wherein the organic solvent is toluene, ethyl acetate, CPME, MTBE, MEK or 1-butanol and 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., heating to above 50°C, then cooling to 0°C and optionally repeating the heating and cooling in a cycle) or cooling the mixture from its reaction temperature to 5°C or below; and (e) recovering the salt thus formed, for example recovering the salt of any one of claims 1 to 5.

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

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

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

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

11. The composition of claim 9 or 10, wherein the composition comprises water (eg, sterile water for injection) and one or more excipients (eg, water-soluble excipients), such as thickeners, buffers, osmotic agents, surfactants and antioxidants.

12. The composition of claim 11, wherein the one or more water-soluble excipients comprise: a thickener selected from carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), microcrystalline cellulose, non-crystalline cellulose, polyacrylate polymers, polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol; and / or a surfactant selected from sorbitan esters (e.g., sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan ole ... Sorbitol stearate), polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), polyoxyethylene alkyl ethers, fatty acid esters (e.g., glyceryl monostearate, glyceryl monolaurate), poloxamers, and fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, cetearyl alcohol); and a filler selected from mannitol, sucrose, fructose, maltose, xylitol, glucose, starch, sorbitol, magnesium aluminum silicate, and silicon dioxide (e.g., colloidal silicon dioxide).

13. The composition of any one of claims 11-13, wherein the composition comprises an acid addition salt of lumepirone (e.g. lumepirone 4-octylbenzenesulfonate or lumepirone 4-tert-butylbenzenesulfonate), water (e.g. sterile water for injection), a thickener (e.g. sodium carboxymethylcellulose), a filler (e.g. mannitol), a nonionic surfactant (e.g. polysorbate 80) and optionally one or more pH-adjusting agents or buffers (e.g. NaOH or HCl and / or sodium phosphate or potassium phosphate).

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

15. The composition of any one of claims 9 to 15, wherein the composition has the following components: 。 16. The composition of any one of claims 9-15, 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 lumepirone and one or more diluents, carriers or excipients (e.g., water-soluble excipients), and wherein prior to administration, the solid is reconstituted with sterile water for injection into a long-acting injectable pharmaceutical composition.

18. A method for preventing or treating a human suffering from a disease or abnormal condition involving 5-HT 2A A method of treating a human that activates or is mediated by a receptor, a serotonin transporter (SERT), and / or a dopamine D1 / D2 receptor signaling pathway, the method comprising administering to the 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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