Xanomeline quercetin complexes and trospium salts

Abstract

Complexes (e.g., co-crystals) of xanomeline-quercetin, which may be in specific crystalline form, and trospium pamoate salt, which may be in specific crystalline form, as well as pharmaceutical compositions comprising such and methods for their uses, singly or in combination.

Description

XANOMELINE QUERCETIN COMPLEXES AND TROSPIUM SALTS

[0001] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 656,787, filed on June 6, 2024, the entire contents of which is incorporated by reference herein.

[0002] The present disclosure generally relates to complexes of xanomeline and quercetin (for example, co-crystals of xanomeline and quercetin), pamoate salts of trospium, and related pharmaceutical compositions and methods of treatment.BACKGROUND

[0003] Solids exist in either amorphous or crystalline forms. In the case of crystalline forms, molecules are positioned in three-dimensional lattice sites. When a compound recrystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, and the different crystalline forms are sometimes referred to as “polymorphs.” The different crystalline forms of a given substance may differ from each other with respect to one or more physicochemical properties (e.g., dissolution rate, solubility), biological properties (e.g., bioavailability, pharmacokinetics), and / or material properties (e.g., mechanical strength, compaction behavior, flow properties, particle size, shape, melting point, degree of hydration or solvation, caking tendency, compatibility with excipients). The variation in properties among different crystalline forms usually means that one crystalline form may be more useful than other forms.

[0004] Xanomeline is a muscarinic agonist and trospium is a muscarinic antagonist. Together, these active compounds have been administered to preferentially stimulate muscarinic receptors in the CNS and unlock the therapeutic potential of xanomeline while ameliorating side effects seen in earlier studies. Research indicates that activity at Ml and M4 receptors indirectly affects dopamine neurotransmission in brain regions involved in mediating symptoms of serious mental illness, such as psychosis in Alzheimer’s disease, as well as the positive, negative, and cognitive symptoms of schizophrenia. This dual mechanism does not rely on the dopaminergic or serotonergic pathway to treat symptoms of serious mental illness. This approach has the potential to provide a differentiated therapy, and to beneficially impact the lives of millions of people with serious mental illness.

[0005] There is a need for improved forms of both compounds and methods of preparing such, particularly regarding controlling or modifying solubility, bioavailability, ease of synthesis,ability to be readily formulated, and / or physical stability.SUMMARY

[0006] It has been shown herein that xanomeline forms complexes with quercetin (e.g. as cocrystals or as salts), and the complexes of xanomeline and quercetin exist in different crystalline forms such as Forms I, IA, II, III, IV, V and VI. A number of the crystalline forms of the complexes of xanomeline and quercetin, such as Form I, showed significantly lower solubility in water, increased thermal and / or solvent stability, and suitable particle size, which are favourable properties that can be advantageous in pharmaceutical formulations such as long- acting or long release formulations. Further, it has been shown herein that salts comprising trospium pamoate, such as trospium hemipamoate (z.<?. trospium:pamoate 2:1) and 1 :1 trospium pamoate (such as trospium alkali pamoate) exist in different crystalline forms such as Forms A, B, C, D, E, F, and M. The salt of trospium and pamoate showed significantly lower solubility in water compared to the commonly used trospium chloride. In particular, Form C showed significantly lower (about 100,000-fold lower) solubility in water than trospium chloride. Form C was also the most stable crystalline form among the studied crystalline forms of trospium and pamoate. The lower solubility can be useful in pharmaceutical formulation such as long acting or long release formulations.

[0007] Accordingly, the present disclosure provides complexes of xanomeline and quercetin. For example, the xanomeline quercetin complex can be cocrystals of xanomeline and quercetin. In other examples, the xanomeline quercetin complex can be salts of xanomeline and quercetin. In some examples, provided herein are cocrystals of xanomeline and quercetin. In other examples, provided herein are salts of xanomeline and quercetin. In some embodiments, the xanomeline quercetin complex is in a crystalline form. For example, the crystalline form can be Form I, Form IA, Form II, Form III, Form IV, and Form V, or Form VI as described herein.

[0008] In some embodiments, the complex of xanomeline and quercetin is in crystalline Form I. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.4+0.2, 8.9+0.2, 13.3+0.2, 18.2+0.2, 25.3+0.2, and 26.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 1; a thermogravimetric analysis showing a mass loss of about 1.4% at between about 50 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profilesubstantially as shown in FIG. 3; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 117 °C and about 143 °C; a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeak between about 129 °C and about 136 °C; and a differential scanning calorimetry trace substantially as shown in FIG 2.

[0009] In some embodiments, the complex is a hydrate comprising about 0.5 to about 1 mole of water per mole of xanomeline-quercetin complex.

[0010] In some embodiments, the complex of xanomeline and quercetin is in crystalline Form IA. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.5+0.2, 9.0+0.2, 12.7+0.2, 13.6+0.2, 25.1+0.2, and 26.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 4; a thermogravimetric analysis showing a mass loss of about 1.8% at between about 40 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 5; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 113 and about 142 °C; and a differential scanning calorimetry trace substantially as shown in FIG 6.

[0011] In some embodiments, the complex is a hydrate comprising about 0.5 to about 0.6 moles of water per mole of xanomeline-quercetin complex.

[0012] In some embodiments, the complex of xanomeline and quercetin is in crystalline Form II. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 7.4+0.2, 8.6+0.2, 12.6+0.2, 19.1+0.2, 23.6+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 7; a thermogravimetric analysis showing a mass loss of about 0.35% at between about 40 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 8; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 160 °C; anda differential scanning calorimetry trace substantially as shown in FIG 9.

[0013] In some embodiments, the complex is anhydrous.

[0014] In some embodiments, the complex of xanomeline and quercetin is in crystalline FormIII. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 8.1+0.2, 24.2+0.2, 25.0+0.2, 25.3+0.2, 26.1+0.2, and 27.1+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 10; a thermogravimetric analysis showing a mass loss of about 0.3% at between about 25 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 11; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 161 and about 168 °C; a differential scanning calorimetry profile having a melt at a Tpeak between about 162 °C and about 166 °C; and a differential scanning calorimetry trace substantially as shown in FIG 12.

[0015] In some embodiments, the complex is anhydrous.

[0016] In some embodiments, the complex of xanomeline and quercetin is in crystalline FormIV. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.8+0.2, 13.0+0.2, 19.5+0.2, 23.7+0.2, 24.5+0.2, and 25.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 13; a thermogravimetric analysis showing a mass loss of about 2.2% at between about 40 °C and about 140 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 14; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 161 °C; a differential scanning calorimetry profile showing a phase transition to Form II followed by a melt of the Form II, optionally comprising endotherm / exotherm events between about 98 °C and 113 °C; anda differential scanning calorimetry trace substantially as shown in FIG 15.

[0017] In some embodiments, the complex is a hydrate comprising about 0.7 moles of water per mole of xanomeline-quercetin complex.

[0018] In some embodiments, the complex of xanomeline and quercetin is in crystalline Form V.In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 6. 1+0.2, 7.9+0.2, 14.2+0.2, 20.2+0.2, 24.8+0.2, and 25.8+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 16; a thermogravimetric analysis showing a mass loss of about 7.3% at between about 80 °C and about 160 °C due to a loss of tert-butyl methyl ether as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 17; a differential scanning calorimetry profile having endotherm / exotherm events between about 125 and 139 °C, about 139 °C to 141 °C, and between about 149 °C and 156 °C; and a differential scanning calorimetry trace substantially as shown in FIG 18.

[0019] In some embodiments, the complex is a tert-butyl methyl ether (TBME) solvate comprising about 0.5 moles of TBME per mole of xanomeline-quercetin complex.

[0020] In some embodiments, the complex of xanomeline and quercetin is in crystalline Form VI. In some embodiments, the complex is characterised by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.6+0.2, 9.2+0.2, 13.0+0.2, and 13.9+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 38; a thermogravimetric analysis showing a mass loss of about 1.9% at between about 120°C and about 140 °C due to a loss of tert-butyl methyl ether as indicated by mass spectroscopy; a differential scanning calorimetry profile having endotherm / exotherm events at between about 120 and 140 °C; a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeak between about 122 °C and about 126 °C; and a differential scanning calorimetry trace substantially as shown in FIG 40.

[0021] In some embodiments, the complex is a hydrate comprising about 0.5 to about 1 mole of water per mole of xanomeline-quercetin complex.

[0022] In some embodiments, the stoichiometry of xanomeline to quercetin is about 1 :1 as demonstrated by proton nuclear magnetic resonance spectroscopy.

[0023] In some embodiments, the complex of xanomeline and quercetin as disclosed herein is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours. In some embodiments, the complex is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks. In some embodiments, the complex is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks. In some embodiments, the complex has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%, optionally by high-performance liquid chromatography. In some embodiments, the complex has total chemical impurities of not more than about 0.5%, optionally as determined by high-performance liquid chromatography.

[0024] In another aspect, the present disclosure provides salt that comprises trospium pamoate and crystalline forms thereof. For example, trospium pamoate can be trospium hemipamoate (trospiurmpamoate at 2: 1) or 1 :1 trospium pamoate. In some embodiments, the trospium pamoate is in a crystalline form. For example, the crystalline form of trospium pamoate can be chosen from Form A, Form B, Form C, Form D, Form E, Form F, and Form M as described herein.

[0025] In some embodiments, the trospium pamoate is in crystalline Form A. In some embodiments, the salt of trospium and pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 10.39+0.2, 12.31+0.2, 13.11+0.2, 13.61+0.2, and 16.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 32; a thermogravimetric analysis showing a mass loss of between about 1.8% at between about 25 °C and about 200 °C due to a loss of ethanol and water as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 19; a differential scanning calorimetry profile having endotherm / exotherm events at between about 31 °C and about 82 °C, between about 301 °C and about 312 °C, and between about 312 °C and about 338 °C: and a differential scanning calorimetry trace substantially as shown in FIG. 20.

[0026] In some embodiments, the trospium pamoate of crystalline Form Ais anhydrous and wherein the stoichiometry of trospium to pamoate is 1: 1 as demonstrated by proton nuclearmagnetic resonance spectroscopy.

[0027] In some embodiments, the trospium pamoate is in crystalline Form B. In some embodiments, the trospium pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 5.4+0.2, 9.9+0.2, 13.2+0.2, 14.8+0.2, 15.4+0.2, 18.9+0.2, 20.3+0.2, 20.4+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 33; a thermogravimetric analysis showing a mass loss of about 4.8% at between about 25 °C and about 200 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 21; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 60 °C and about 85 °C, between about 93 °C and about 113 °C, between about 226 °C and about 247 °C, between about 300 °C and about 308 °C, and between about 329 °C and about 337 °C; and a differential scanning calorimetry trace substantially as shown in FIG 22.

[0028] In some embodiments, the trospium pamoate of crystalline Form Bis a hydrate comprising about 2 to 3 moles of water per 1 mole of trospium and 1 mole of pamoate.

[0029] In some embodiments, the trospium pamoate is in crystalline Form C. In some embodiments, the trospium pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 6.5+0.2, 9.8+0.2, 10.1+0.2, 10.6+0.2, 14.2+0.2, 18.2+0.2, 19.8+0.2, 20.8+0.2, and 21.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 34; a thermogravimetric analysis showing a mass loss of about 7.4% at between about 40 °C and about 200 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 24; a differential scanning calorimetry profile having an endothermic event with an onset at about 130 °C and peak about 134 °C; and a differential scanning calorimetry trace substantially as shown in FIG 25.

[0030] In some embodiments, the trospium pamoate of crystalline Form C is a hemipamoate hydrate comprising about 1 mole of pamoate and up to about 7 moles of water per 2 moles oftrospium.

[0031] In some embodiments, the trospium pamoate is in crystalline Form D. In some embodiments, the salt of trospium and pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 8.3+0.2, 16.8+0.2, 20.0+0.2, and 20.7+0.2 with radiation Cu Kot; an X-ray powder diffraction pattern substantially as shown in FIG. 35; a thermogravimetric analysis showing a mass loss of about 8% at between about 25 °C and about 220 °C due to a loss of tetrahydrofuran as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 26; a differential scanning calorimetry profile having endotherm / exotherm events at between about 115 °C and about 141 °C, and between about 258 °C and about 273 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 27.

[0032] In some embodiments, the trospium pamoate of crystalline Form Dis a tetrahydrofuran solvate comprising about 1 mole of tetrahydrofuran per 1 mole of trospium and 1 mole of pamoate.

[0033] In some embodiments, the trospium pamoate is in crystalline Form E. In some embodiments, the salt of trospium and pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 4.6+0.2, 9.3+0.2, and 19.5+0.2 with radiation Cu Kot; an X-ray powder diffraction pattern substantially as shown in FIG. 36; a thermogravimetric analysis showing a mass loss of about 12% at between about 25 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG 28; a differential scanning calorimetry profile having endotherm / exotherm events between about 40 °C and about 75 °C, between about 75 °C and about 125 °C, between about 195 °C and about 250 °C, between about 280 °C and about 318 °C, and between about 319 °C and about 360 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 29.

[0034] In some embodiments, the trospium pamoate of Crystalline Form Dis a hexahydratecomprising about 6 moles of water per 1 mole of trospium and 1 mole of pamoate.

[0035] In some embodiments, the trospium pamoate is in crystalline Form F. In some embodiments, the trospium pamoate is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 7.8+0.2, 10.8+0.2, 14.0+0.2, 15.6+0.2, 17.5+0.2, 18.4+0.2, and 20.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 37; a thermogravimetric analysis showing a mass loss of about 2.25% at between about 25 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 30; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 110 °C and about 150 °C, between about 290 °C and about 320 °C, and between about 321 °C and about 360 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 31.

[0036] In some embodiments, the trospium pamoate of crystalline Form Fis a monohydrate comprising about 1 moles of water per 1 mole of trospium and 1 mole of pamoate.

[0037] In some embodiments, the trospium pamoate is in crystalline Form M. In some embodiments, the salt of trospium and pamoate characterised by an XRPD pattern comprising three or more peaks at 5.3+0.2020, 7.O+O.2020, 8.6+0.2020, 10.7+0.2° 20, 19.0+0.2° 20, or 21.3+0.2° 20.

[0038] In some embodiments, the trospium pamoate as disclosed herein is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours. In some embodiments, the trospium pamoate is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks. In some embodiments, the trospium pamoate is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks.

[0039] In some embodiments, the trospium pamoate has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%, optionally determined by high-performance liquid chromatography. In some embodiments, the trospium pamoate has total chemical impurities of not more than about 0.5%, as determined by high-performance liquid chromatography.

[0040] In another aspect, the present disclosure provides a composition comprising a complex of xanomeline and quercetin as disclosed herein and a pharmaceutically acceptable excipient. Insome embodiments, the composition further comprises a trospium salt such as a salt that comprises trospium pamoate as disclosed herein. In some examples, the composition may comprise a complex of xanomeline and quercetin in crystalline Form I and a trospium pamoate in crystalline Form C.

[0041] In another aspect, the present disclosure provides a pharmaceutical composition comprising trospium pamoate as disclosed herein, and a pharmaceutically acceptable excipient.

[0042] The disclosure provides a method of treating or reducing the symptoms of a disease or disorder ameliorated by activating muscarinic receptors in a subject in need thereof. This method comprises administering to a patient in need thereof, a therapeutically effective amount of a complex of xanomeline and quercetin as disclosed herein and / or a trospium pamoate as also disclosed herein, or one or more pharmaceutical compositions, which collectively comprise the complex of xanomeline and quercetin and the trospium pamoate. In some examples, the method comprises administering to the patient a complex of xanomeline and quercetin in crystalline Form I and a trospium pamoate in crystalline Form C, or a pharmaceutical composition comprising both.

[0043] Also within the scope of the present disclosure are any of the complexes of xanomeline and quercetin (e.g., the complex of xanomeline and quercetin in crystalline Form I) and salts of trospium and pamoate (e.g., the salt of trospium and pamoate in crystalline Form C) as disclosed herein, as well as a pharmaceutical composition comprising such, for use in treating a target disease or disorder as also disclosed herein, and uses of the complexes of xanomeline and quercetin (e.g., the complex of xanomeline and quercetin in crystalline Form I) and salts trospium and pamoate (e.g., the trospium pamoate in crystalline Form C) for manufacturing a medicament for treatment of the target disease or disorder.

[0044] In some embodiments, the target disease is a disease treatable or that can be ameliorated by activating a muscarinic receptor. In some embodiments, the disease or disorder is a CNS disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is selected from schizophrenia, autism, Alzheimer’s disease, bipolar, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction or addictive disorder, schizoaffective disorder, tauopathy, and synucleinopathy. For example, Alzheimer’s disease can be Alzheimer’s disease with agitation and / or Alzheimer’s disease with cognitive impairment. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is Alzheimer’s disease. In some embodiments, the disease or disorder is bipolardisorder.

[0045] Also provided herein are methods of treating schizophrenia in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of treating Alzheimer’s disease in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of alleviating agitation, optionally agitation associated with Alzheimer’s disease, in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of treating a patient with Alzheimer’s disease comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C, wherein the method alleviates cognitive impairment and / or global functioning impairment. Also provided herein are methods of alleviating cognitive impairment or global functioning impairment in a patient with Alzheimer’s disease comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of alleviating mania, optionally mania associated with bipolar disorder, in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of treating bipolar disorder in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C.

[0046] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, and also from the appended claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to the drawing in combination with the detailed description of specific embodiments presented herein.

[0048] FIG. 1 shows two X-ray powder diffraction (XRPD) patterns of xanomeline-quercetin (XQ) crystalline Form I.

[0049] FIG. 2 shows a differential scanning calorimetry (DSC) profile of XQ crystalline Form I.

[0050] FIG. 3 shows a thermogravimetric analysis coupled with different scanning calorimetry (TGA / DSC) of XQ crystalline Form I.

[0051] FIG. 4 shows an overlay of XRPD patterns of XQ crystalline Form I (middle) between a Form I reference pattern (top) and Form IA (bottom).

[0052] FIG. 5 shows a TGA / DSC of XQ crystalline Form IA.

[0053] FIG. 6 shows a DSC profile of XQ crystalline Form IA.

[0054] FIG. 7 shows an XRPD of XQ crystalline Form II (top) converted at about 125 °C from Form IV (bottom).

[0055] FIG. 8 shows a TGA / DSC of XQ crystalline Form II.

[0056] FIG. 9 shows a DSC profile of XQ crystalline Form II.

[0057] FIG. 10 shows two XRPD patterns of XQ crystalline Form III.

[0058] FIG. 11 shows a TGA / DSC of XQ crystalline Form III.

[0059] FIG. 12 shows a DSC profile of XQ crystalline Form III.

[0060] FIG. 13 shows an XRPD pattern of XQ crystalline Form IV.

[0061] FIG. 14 shows a TGA / DSC of XQ crystalline Form IV.

[0062] FIG. 15 shows a DSC profile of XQ crystalline Form IV.

[0063] FIG. 16 shows an XRPD pattern of XQ crystalline Form V.

[0064] FIG. 17 shows a TGA / DSC of XQ crystalline Form V.

[0065] FIG. 18 shows a DSC profile of XQ crystalline Form V.

[0066] FIG. 19 shows a TGMS pattern of trospium pamoate crystalline Form A.

[0067] FIG. 20 shows a DSC profile of trospium pamoate crystalline Form A and NaCl.

[0068] FIG. 21 shows a TGMS of trospium pamoate crystalline Form B and NaCl.

[0069] FIG. 22 shows a DSC profile of trospium pamoate crystalline Form B and NaCl.

[0070] FIG. 23 shows a comparison of the simulated powder pattern from the single crystal data of Form C with a FWHM = 0.1° 29 (bottom) and the experimentally collected XPRD pattern (top).

[0071] FIG. 24 shows a TGMS of trospium pamoate crystalline Form C.

[0072] FIG. 25 shows a DSC profile of trospium pamoate crystalline Form C.

[0073] FIG. 26 shows a TGMS of trospium pamoate crystalline Form D.

[0074] FIG. 27 shows a DSC profile of trospium pamoate crystalline Form D.

[0075] FIG. 28 shows a TGA of trospium pamoate crystalline Form E.

[0076] FIG. 29 shows a DSC profile of trospium pamoate crystalline Form E.

[0077] FIG. 30 shows a TGA of trospium pamoate crystalline Form F.

[0078] FIG. 31 shows a DSC profile of trospium pamoate crystalline Form F.

[0079] FIG. 32 shows an XRPD diffractogram for trospium pamoate crystalline Form A.

[0080] FIG. 33 shows an XRPD diffractogram for trospium pamoate crystalline Form B.

[0081] FIG. 34 shows an XRPD diffractogram for trospium pamoate crystalline Form C.

[0082] FIG. 35 shows an XRPD diffractogram for trospium pamoate crystalline Form D.

[0083] FIG. 36 shows an XRPD diffractogram for trospium pamoate crystalline Form E.

[0084] FIG. 37 shows an XRPD diffractogram for trospium pamoate crystalline Form F.

[0085] FIG. 38 shows an XRPD pattern of XQ crystalline Form VI.

[0086] FIG. 39 shows an HT-XRPD of trospium pamoate Form C (Tpam3) solids after equilibration in water and phosphate buffer.

[0087] FIG. 40 shows a DSC profile of XQ crystalline Form VI.

[0088] FIG. 41 A shows the mean (±SD) plasma concentration vs time profile of xanomeline for Example 12 Leg 1 Group 1, Leg 1 Group 2, and Leg 2 Group 2 for 672 hours (28 days) after dosing.

[0089] FIG. 41B shows the same data as FIG. 41 A but for 120 hours (5 days) after dosing.

[0090] FIG. 42 shows the mean (±SD) plasma concentration vs time profile of trospium after IM and IV dosing of trospium chloride in New Zealand white rabbits as described in Example 13.

[0091] FIG. 43 shows the mean (±SD) plasma concentration vs time profile of xanomeline following a single intramuscular dose of 12 mg / kg xanomeline quercetin in New Zealand white rabbits as described in Example 14.

[0092] FIG. 44 shows the mean (±SD) plasma concentration vs time profile of trospium following a single intramuscular dose of 12 mg / kg trospium pamoate in New Zealand white rabbits as described in Example 14.

[0093] FIG. 45 shows mean (±SD) xanomeline plasma concentration vs time profiles for Example 15 Groups 1-4.

[0094] FIG. 46 shows mean (±SD) trospium plasma concentration vs time profiles for Example15 Groups 1-4.

[0095] FIG. 47A shows mean (±SD) xanomeline plasma concentrations for Example 16 Groups 2-5 for 672 hours after dosing.

[0096] FIG. 47B shows the same data as FIG. 47A for 50 hours after dosing.

[0097] FIG. 48 shows mean (+SD) trospium plasma concentrations for Example 16 Groups 2-5.

[0098] FIG. 49 shows an XRPD diffractogram for trospium pamoate crystalline Form M.DETAILED DESCRIPTIONI. Complexes of Xanomeline and Quercetin

[0099] The present disclosure includes complexes of xanomeline and quercetin. For example, the complexes of xanomeline and quercetin can be cocrystals of xanomeline and quercetin. For example, the complexes of xanomeline and quercetin can be salts of xanomeline and quercetin.

[0100] In some embodiments, the complexes of xanomeline and quercetin are cocrystals of xanomeline and quercetin.

[0101] The complex of xanomeline and quercetin can adopt a variety of crystalline forms, including but not limited to the crystal forms described herein, which can be characterized by features such as XRPD, DSC, TGA, and vapour sorption. Specific examples of crystalline forms of the complex of xanomeline and quercetin include Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI. The complex of xanomeline and quercetin can comprise a mixture of two or more crystalline forms. Alternatively, the complex can comprise substantially one specific crystalline form as described herein. In some instances, the xanomeline quercetin complex can be substantially free of one or more specific crystalline forms.

[0102] In certain embodiments, the complex of xanomeline and quercetin is a crystal form comprising Form I, Form IA, Form II, Form III, Form IV, Form V, or Form VI.

[0103] In some embodiments, the complex of xanomeline and quercetin is crystalline Form I. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X-ray powder diffraction pattern comprising three or more peaks at 4.4+O.2020, 8.9+0.2° 20, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, or 26.3+0.2° 20.

[0104] In some embodiments, the complex of xanomeline and quercetin is Form IA. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 4.5+0.2° 20, 9.0+0.2° 20, 12.7+0.2° 20, 13.6+0.2° 20, 25.1+0.2° 20, or 26.4+0.2° 20.

[0105] In some embodiments, the complex of xanomeline and quercetin is Form II. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 7.4+0.2° 20, 8.6+0.2° 20, 12.6+0.2° 20, 19.1+0.2° 20, 23.6+0.2° 20, or 25.3+0.2° 20.

[0106] In some embodiments, the complex of xanomeline and quercetin is Form III. In someembodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 8.1+0.2° 20, 24.2+0.2° 20, 25.0+0.2° 20, 25.3+0.2° 20, 26.1+0.2° 20, or 27.1+0.2° 20.

[0107] In some embodiments, the complex of xanomeline and quercetin is Form IV. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 4.8+0.2° 20, 13.0+0.2° 20, 19.5+0.2° 20, 23.7+0.2° 20, 24.5+0.2° 20, or 25.5+0.2° 20.

[0108] In some embodiments, the complex of xanomeline and quercetin is Form V. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 6.1+0.2° 20, 7.9+0.2° 20, 14.2+0.2° 20, 20.2+0.2° 20, 24.8+0.2° 20, or 25.8+0.2° 20.

[0109] In some embodiments, the complex of xanomeline and quercetin is Form VI. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X- ray powder diffraction pattern comprising three or more peaks at 4.6+0.2° 20, 9.2+0.2° 20, 13.0+0.2° 20, or 13.9+0.2° 20.

[0110] In certain embodiments, the complex of xanomeline and quercetin is prepared from a low-crystallinity solid complex from evaporative co-crystallization of xanomeline and quercetin followed by freeze-drying.

[0111] In certain embodiments, the complex of xanomeline and quercetin has a stoichiometry of xanomeline to quercetin of about 1 : 1 as demonstrated by proton nuclear magnetic resonance spectroscopy. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently has a stoichiometry of xanomeline to quercetin of about 1 :1.

[0112] In certain embodiments, the complex of xanomeline and quercetin is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently has is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours.

[0113] In certain embodiments, the complex of xanomeline and quercetin is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks.

[0114] In certain embodiments, the complex of xanomeline and quercetin is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks.

[0115] In certain embodiments, the complex of xanomeline and quercetin has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by high-performance liquid chromatography. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by high-performance liquid chromatography.In certain embodiments, the complex of xanomeline and quercetin has total chemical impurities of not more than about 0.5% by high-performance liquid chromatography. In some embodiments, the complex of xanomeline and quercetin of Form I, Form IA, Form II, Form III, Form IV, Form V, and Form VI each independently has total chemical impurities of not more than about 0.5% by high-performance liquid chromatography.A. Xanomeline Quercetin Form I

[0116] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form I as described herein. In some exemplary embodiments of the crystalline form I, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form I of the complex of xanomeline and quercetin are shown in Example 2.

[0117] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form I characterised by an X-ray powder diffraction pattern comprising three or more, four or more, or five or more peaks at 4.4+O.2026, 8.9+0.2° 20, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, or 26.3+0.2° 20. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X-ray powder diffraction pattern comprising peaks at 4.4+O.2026, 8.9+0.2° 20, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, or 26.3+0.2° 20. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X-ray powder diffraction pattern comprising three or more peaks at 4.4+O.2020, 8.9+O.2020, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, or 26.3+0.2° 20. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X-ray powder diffraction pattern comprisingfour or more peaks at 4.4+O.2020, 8.9+O.2020, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, or 26.3+0.2° 20. In some embodiments, the complex of xanomeline and quercetin is a crystal form characterised by an X-ray powder diffraction pattern comprising five or more peaks at 4.4+O.2020, 8.9+O.2020, 13.3+0.2° 20, 18.2+0.2° 20, 25.3+0.2° 20, and 26.3+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 3. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 1.

[0118] In certain embodiments, the complex of xanomeline and quercetin is a cocrystal and has a crystalline form of Form I that is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.4+0.2, 8.9+0.2, 13.3+0.2, 18.2+0.2, 25.3+0.2, and 26.3+0.2 with radiation Cu Ka; an X- ray powder diffraction pattern substantially as shown in FIG. 1 ; a thermogravimetric analysis showing a mass loss of about 1.4% between about 50 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 3; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 117 °C and about 143 °C; a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeaj between about 129 °C and about 136 °C; and a differential scanning calorimetry trace substantially as shown in FIG 2.

[0119] In some embodiments, the complex of xanomeline and quercetin of Form I is characterised by a thermogravimetric analysis showing a mass loss of about 1.4% between about 50 °C and about 150 °C due to a water loss. In some embodiments, the complex of xanomeline and quercetin of Form I is characterised by a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 3. In some embodiments, the complex of xanomeline and quercetin of Form I is characterised by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 117 °C and about 143 °C. In some embodiments, the complex of xanomeline and quercetin of Form I is characterised by a differential scanning calorimetry (DSC) profile having a melt simultaneous with water release at a Tpeak between about 129 °C and about 136 °C. In some embodiments, the DSC trace is substantially as shown in FIG. 2.

[0120] In certain embodiments, the complex of xanomeline and quercetin of Form I is prepared by a process comprising the steps of concentrating by evaporation at room temperature a solution of xanomeline and quercetin in acetone / water (95 / 5; v / v), and isolating cry stals from a slurry in the solution.

[0121] In certain embodiments, the complex of xanomeline and quercetin of Form I is a hydrate comprising about 0.5 to about 1 mole of water per mole of xanomeline-quercetin complex.B. Xanomeline Quercetin Form IA

[0122] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form IA as described herein. In some exemplary embodiments of the crystalline Form IA, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form IA of the complex of xanomeline and quercetin are shown in Example 3.

[0123] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form IA characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 4.5+0.2020, 9.O+O.2020, 12.7+0.2° 20, 13.6+0.2° 20, 25.1+0.2° 20, or 26.4+0.2° 20. In some embodiments, the XRPD comprises four or more peaks at 4.5+O.2020, 9.O+O.2020, 12.7+0.2° 20, 13.6+0.2° 20, 25.1+0.2° 20, or 26.4+0.2° 20. In some embodiments, the XRPD comprises five or more peaks at 4.5+0.2° 20, 9.0+0.2° 20, 12.7+0.2° 20, 13.6+0.2° 20, 25.1+0.2° 20, or 26.4+0.2° 20. In some embodiments, the XRPD comprises peaks at 4.5+0.2° 20, 9.O+O.2020, 12.7+0.2° 20, 13.6+0.2° 20, 25.1+0.2° 20, and 26.4+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 4. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 4.

[0124] In certain embodiments, the complex of xanomeline and quercetin of Form IA is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.5+0.2, 9.0+0.2, 12.7+0.2, 13.6+0.2, 25.1+0.2, and 26.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 4; a thermogravimetric analysis showing a mass loss of about 1.8% between about 40 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 5; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 113 and about 142 °C; and a differential scanning calorimetry trace substantially as shown in FIG 6.

[0125] In some embodiments, the complex of xanomeline and quercetin of Form IA is characterized by a thermogravimetric analysis showing a mass loss of about 1.8% between about 40 °C and about 150 °C due to a water loss. In some embodiments, the complex of xanomeline and quercetin of Form IA is characterized by a thermogravimetric analysis coupled with adifferential scanning calorimetry profile substantially as shown in FIG. 5. In some embodiments, the complex of xanomeline and quercetin of Form IA is characterized by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 113 and about 142 °C. In some embodiments, the complex of xanomeline and quercetin of Form IA is characterized by a differential scanning calorimetry trace substantially as shown in FIG 6.

[0126] In certain embodiments, the complex of xanomeline and quercetin of Form IA is prepared by a process comprising the steps of slowly concentrating by evaporation at room temperature a solution of xanomeline and quercetin in ethanol and isolating crystals.

[0127] In certain embodiments, the complex of xanomeline and quercetin of Form IA is a hydrate comprising about 0.5 to about 0.6 moles of water per mole of xanomeline-quercetin complex.C. Xanomeline Quercetin Form II

[0128] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form II as described herein. In some exemplary embodiments of the crystalline Form II, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form II of the complex of xanomeline and quercetin are shown in Example 4.

[0129] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form II characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more, four or more, or five or more peaks at 7.4+0.2° 20, 8.6+0.2° 20, 12.6+0.2° 20, 19.1+0.2° 20, 23.6+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern comprises four or more peaks at 7.4+O.2020, 8.6+O.2020, 12.6+0.2° 20, 19.1+0.2° 20, 23.6+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern comprises five or more peaks at 7.4+0.2° 20, 8.6+0.2° 20, 12.6+0.2° 20, 19.1+0.2° 20, 23.6+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern comprises peaks at 7.4+0.2° 20, 8.6+0.2° 20, 12.6+0.2° 20, 19.1+0.2° 20, 23.6+0.2° 20, and 25.3+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 5. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 7.

[0130] In certain embodiments, the complex of xanomeline and quercetin of Form II is further characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, chosen from 7.4+0.2, 8.6+0.2, 12.6+0.2, 19.1+0.2, 23.6+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 7 ; a thermogravimetric analysis showing a mass loss of about0.35% between about 40 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 8; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 160 °C; and a differential scanning calorimetry trace substantially as shown in FIG 9.

[0131] In some embodiments, the complex of xanomeline and quercetin of Form II is characterised by a thermogravimetric analysis showing a mass loss of about 0.35% between about 40 °C and about 150 °C due to a water loss. In some embodiments, the complex of xanomeline and quercetin of Form II is characterised by a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 8. In some embodiments, the complex of xanomeline and quercetin of Form II is characterised by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 160 °C. In some embodiments, the complex of xanomeline and quercetin of Form II is characterised by a differential scanning calorimetry trace substantially as shown in FIG 9.

[0132] In certain embodiments, the complex of xanomeline and quercetin of Form II is prepared by a process comprising the steps of heating Form IV to a temperature of about 115°C to about 135°C, optionally about 125 °C, holding the temperature at about 115°C to about 135°C, optionally about 125 °C, for about 5 min to 25 min, optionally about 10 min, and isolating crystals.

[0133] In certain embodiments, the complex of xanomeline and quercetin of Form II is anhydrous.D. Xanomeline Quercetin Form III

[0134] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form III as described herein. In some exemplary embodiments of the crystalline Form III, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form III of the complex of xanomeline and quercetin are shown in Example 5.

[0135] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form III characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 8.1+0.2° 20, 24.2+0.2° 20, 25.0+0.2° 20, 25.3+0.2° 20, 26.1+0.2° 20, or 27.1+0.2° 20. In some embodiments, the XRPD comprises four or more peaks at 8.1+0.2020, 24.2+0.2° 20, 25.0+0.2° 20, 25.3+0.2° 20, 26.1+0.2° 20, or 27.1+0.2° 20. In some embodiments, the XRPD comprises five or more peaks at 8.1+0.2° 20, 24.2+0.2° 20, 25.0+0.2° 20, 25.3+0.2° 20, 26.1+0.2° 20, or 27.1+0.2° 20. In some embodiments, the XRPDcomprises peaks at 8.1+O.2020, 24.2+0.2° 20, 25.0+0.2° 20, 25.3+0.2° 20, 26.1+0.2° 20, and 27.1+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 6. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 10.

[0136] In certain embodiments, the complex of xanomeline and quercetin of Form III is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, chosen from 8.1+0.2, 24.2+0.2, 25.0+0.2, 25.3+0.2, 26.1+0.2, and 27.1+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 10; a thermogravimetric analysis showing a mass loss of about 0.3% between about 25 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 11 ; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 161 and about 168 °C; a differential scanning calorimetry profile having a melt at a Tpcak between about 162 °C and about 166 °C; and a differential scanning calorimetry trace substantially as shown in FIG 12.

[0137] In some embodiments, the complex of xanomeline and quercetin of Form Ill is characterised by a thermogravimetric analysis showing a mass loss of about 0.3% between about 25 °C and about 150 °C due to a water loss. In some embodiments, the complex of xanomeline and quercetin of Form III is characterised by a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 11. In some embodiments, the complex of xanomeline and quercetin of Form III is characterised by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 161 and about 168 °C. In some embodiments, the complex of xanomeline and quercetin of Form III is characterised by a differential scanning calorimetry profile having a melt at a Tpeak between about 162 °C and about 166 °C In some embodiments, the complex of xanomeline and quercetin of Form III is characterised by a differential scanning calorimetry trace substantially as shown in FIG 12.

[0138] In certain embodiments, the cocrystal of Form III is anhydrous.E. Xanomeline Quercetin Form IV

[0139] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form IV as described herein. In some exemplary embodiments of the crystalline Form IV, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form IV of the complex of xanomeline and quercetin are shown inExample 6.

[0140] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form IV characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 4.8+O.2020, 13.0+0.2° 20, 19.5+0.2° 20, 23.7+0.2° 20, 24.5+0.2° 20, or 25.5+0.2° 20. In some embodiments, the XRPD comprises four or more peaks at 4.8+O.2020, 13.0+0.2° 20, 19.5+0.2° 20, 23.7+0.2° 20, 24.5+0.2° 20, or 25.5+0.2° 20. In some embodiments, the XRPD comprises five or more peaks at 4.8+0.2° 20, 13.0+0.2° 20, 19.5+0.2° 20, 23.7+0.2° 20, 24.5+0.2° 20, or 25.5+0.2° 20. In some embodiments, the XRPD comprises peaks at 4.8+O.2020, 13.0+0.2° 20, 19.5+0.2° 20, 23.7+0.2° 20, 24.5+0.2° 20, and 25.5+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 7. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 13.

[0141] In certain embodiments, the complex of xanomeline and quercetin of Form IV is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, chosen from 4.8+0.2, 13.0+0.2, 19.5+0.2, 23.7+0.2, 24.5+0.2, and 25.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 13; a thermogravimetric analysis showing a mass loss of about 2.2% between about 40 °C and about 140 °C due to a water loss; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 14; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 92 and 161 °C; a differential scanning calorimetry profile showing a phase transition to Form II followed by a melt of the Form II; and a differential scanning calorimetry trace substantially as shown in FIG 15.

[0142] In some embodiments, the complex of xanomeline and quercetin of Form IV is characterised by a thermogravimetric analysis showing a mass loss of about 2.2% between about 40 °C and about 140 °C due to a water loss. In some embodiments, the complex of xanomeline and quercetin of Form IV is characterised by a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 14. In some embodiments, the complex of xanomeline and quercetin of Form IV is characterised by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 92 and 161 °C. In some embodiments, the complex of xanomeline and quercetin of Form IV is characterised by a differential scanning calorimetry profile showing a phase transition to Form II followed by a melt of the Form II. In some embodiments, the complex of xanomeline andquercetin of Form IV is characterised by a differential scanning calorimetry trace substantially as shown in FIG 15.

[0143] In certain embodiments, the complex of xanomeline and quercetin of Form IV is prepared by a process comprising the steps of slowly concentrating by evaporation at room temperature a solution of xanomeline and quercetin in acetone or acetonitrile, and isolating crystals.

[0144] In certain embodiments, the complex of xanomeline and quercetin of Form IV is a hydrate comprising about 0.7 moles of water per mole of xanomeline-quercetin cocrystal.F. Xanomeline Quercetin Form V

[0145] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form V as described herein. In some exemplary embodiments of the crystalline Form V, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form V of the complex of xanomeline and quercetin are shown in Example 7.

[0146] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form V characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 6. 1+0.2° 20, 7.9+0.2° 20, 14.2+0.2° 20, 20.2+0.2° 20, 24.8+0.2° 20, or 25.8+0.2° 20. In some embodiments, the XRPD comprises four or more peaks at 6.1+0.2° 20, 7.9+0.2° 20, 14.2+0.2° 20, 20.2+0.2° 20, 24.8+0.2° 20, or 25.8+0.2° 20. In some embodiments, the XRPD comprises five or more peaks at 6.1+0.2° 20, 7.9+0.2° 20, 14.2+0.2° 20, 20.2+0.2° 20, 24.8+0.2° 20, or 25.8+0.2° 20. In some embodiments, the XRPD comprises peaks at 6.1+O.2020, 7.9+O.2020, 14.2+0.2° 20, 20.2+0.2° 20, 24.8+0.2° 20, and 25.8+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 8. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 16.

[0147] In certain embodiments, the complex of xanomeline and quercetin of Form V is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, chosen from 6.1+0.2, 7.9+0.2, 14.2+0.2, 20.2+0.2, 24.8+0.2, and 25.8+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 16; a thermogravimetric analysis showing a mass loss of about 7.3% between about 80 °C and about 160 °C due to a loss of rert-butyl methyl ether; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 17; a differential scanning calorimetry profile having endotherm / exothermevents at between about 125 and 139 °C, about 141 °C, and between about 149 and 156 °C; and a differential scanning calorimetry trace substantially as shown in FIG 18.

[0148] In some embodiments, the complex of xanomeline and quercetin of Form V is characterised by a thermogravimetric analysis showing a mass loss of about 7.3% between about 80 °C and about 160 °C due to a loss of tert-butyl methyl ether. In some embodiments, the complex of xanomeline and quercetin of Form V is characterised by. In some embodiments, the complex of xanomeline and quercetin of Form V is characterised by a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 17. In some embodiments, the complex of xanomeline and quercetin of Form V is characterised by a differential scanning calorimetry profile having endotherm / exotherm events at between about 125 and 139 °C, about 141 °C, and between about 149 and 156 °C. In some embodiments, the complex of xanomeline and quercetin of Form V is characterised by a differential scanning calorimetry trace substantially as shown in FIG 18.

[0149] In certain embodiments, the complex of xanomeline and quercetin of Form V is prepared by a process comprising the step of thermocycling crystallization of a solution of xanomeline and quercetin in tert-butyl methyl ether (TBME), and isolating crystals.

[0150] In certain embodiments, the complex of xanomeline and quercetin of Form V is a tertbutyl methyl ether (TBME) solvate comprising about 0.5 moles of TBME per mole of xanomeline-quercetin cocrystal.G. Xanomeline Quercetin Form VI

[0151] In some embodiments, the complex of xanomeline and quercetin is a crystalline form of Form VI as described herein. In some exemplary embodiments of the crystalline Form VI, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form VI of the complex of xanomeline and quercetin are shown in Example 8.

[0152] In some embodiments, the complex of xanomeline and quercetin is a crystal form of Form VI characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 4.6+0.2020, 9.2+O.2020, 13.0+0.2° 20, or 13.9+0.2° 20. In some embodiments, the XRPD comprises peaks at 4.6+O.2020, 9.2+O.2020, 13.0+0.2° 20, and 13.9+0.2° 20. In some embodiments, the X-Ray -powder diffraction pattern further comprises one or more peaks identified in Table 9. In some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 38.

[0153] In certain embodiments, the complex of xanomeline and quercetin of Form VI is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.6+0.2, 9.2+0.2, 13.0+0.2, and 13.9+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 38; a thermogravimetric analysis showing a mass loss of about 1.9% between about 120 °C and about 150 °C due to a loss of tert-butyl methyl ether; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 120 °C and about 140 °C, a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeaj between about 122 °C and about 126 °C, and a differential scanning calorimetry trace substantially as shown in FIG 40.

[0154] In some embodiments, the complex of xanomeline and quercetin of Form VI is characterised by a thermogravimetric analysis showing a mass loss of about 1.9% between about 120 °C and about 150 °C due to a loss of tert-butyl methyl ether. In some embodiments, the complex of xanomeline and quercetin of Form VI is characterised by a differential scanning calorimetry profile having an endotherm / exotherm event at between about 120 °C and about 140 °C. In some embodiments, the complex of xanomeline and quercetin of Form VI is characterised by a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeak between about 122 °C and about 126 °C. In some embodiments, the complex of xanomeline and quercetin of Form VI is characterised by a differential scanning calorimetry trace substantially as shown in FIG 40.

[0155] In certain embodiments, the complex of xanomeline and quercetin of Form VI is prepared by a process comprising the steps of seeding a solution of xanomeline and quercetin in acetone / water with Form I crystals, cooling to about 3 °C to about 10 °C, optionally about 5 °C, aging for about 30 hours to about 60 hours, optionally about 48 h, and isolating crystals. For example, the acetone / water is about 95 / 5; v / v.

[0156] In certain embodiments, the complex of xanomeline and quercetin of Form VI is a hydrate comprising about 0.25 to about 1 mole of water per mole of xanomeline-quercetin cocrystal.IL Trospium Pamoate

[0157] In another aspect, the present disclosure includes salts that comprise trospium pamoate. For example, the salt of trospium pamoate can be a 1:1 trospium pamoate such as a trospium alkali pamoate salt (e.g. trospium sodium pamoate or trospium potassium pamoate) or atrospium hemipamoate salt (e.g. ditrospium pamoate). The trospium pamoate of the present disclosure can adopt a variety of crystalline forms, including but not limited to the crystal forms depicted herein, which can be characterized by features such as XRPD, DSC, TGA, and vapour sorption. Specific examples include Form A, Form B, Form C, Form D, Form E, Form F and Form M. The salt of trospium and pamoate can comprise a mixture of two or more crystalline forms. Alternatively, the trospium pamoate of the present disclosure can comprise substantially one specific crystalline form as disclosed herein. In other instances, the trospium pamoate of the present disclosure can be substantially free of one or more specific crystalline forms. Tn some embodiments, the present disclosure includes crystalline forms of the trospium pamoate of the present disclosure. For example, the crystalline form can be Form A, Form B, Form C, Form D, Form E, Form F, Form M, or those having substantially the same essential features as any of these specific crystalline forms.

[0158] In some embodiments, the trospium pamoate is of crystalline Form A. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 10.39+0.2° 29, 12.31+0.2° 29, 13.11+0.2° 29, 13.61+0.2° 29, or 16.5+0.2° 29.

[0159] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form B. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 5.4+O.2029, 9.9+0.2029, 13.2+0.2° 29, 14.8+0.2, 15.4+0.2° 29, 18.9+0.2° 29, 20.3+0.2° 20, 20.4+0.2° 29, or 25.3+0.2° 20.

[0160] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form C. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 6.5+0.2029, 9.8+0.2029, 10.1+0.2° 29, 10.6+0.2° 29, 14.2+0.2° 29, 18.2+0.2° 29, 19.8+0.2° 20, 20.8+0.2° 29, or 21.4+0.2° 20.

[0161] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form D. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 8.3+0.2020, 16.8+0.2° 20, 20.0+0.2° 20, or 20.7+0.2° 20.

[0162] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form E. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising peaks at4.6+0.2° 20, 9.3+0.2° 20, and 19.5+0.2° 20.

[0163] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form F. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 7.8+O.2020, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20.

[0164] In some embodiments, the trospium pamoate of the present disclosure is of crystalline Form M. In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is characterised by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 5.3 + 0.2° 20, 7.0 + 0.2° 20, 8.6 + 0.2° 20, 10.7 + 0.2° 20, 19.0 + 0.2° 20, or 21.3 + 0.2° 20.

[0165] In certain embodiments, any trospium pamoate described herein is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours.

[0166] In certain embodiments, any trospium pamoate described herein is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks.

[0167] In certain embodiments, any trospium pamoate described herein is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks.

[0168] In certain embodiments, any trospium pamoate described herein has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%, optionally determined by high-performance liquid chromatography.

[0169] In certain embodiments, any trospium pamoate described herein has total chemical impurities of not more than about 0.5%, optionally determined by high-performance liquid chromatography.A. Trospium Pamoate Form A

[0170] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form A as described herein. In some exemplary embodiments of the crystalline Form A, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form A of the salt of trospium and pamoate are shown in Example 10.

[0171] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form A characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more,or four or more peaks at 10.39+0.2° 20, 12.31+0.2° 20, 13.11+0.2° 20, 13.61+0.2° 20, or 16.5+0.2° 20. In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form A characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more at 10.39+0.2° 20, 12.31+0.2° 20, 13.11+0.2° 20, 13.61+0.2° 20, or 16.5+0.2° 20. In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form A characterised by an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at 10.39+0.2° 20, 12.31+0.2° 29, 13.11+0.2° 20, 13.61+0.2° 20, or 16.5+0.2° 20. In some embodiments, the XRPD comprises peaks at 10.39+0.2° 20, 12.31+0.2° 20, 13.11+0.2° 20, 13.61+0.2° 20, or 16.5+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 12. In some embodiments, the XRPD pattern is substantially as shown in FIG. 32.

[0172] In certain embodiments, the trospium pamoate of the present disclosure of Form A is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, at 10.39+0.2, 12.31+0.2, 13.11+0.2, 13.61+0.2, and 16.5+0.2 with radiation Cu Kot; an X-ray powder diffraction pattern substantially as shown in FIG. 32; a thermogravimetric analysis showing a mass loss of about 1.8% at between about 25 °C and about 200 °C due to a loss of ethanol and water; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 19; a differential scanning calorimetry profile having endotherm / exotherm events at between about 31 °C and about 81 °C, between about 301 °C and about 312 °C, and between about 312 °C and about 336 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 20.

[0173] In some embodiments, the trospium pamoate of Form A is characterised by a thermogravimetric analysis showing a mass loss of about 1.8% at between about 25 °C and about 200 °C due to a loss of ethanol and water. In some embodiments, the trospium pamoate of Form A is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 19. In some embodiments, the trospium pamoate of Form A is characterised by a differential scanning calorimetry profile having endotherm / exotherm events at between about 31 °C and about 81 °C, between about 301 °C and about 312 °C, and between about 312 °C and about 336 °C. In some embodiments, the trospium pamoate of Form A is characterised by a differential scanning calorimetry trace substantially as shown in FIG. 20.

[0174] In another aspect, the present disclosure includes processes of preparing a trospium pamoate of Form A.

[0175] In certain embodiments, the trospium pamoate of Form A is prepared by a processcomprising the steps of slowly concentrating by evaporation at room temperature a solution of trospium chloride and pamoic acid disodium salt in water, and isolating crystals.

[0176] In some embodiments, the trospium pamoate of Form A is prepared by a process comprising incubating a composition of a trospium halide salt and pamoic acid dialkali in ethanol at about 30 °C to about 60 °C, optionally about 50 °C, for about 3 hours to about 6 hours, optionally about 4 hours, to obtain a solution of trospium and pamoate, incubating the solution of trospium and pamoate at room temperature for about 18 hours to about 35 hours, optionally about 24 hours, to obtain an aged solution, and incubating the aged solution at about 3 °C to about 10 °C, optionally about 5 °C, for about 18 hours to about 35 hours, optionally about 24 hours, to obtain the trospium pamoate of Form A. For example, the pamoic acid dialkali can be pamoic acid disodium, pamoic acid dipotassium or pamoate sodium potassium. In some embodiments, the process for preparing the trospium pamoate of Form A further comprises isolating the trospium pamoate of Form A, optionally by centrifugation. In some embodiments, the process further comprises drying the trospium pamoate of Form A in vacuum, optionally at room temperature for about 24 hours. In some embodiments, the composition of the trospium halide salt and pamoic acid disodium in ethanol has a concentration of trospium equivalent to about 20 mg / mL to about 40 mg / mL, or about 30 mg / mL, trospium chloride. In some embodiments, the composition of the trospium halide salt and pamoic acid disodium in ethanol comprises pamoate in slight molar excess relative to trospium. Optionally, the composition of the trospium halide salt and pamoic acid disodium in ethanol comprises about 1 molar equivalent trospium to about 1.1 molar equivalent of pamoate. In some embodiments, the trospium halide salt is trospium chloride.

[0177] In certain embodiments, the trospium pamoate of Form A is an anhydrous form, wherein the stoichiometry of trospium to pamoate is 1 : 1 as demonstrated by proton nuclear magnetic resonance spectroscopy. For example, the trospium pamoate of Form A can be a trospium alkali pamoate salt, such as a trospium sodium pamoate salt or a trospium potassium pamoate salt. In some embodiments, the trospium pamoate of Form A is a trospium sodium pamoate salt.B. Trospium Pamoate Form B

[0178] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form B as described herein. In some exemplary embodiments of the crystalline Form B, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form B of the salt of trospium and pamoate are shown in Example 10.

[0179] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form B characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, five or more, six or more, seven or more, or eight or more peaks at 5.4+O.2020, 9.9+0.2° 20, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 29, 20.3+0.2° 20, 20.4+0.2° 29, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises three or more peaks at 5.4+O.2020, 9.9+0.2020, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 20, 20.4+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises four or more peaks at 5.4+O.2020, 9.9+O.2020, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 20, 20.4+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises five or more peaks at 5.4+0.2° 20, 9.9+O.2020, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 20, 20.4+0.2° 29, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises six or more peaks at 5.4+0.2° 29, 9.9+O.2020, 13.2+0.2° 29, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 29, 20.3+0.2° 20, 20.4+0.2° 20, or 25.3+0.2° 29. In some embodiments, the XRPD pattern of Form B comprises seven or more peaks at 5.4+0.2° 20, 9.9+0.2020, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 29, 20.4+0.2° 20, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises eight or more peaks at 5.4+0.2° 20, 9.9+O.2020, 13.2+0.2° 20, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 20, 20.4+0.2° 29, or 25.3+0.2° 20. In some embodiments, the XRPD pattern of Form B comprises peaks at 5.4+0.2° 29, 9.9+0.2020, 13.2+0.2° 29, 14.8+0.2° 20, 15.4+0.2° 20, 18.9+0.2° 20, 20.3+0.2° 20, 20.4+0.2° 20, and 25.3+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 13. In some embodiments, the XRPD pattern of Form B is substantially as shown in FIG. 33.

[0180] In certain embodiments, the trospium pamoate of Form B is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 5.4+0.2, 9.9+0.2, 13.2+0.2, 14.8+0.2, 15.4+0.2, 18.9+0.2, 20.3+0.2, 20.4+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 33; a thermogravimetric analysis showing a mass loss of about 4.8% at between about 25 °C and about 200 °C due to a water loss; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 21; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 60 °C and about 85 °C, between about 93 °C and about 113 °C, between about 226 °C and about 247 °C, between about 300 °C and about 308 °C, and between about 329 °C and about 337 °C; and a differentialscanning calorimetry trace substantially as shown in FIG 22.

[0181] In some embodiments, the trospium pamoate of Form B is characterised by a thermogravimetric analysis showing a mass loss of about 4.8% at between about 25 °C and about 200 °C due to a water loss. In some embodiments, the trospium pamoate of Form B is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 21. In some embodiments, the trospium pamoate of Form B is characterised by In some embodiments, the trospium pamoate of Form B is characterised by a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 60 °C and about 85 °C, between about 93 °C and about 113 °C, between about 226 °C and about 247 °C, between about 300 °C and about 308 °C, and between about 329 °C and about 337 °C. In some embodiments, the trospium pamoate of Form B is characterised by a differential scanning calorimetry trace substantially as shown in FIG 22.

[0182] In another aspect, the present disclosure includes processes of preparing a trospium pamoate of Form B.

[0183] In certain embodiments, the trospium pamoate of Form B is prepared by a process comprising the steps of slowly concentrating by evaporation at room temperature a solution of trospium chloride and pamoic acid disodium salt in water and ethanol, and isolating crystals in a solvent.

[0184] In some embodiments, the trospium pamoate of Form B is prepared by a process comprising (i) incubating a solution of trospium halide and pamoic acid dialkali salt in water at about 40 °C to about 60 °C, optionally about 50 °C, for about 3 hours to about 5 hours, optionally about 4 hours, (ii) incubating the solution at room temperature for about 18 hours to about 35 hours, optionally about 24 hours to obtain an aged solution, and (III) incubating the aged solution at about 3 °C to about 10 °C, optionally about 5 °C for about 18 hours to about 35 hours, optionally about 24 hours to obtain the trospium pamoate of Form B. For example, the pamoic acid dialkali salt can be a pamoic acid disodium salt, a pamoic acid dipotassium salt, or pamoate sodium potassium. In some embodiments, the process of preparing the trospium pamoate of Form B further comprises isolating the trospium pamoate of Form B, optionally by centrifugation. In some embodiments, the process of preparing the trospium pamoate of Form B further comprises drying the trospium pamoate of Form B, optionally under vacuum at about 30 °C to about 60 °C, optionally about 50 °C. In some embodiments, the trospium halide is trospium chloride.

[0185] In certain embodiments, the trospium pamoate of Form B is a hydrate comprising about 2to 3 moles of water per 1 mole of trospium and 1 mole of pamoate. For example, the trospium pamoate of Form B can be a trospium alkali pamoate salt, such as a trospium sodium pamoate salt or a trospium potassium pamoate salt. In some embodiments, the salt of Form B is a trospium sodium pamoate salt.C. Trospium Pamoate Form C

[0186] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form C as described herein. In some exemplary embodiments of the crystalline Form C, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form C of the trospium pamoate of the present disclosure are shown in Example 10.

[0187] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form C characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, five or more, six or more, seven or more, or eight or more peaks at 6.5+O.2020, 9.8+0.2° 20, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 29, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises three or more peaks at 6.5+0.2020, 9.8+O.2020, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 20, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises four or more peaks at 6.5+0.2° 20, 9.8+O.2020, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 20, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises five or more peaks at 6.5+0.2° 20, 9.8+0.2° 20, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 20, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises six or more peaks at 6.5+0.2° 29, 9.8+0.2029, 10.1+0.2° 29, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 29, 19.8+0.2° 29, 20.8+0.2° 20, or 21.4+0.2° 29. In some embodiments, the XRPD pattern of Form C comprises seven or more peaks at 6.5+0.2° 20, 9.8+O.2020, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 20, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises eight or more peaks at 6.5+0.2° 20, 9.8+0.2029, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 20, 19.8+0.2° 20, 20.8+0.2° 29, or 21.4+0.2° 20. In some embodiments, the XRPD pattern of Form C comprises peaks at 6.5+0.2° 20, 9.8+O.2020, 10.1+0.2° 20, 10.6+0.2° 20, 14.2+0.2° 20, 18.2+0.2° 29, 19.8+0.2° 20, 20.8+0.2° 20, and 21.4+0.2° 20. In some embodiments, the X-Ray -powder diffraction pattern further comprises one or more peaks identified in Table 14. In some embodiments, the XRPDpattern of Form C is substantially as shown in FIG. 34.

[0188] In certain embodiments, the trospium pamoate of Form C is further characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 6.5+0.2, 9.8+0.2, 10.1+0.2, 10.6+0.2, 14.2+0.2, 18.2+0.2, 19.8+0.2, 20.8+0.2, and 21.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 34; a thermogravimetric analysis showing a mass loss of about 7.4% at between about 40 °C and about 200 °C due to a water loss; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 24; a differential scanning calorimetry profile comprising an endothermic event having an onset at about 130 °C and a peak at about 134 °C; and a differential scanning calorimetry trace substantially as shown in FIG 25.

[0189] In some embodiments, the trospium pamoate of Form C is characterised by a thermogravimetric analysis showing a mass loss of about 7.4% at between about 40 °C and about 200 °C due to a water loss. In some embodiments, the trospium pamoate of Form C is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 24. In some embodiments, the trospium pamoate of Form C is characterised by a differential scanning calorimetry profile comprising an endothermic event having an onset at about 130 °C and a peak at about 134 °C. In some embodiments, the trospium pamoate of Form C is characterised by a differential scanning calorimetry trace substantially as shown in FIG 25.

[0190] In another aspect, the present disclosure includes processes of preparing a trospium pamoate of Form C.

[0191] In certain embodiments, the trospium pamoate of Form C is prepared by a process comprising the steps of contacting a sodium pamoate and a solution of trospium chloride in water and ethanol, isolating crystals, and washing the isolated crystals with water to remove sodium and chloride.

[0192] In some embodiments, the trospium pamoate of Form C is prepared by a process comprising (i) incubating a solution of trospium halide and pamoic acid dialkali salt in water at about 40°C to about 60°C, optionally about 50°C, for about 3 hours to about 5 hours, optionally about 4 hours, (ii) incubating the solution at room temperature for about 24 hours to obtain an aged solution, and (III) incubating the solution at 5 °C for about 24 hours to obtain the salt of Form C. For example, the pamoic acid dialkali can be pamoic acid disodium pamoic acid dipotassium, or pamoate sodium potassium. In some embodiments, the process of preparing the trospium pamoate of Form C further comprises isolating the trospium pamoate of Form C, optionally by centrifugation. In some embodiments, the process of preparing the trospiumpamoate of Form C further comprises drying the salt of Form C, optionally under vacuum at about 50°C. In some embodiments, the trospium halide is trospium chloride. In some embodiments, the solution of trospium halide and pamoic acid dialkali salt comprises about 1 molar equivalent of trospium to about 1.1 molar equivalent of pamoate.

[0193] In some embodiments, the trospium pamoate of Form C is prepared by a process comprising incubating a solution of trospium halide and pamoic acid dialkali in water at about 40 °C to about 60 °C, optionally about 50 °C, for about 18 hours to about 35 hours, optionally about 24 hours to obtain the trospium pamoate of Form C. For example, the pamoic acid dialkali can be pamoic acid disodium or pamoic acid dipotassium. In some embodiments, the process of preparing the trospium pamoate of Form C further comprises isolating the trospium pamoate of Form C, optionally by centrifugation. In some embodiments, the trospium halide is trospium chloride. In some embodiments, the solution of trospium halide and pamoic acid disodium comprises about 1 molar equivalent of trospium to about 0.5 to about 0.6, optionally about 0.55 molar equivalent of pamoate. In some embodiments, the solution of trospium halide and pamoic acid dialkali has a concentration of trospium equivalent to about 40 mg / mL to about 50 mg / mL, optionally about 30 mg / mL, of trospium chloride.

[0194] In some embodiments, the trospium pamoate of Form C is prepared by a process comprising adding a composition of pamoic acid dialkali in alcohokwater to a composition of trospium halide in alcohokwater to obtain a slurry, incubating the slurry at about 10 °C to about 25 °C, optionally about 18 °C, for about 30 min to about 2 hours, optionally for about an hour, to obtain the salt of trospium and pamoate as a solid. For example, the trospium halide can be trospium chloride. For example, the pamoic acid dialkali can be pamoic acid disodium or pamoic acid dipotassium. For example, the alcohokwater can be ethanokwater or methanol: water. In some embodiments, the alcohol: water is methanol: water. The alcohol :water mixture can be about 40:60 to 60:40, optionally 50:50 v / v in alcohol: water. In some embodiments, the alcohohwater mixture is a 50:50 v / v meth anol: water. For example, the process of preparing the trospium pamoate of Form C can further include isolating the trospium pamoate of Form C, optionally by filtration of the trospium pamoate of Form C as the solid. The process of preparing the trospium pamoate of Form C can further include washing the isolated trospium pamoate of Form C, optionally with the alcohohwater mixture. The process of preparing the trospium pamoate of Form C can further include drying the trospium pamoate of Form C, optionally under vacuum for overnight, at about room temperature to about 40 °C, such as at about 35 °C. For example, the slurry can comprise about 1 molar equivalent of trospium to about 0.4 to 0.6,optionally to about 0.5 to 0.55 molar equivalent of pamoate. In some embodiments, the slurry comprises about 1 molar equivalent of trospium to about 0.55 molar equivalent of pamoate. The composition of pamoic acid dialkali in alcohokwater can have a concentration of pamoate equivalent to about 20 mg / mL to about 40 mg / mL of pamoic acid disodium, optionally about 25 mg / ml to about 30 mg / mL of pamoic acid disodium. In some embodiments, the composition of pamoic acid dialkali in alcohol: water has a concentration of pamoate equivalent to about 27.8 mg / ml of pamoic acid disodium. The composition of trospium halide in alcohokwater can have a concentration of trospium equivalent to about 40 mg / mL to about 60 mg / mL of trospium chloride, optionally about 45 mg / mL to about 55 mg / mL of trospium chloride. In some embodiments, the composition of trospium halide in alcohol: water has a concentration of trospium equivalent to about 50 mg / ml of trospium chloride.

[0195] In certain embodiments, the trospium pamoate of Form C is a hemipamoate hydrate comprising about 1 mole of pamoate and up to about 7 moles of water per 2 moles of trospium. In certain embodiments, the hemipamoate hydrate comprises about 1 mole of pamoate, between about 5 and about 7 moles of water per 2 moles of trospium.D. Trospium Pamoate Form D

[0196] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form D as described herein. In some exemplary embodiments of the crystalline Form D, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form D of the salt of trospium and pamoate are shown in Example 10.

[0197] In some embodiments, the trospium pamoate is a crystal form of Form D characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more peaks at 8.3+0.2° 26, 16.8+0.2° 20, 20.0+0.2° 20, or 20.7+0.2° 20. In some embodiments, the XRPD of Form D comprises peaks at 8.3+0.2° 20, 16.8+0.2° 20, 20.0+0.2° 20, and 20.7+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 18. In some embodiments, the XRPD of Form D is substantially as shown in FIG. 35.

[0198] In certain embodiments, the trospium pamoate of Form D is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of ° 20, at 8.3+0.2, 16.8+0.2, 20.0+0.2, and 20.7+0.2 with radiation Cu Ka: an X- ray powder diffraction pattern substantially as shown in FIG. 35; a thermogravimetric analysisshowing a mass loss of about 8% at between about 25 °C and about 220 °C due to a loss of tetrahydrofuran; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 26; a differential scanning calorimetry profile having endotherm / exotherm events at between about 115 °C and about 141 °C, and between about 258 °C and about 273 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 27.

[0199] In some embodiments, the trospium pamoate of Form D is characterised by a thermogravimetric analysis showing a mass loss of about 8% at between about 25 °C and about 220 °C due to a loss of tetrahydrofuran. In some embodiments, the trospium pamoate of Form D is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 26. In some embodiments, the trospium pamoate of Form D is characterised by a differential scanning calorimetry profile having endotherm / exotherm events at between about 115 °C and about 141 °C, and between about 258 °C and about 273 °C. In some embodiments, the trospium pamoate of Form D is characterised by a differential scanning calorimetry trace substantially as shown in FIG. 27.

[0200] In some embodiments, the trospium pamoate of Form D is prepared by a process comprising incubating a composition comprising a trospium halide salt and pamoic acid dialkali salt in THF / water at about 50°C for about 4 hours to obtain a solution of trospium and pamoate, incubating the solution of trospium and pamoate at room temperature for about 24 hours to obtain an aged solution of trospium and pamoate, incubating the aged solution at about 5°C for about 24 hours, and evaporating the aged solution at room temperature for about 24 hours to obtain the trospium pamoate of Form D. For example, the pamoic acid dialkali can be pamoic acid disodium, pamoic acid dipotassium, or pamoate sodium potassium. In some embodiments, the pamoic acid dialkali is pamoic acid disodium. In some embodiments, the process further comprises isolating the trospium pamoate of Form D and drying the salt of Form D in vacuo. In some embodiments, the THF / water is about 9: 1 THF / water. In some embodiments, the trospium halide salt is trospium chloride. In some embodiments, the composition comprising the trospium halide salt and the pamoate acid disodium comprises about 1 molar equivalent of trospium to 1.1 molar equivalent of pamoate. In some embodiments, the composition comprising the trospium halide salt and the pamoate acid disodium has a trospium concentration equivalent to about 60 to 65 mg / mL of trospium chloride. In another aspect, the present disclosure also includes a process for preparing a trospium pamoate of Form D.

[0201] In some embodiments, the trospium pamoate of Form D is a trospium alkali pamoate salt, such as a trospium sodium pamoate or a trospium potassium pamoate. In some embodiments, thetrospium pamoate of Form D is a trospium sodium pamoate. In certain embodiments, the salt of Form D is a tetrahydrofuran solvate comprising about 1 mole of tetrahydrofuran per 1 mole of trospium and 1 mole of pamoate.E. Trospium Pamoate Form E

[0202] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form E as described herein. In some exemplary embodiments of the crystalline Form E, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form E of the salt of trospium and pamoate are shown in Example 10.

[0203] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form E characterised by an X-ray powder diffraction pattern (XRPD) comprising peaks at 4.6+0.2° 20, 9.3+0.2° 20, and 19.5+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 19. In some embodiments, the XRPD of Form E is substantially as shown in FIG. 36.

[0204] In certain embodiments, the trospium pamoate of Form E is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 4.6+0.2, 9.3+0.2, and 19.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 36; a thermogravimetric analysis showing a mass loss of about 12% at between about 25 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 28; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 40 °C and about 75 °C, between about 75 °C and about 125 °C, between about 195 °C and about 250 °C, between about 280 °C and about 318 °C, and between about 319 °C and about 360 °C, optionally between about 40 °C and about 75 °C, and between about 75 °C and about 125 °C; and a differential scanning calorimetry trace substantially as shown in FIG 29.

[0205] In some embodiments, the trospium pamoate of Form E is characterised by a thermogravimetric analysis showing a mass loss of about 12% at between about 25 °C and about 150 °C due to a water loss. In some embodiments, the trospium pamoate of Form E is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 28. In some embodiments, the trospium pamoate of Form E is characterised by a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 40 °C and about 75 °C, between about 75 °C and about 125 °C, between about 195 °C and about 250 °C, between about 280 °C and about 318 °C, and between about 319 °Cand about 360 °C, optionally between about 40 °C and about 75 °C, and between about 75 °C and about 125 °C. In some embodiments, the trospium pamoate of Form E is characterised by a differential scanning calorimetry trace substantially as shown in FIG 29.

[0206] In certain embodiments, the trospium pamoate of Form E is prepared by a process comprising the steps of slowly concentrating by evaporation at room temperature a solution of trospium chloride and pamoic acid disodium salt in water and ethanol, and isolating crystals in a solvent. In some embodiments, the trospium pamoate of Form E is prepared by a process comprising incubating a slurry of a trospium halide salt and pamoic acid dialkali in water at room temperature to obtain a slurry comprising the trospium pamoate of Form E. In some embodiments, the process further comprises isolating the trospium pamoate of Form F. For example, the pamoic acid dialkali can be pamoic acid disodium, pamoic acid dipotassium, or pamoate sodium potassium. In some embodiments, the pamoic acid dialkali is pamoic acid disodium. In some embodiments, the trospium halide salt is trospium chloride. In some embodiments, the slurry of the trospium halide and the pamoic acid dialkali comprises about 1 molar equivalent of trospium to about 1 to about 1.3 molar equivalent, optionally about 1.1 molar equivalent of pamoate. In some embodiments, the slurry of the trospium halide and the pamoic acid dialkali has a concentration of trospium equivalent to about 20 mg / mL to about 40 mg / mL, optionally about 30 mg / mL, trospium chloride. In another aspect, the present disclosure also includes a process for preparing a trospium pamoate of Form E.

[0207] In some embodiments, the trospium pamoate of Form E is a trospium alkali pamoate salt, such as a trospium sodium pamoate or a trospium potassium pamoate. In some embodiments, the salt of Form E is a trospium sodium pamoate. In certain embodiments, the trospium pamoate of Form E is a hexahydrate comprising about 6 moles of water per 1 mole of trospium and 1 mole of pamoate.F. Trospium Pamoate Form F

[0208] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form F as described herein. In some exemplary embodiments of the crystalline Form F, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form F of the trospium pamoate are shown in Example 10.

[0209] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form F characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more,four or more, five or more, or six or more peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20. In some embodiments, the XRPD of Form F is characterized by three or more peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20. In some embodiments, the XRPD of Form F is characterized by four or more peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20. In some embodiments, the XRPD of Form F is characterized by five or more peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20. In some embodiments, the XRPD of Form F is characterized by six or more peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, or 20.5+0.2° 20. In some embodiments, the XRPD of Form F is characterized by peaks at 7.8+0.2° 20, 10.8+0.2° 20, 14.0+0.2° 20, 15.6+0.2° 20, 17.5+0.2° 20, 18.4+0.2° 20, and 20.5+0.2° 20. In some embodiments, the X-Ray -powder diffraction pattern further comprises one or more peaks identified in Table 20. In some embodiments, the XRPD of Form F is substantially as shown in FIG. 37.

[0210] In certain embodiments, the trospium pamoate of Form F is further characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 7.8+0.2, 10.8+0.2, 14.0+0.2, 15.6+0.2, 17.5+0.2, 18.4+0.2, and 20.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 37; a thermogravimetric analysis showing a mass loss of about 2.25% at between about 25 °C and about 150 °C due to a water loss; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 30; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 110 °C and about 150 °C, between about 290 °C and about 320 °C, and between about 321 °C and about 360 °C; and a differential scanning calorimetry trace substantially as shown in FIG 31.

[0211] In some embodiments, the trospium pamoate of Form F is characterised by a thermogravimetric analysis showing a mass loss of about 2.25% at between about 25 °C and about 150 °C due to a water loss. In some embodiments, the trospium pamoate of Form F is characterised by a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 30. In some embodiments, the trospium pamoate of Form F is characterised by a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 110 °C and about 150 °C, between about 290 °C and about 320 °C, and between about 321 °C and about 360 °C. In some embodiments, the trospium pamoate of Form F is characterised by a differential scanning calorimetry trace substantially as shown in FIG 31.

[0212] In certain embodiments, the trospium pamoate of Form F is prepared by a process comprising the steps of slowly concentrating by evaporation at room temperature a solution of trospium chloride and pamoic acid disodium salt in water and ethanol, and isolating crystals in a solvent. In some embodiments, the trospium pamoate of Form F is prepared by a process comprising incubating a slurry of a trospium halide salt and pamoic acid dialkali in water at about 40 °C to about 60 °C, optionally about 50 °C, to obtain a slurry comprising the trospium pamoate of Form F. In some embodiments, the process further comprises isolating the trospium pamoate of Form F. For example, the pamoic acid dialkali can be pamoic acid disodium, pamoic acid dipotassium, or pamoate sodium potassium. In some embodiments, the pamoic acid dialkali is pamoic acid disodium. In some embodiments, the trospium halide salt is trospium chloride. In some embodiments, the slurry of the trospium halide and the pamoic acid disodium comprises about 1 molar equivalent of trospium to about 1 to about 1.3, optionally about 1.1 molar equivalent of pamoate. In some embodiments, the slurry of the trospium halide and the pamoic acid disodium has a concentration of trospium equivalent to about 50 mg / mL to about 70 mg / mL, optionally about 60 mg / mL, of trospium chloride. In another aspect, the present disclosure also includes a process for preparing a trospium pamoate of Form F.

[0213] In some embodiments, the salt of trospium and pamoate of Form F is a trospium alkali pamoate salt, such as a trospium sodium pamoate or a trospium potassium pamoate salt. In some embodiments, the salt of Form F is a trospium sodium pamoate salt. In certain embodiments, the trospium pamoate of Form F is a monohydrate comprising about 1 moles of water per 1 mole of trospium and 1 mole of pamoate.G. Trospium Pamoate Form M

[0214] In some embodiments, the crystalline form of the trospium pamoate of the present disclosure is Form M as described herein. In some exemplary embodiments of the crystalline Form M, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form M of the trospium pamoate are shown in Example 10.

[0215] In some embodiments, the trospium pamoate of the present disclosure is a crystal form of Form M characterised by an X-ray powder diffraction pattern (XRPD) comprising three or more, four or more, or five or more peaks at 5.3+0.2° 20, 7.0+0.2° 20, 8.6+O.2020, 10.7+0.2° 20, 19.0+0.2° 20, or 21.3+0.2° 20. In some embodiments, the XRPD of Form M is characterized by three or more peaks at 5.3+0.2° 20, 7.O+O.2020, 8.6+0.2020, 10.7+0.2° 20, 19.0+0.2° 20, or21.3+0.2° 20. In some embodiments, the XRPD of Form M is characterized by four or more peaks at 5.3+O.2020, 7.0+0.2020, 8.6+0.2020, 10.7+0.2° 20, 19.0+0.2° 20, or 21.3+0.2° 20. In some embodiments, the XRPD of Form M is characterized by five or more peaks at 5.3+0.2° 20, 7.0+0.2° 20, 8.6+0.2° 20, 10.7+0.2° 20, 19.0+0.2° 20, or 21.3+0.2° 20. In some embodiments, the XRPD of Form M is characterized by peaks at 5.3+0.2° 20, 7.O+O.2020, 8.6+0.2° 20, 10.7+0.2° 20, 19.0+0.2° 20, and 21.3+0.2° 20. In some embodiments, the XRPD pattern of Form M is further characterised by one or more peaks at 13.5+0.2° 20, 14.8+0.2° 20, 15.8+0.2° 20, 17.2+0.2° 20, or 18. +0.2° 20. Tn some embodiments, the XRPD pattern of Form M is characterised by peaks at 5.3+0.2° 20, 7.O+O.2020, 8.6+0.2° 20, 10.7+0.2° 20, 13.5+0.2° 20, 14.8+0.2° 20, 15.8+0.2° 20, 17.2+0.2° 20, 18.3+0.2° 20, 19.0+0.2° 20, and 21.3+0.2° 20. In some embodiments, the X-Ray-powder diffraction pattern further comprises one or more peaks identified in Table 21. In some embodiments, the XRPD of Form M is substantially as shown in FIG. 49.

[0216] In some embodiments, the trospium pamoate of Form M is a trospium hemipamoate (e.g. ratio of trospiur pamoate of 2:1). In some embodiments, the salt of trospium and pamoate of Form M is anhydrous.

[0217] In some embodiments, the trospium pamoate of Form M is prepared by a process comprising incubating a trospium pamoate of Form C as described herein at about 5% to about 15%, optionally about 10%, relative humidity and about 60 °C to about 80 °C, optionally about 70 °C, for about one hour under an inert atmosphere, dispersing the incubated salt of trospium and pamoate of Form C on a solid support to obtain a dispersed trospium pamoate, incubating the dispersed salt at about -130 °C to about -200 °C, optionally about -160 °C to about -200 °C, optionally about -196 °C, to obtain the trospium pamoate of Form M. For example, the dispersed salt can be incubated in a liquid nitrogen bath. For example, the solid support can be an electron microscopy stub. In another aspect, the present disclosure also includes a process for preparing a trospium pamoate of Form M.

[0218] In certain embodiments, the trospium pamoate of Form M is a hemipamoate comprising about 1 mole of pamoate per 2 moles of trospium.III. Pharmaceutical Compositions

[0219] While the compound e.g. complex of xanomeline and quercetin, trospium pamoate) can be administered as a raw chemical, it is also possible to present it as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical compositions comprising at least one polymorphic form of the compound and at least one pharmaceutically acceptable excipient.The compound can be a complex of xanomeline and quercetin and / or a trospium pamoate as described herein.

[0220] In another aspect, the present disclosure includes a pharmaceutical composition comprising a complex of xanomeline and quercetin of the present disclosure and a pharmaceutically acceptable excipient. The complex of xanomeline and quercetin can be any complex of xanomeline and quercetin described herein, for example, Form I, Form IA, Form II, Form III, Form IV, Form V, or Form VI. In some embodiments, the composition further comprises a trospium salt, such as a trospium pamoate as disclosed herein. In some examples, the composition may comprise a complex of xanomeline and quercetin in crystalline Form I and a trospium pamoate in crystalline Form C.

[0221] In another aspect, the present disclosure includes a pharmaceutical composition comprising a trospium pamoate of the present disclosure and a pharmaceutically acceptable excipient. The trospium pamoate can be any trospium pamoate described herein, for example a salt of Form A, Form B, Form C, Form D, Form E, Form F, or Form M.

[0222] In certain embodiments, the pharmaceutical composition comprises a complex of xanomeline and quercetin described herein and a trospium salt described herein. In some embodiments, the complex of xanomeline and quercetin and the trospium salt are formulated together. In other embodiments, the complex of xanomeline and quercetin and the trospium salt are formulated separately.

[0223] In some embodiments, the complex of xanomeline and quercetin is Form I. In some embodiments, the complex of xanomeline and quercetin is Form IA. In some embodiments, the complex of xanomeline and quercetin is Form II. In some embodiments, the complex of xanomeline and quercetin is Form III. In some embodiments, the complex of xanomeline and quercetin is Form IV. In some embodiments, the complex of xanomeline and quercetin is Form V. In some embodiments, the complex of xanomeline and quercetin is Form VI.

[0224] In some embodiments, the trospium pamoate is Form A. In some embodiments, the trospium pamoate is Form B. In some embodiments, the trospium pamoate is Form C. In some embodiments, the trospium pamoate is Form D. In some embodiments, the salt of trospium and pamoate is Form E. In some embodiments, the trospium pamoate is Form F. In some embodiments, the trospium pamoate is Form M.

[0225] In certain embodiments, the pharmaceutical composition of the present disclosure comprises the complex of xanomeline and quercetin of Form I and the trospium pamoate ofForm C.

[0226] In certain embodiments, the pharmaceutical composition is formulated as a suspension. In other embodiments, the pharmaceutical composition is lyophilized.

[0227] In certain embodiments, the pharmaceutical composition is administered subcutaneously, intravenously, or intramuscularly.

[0228] The excipient(s) or carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation depends on the route of administration chosen. Any well-known techniques, carriers, and excipients may be used as suitable and as understood in the art, e.g., in Remington 's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g. , through conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0229] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. Typically, these methods include bringing into association a compound of the subject disclosure or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof (“active ingredient”) with the carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0230] Formulations of the compound suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules: as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0231] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface-active, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0232] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials. They may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0233] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable tonicity agents include dextrose, glycerin, mannitol, potassium chloride, and sodium chloride. Suitable lipophilic solvents or vehicles include fattyoils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the suspension’s viscosity, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the compounds’ solubility to prepare highly concentrated solutions.

[0234] For oral or parenteral use, the compounds may be formulated as nanoparticle preparations. Such nanoparticle preparations can include, for example, nanosphere encapsulations of active compounds, inactive nanoparticles to which active compounds can he tethered, or nanoscale powders of active compounds. Nanoparticle preparations can be used to increase the bioavailability of the active compounds, control the rate of release of the active compounds, or deliver active compounds to a location in the body. See A. Dove, “An Easy Pill to Swallow,” Drug Discovery & Development Magazine: 11(11), November 2008, pp. 22-24.

[0235] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0236] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated conventionally. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0237] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0238] The compound may be administered topically, that is, by non-systemic administration. This includes applying the compound externally to the epidermis or the buccal cavity and installing such a compound into the ear, eye, and nose. The compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0239] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may comprise, for example, from0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In some embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1 % to 1% w / w of the formulation.

[0240] Formulations for topical administration in the mouth, for example, buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[0241] Unit dosage formulations contain an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0242] In addition to the ingredients mentioned above, the formulations described above may include other agents conventional in the art regarding the type of formulation in question. For example, those suitable for oral administration may include flavoring agents.

[0243] The amount of active ingredient combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0244] The compounds can be administered in various modes, e.g., orally, topically, transdermally, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.

[0245] In certain instances, it may be appropriate to administer at least one compound described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) combined with another therapeutic agent. By way of example only, if one side effect experienced by a patient upon receiving one compound herein is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one compound described herein may be enhanced by administration of an adjuvant (i.e., by itself, the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may beincreased by administering one compound described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one compound described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0246] In any case, the multiple therapeutic agents (at least one of which is the compound) may be administered in any order or even simultaneously. If simultaneous, the multiple therapeutic agents may be provided in a single, unified form or multiple forms (by example only, either as a single pill or two separate pills). One therapeutic agent may be given in multiple doses, or both may be given multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.IV. Methods of Use

[0247] The present disclosure also provides a method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, the method comprising administrating, to the subject, a therapeutically effective amount of a complex of xanomeline and quercetin of the present disclosure and a therapeutically effective amount of a trospium pamoate of the present disclosure. In another aspect, provided herein is a method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, the method comprising administering a pharmaceutical composition of the present disclosure.

[0248] In certain embodiments, the subject in the method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors is a human.

[0249] In certain embodiments, the disorder in the method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors is a neurodegenerative disease.

[0250] In certain embodiments, the disorder in the method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors is a central nervous system disease.

[0251] In certain embodiments, the disorder in the method of treating or reducing the symptoms of a disorder ameliorated by activating muscarinic receptors is selected from schizophrenia, autism, Alzheimer’s disease, bipolar, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction or addictive disorder, schizoaffectivedisorder, tauopathy, and synucleinopathy. For example, Alzheimer’s disease can be Alzheimer’s disease with agitation and / or Alzheimer’s disease with cognitive impairment. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is Alzheimer’s disease. In some embodiments, the disease or disorder is bipolar disorder.

[0252] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treating companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. More animals include horses, dogs, and cats.

[0253] Information for treating the target diseases such as those disclosed herein with muscarinic receptor activators (e.g., any of the complexes of xanomeline and quercetin as disclosed herein) and muscarinic receptor inhibitors (e.g., any of the salts of trospium and pamoate as also disclosed herein) can be found, for example, in WO 2011 / 011060 and WO 2020069301, the relevant disclosures of each of which are incorporated by reference for the subject matter and purpose referenced herein.

[0254] Also provided herein are methods of treating schizophrenia in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of treating Alzheimer’s disease in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of alleviating agitation, optionally agitation associated with Alzheimer’s disease, in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of treating a patient with Alzheimer’s disease comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C, wherein the method alleviates cognitive impairment and / or global functioning impairment. Also provided herein are methods of alleviating cognitive impairment or global functioning impairment in a patient with Alzheimer’s disease comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C. Also provided herein are methods of alleviating mania, optionally mania associated with bipolar disorder, in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I andtrospium pamoate of crystalline Form C. Also provided herein are methods of treating bipolar disorder in a patient in need thereof comprising administering to the patient a composition comprising a complex of xanomeline and quercetin of crystalline Form I and trospium pamoate of crystalline Form C.DEFINITIONS

[0255] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0256] Xanomeline (LY-246,708; Lumeron, Memcor) is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system disorders. Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic Ml and M4 receptor subtypes.

[0257] Xanomeline is currently being developed as a combination drug (Kar-XT: xanomeline + trospium) by Karuna Therapeutics. Trospium is a non-CNS penetrant non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's mechanism of action is hypothesized to be via rebalancing key neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which are disrupted in schizophrenia and related diseases.

[0258] Xanomeline and trospium have the following structures:

[0259] Quercetin is a plant flavanol that is a polar auxin transport inhibitor. It is widely found in natural sources. Quercetin has the following structure:

[0260] As used herein, the term “cocrystal” refers to a crystalline material containing two or more different molecules in the same crystal lattice. For example, a cocrystal can be a crystalline material of a base molecule (e.g. an active pharmaceutical ingredient) and a co-crystal former (or coformer). For example, a cocrystal can be a solid form in which two or more different molecules form crystal structures in a constant stoichiometric ratio in one crystal lattice; intermolecular bond forms in cocrystals are distinguished from salts and mixtures. A cocrystal can be different from a salt or a polymorph of the base molecule alone.

[0261] In certain embodiments, the compound is a complex of xanomeline and quercetin, such as a xanomeline-quercetin cocrystal. In certain embodiments, the compound is a salt of trospium, such as a salt of trospium and pamoate.

[0262] The compounds can exist as various polymorphic forms. As used herein, “polymorphs” and “polymorphic forms” and related terms refer to crystalline forms of the same molecule. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra because of the arrangement or conformation of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in bioavailability). Differences in stability can also result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical property (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility / dissolution differences, in the extreme case, some polymorphic transitions may result in a lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing. For example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might differ between polymorphs).

[0263] Polymorphs of a molecule can be obtained by several methods, as known in the art. Suchmethods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, reactive crystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0264] Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid-state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

[0265] To “characterize” a solid form of a compound, one may, for example, collect XRPD data on solid forms of the compound and compare the XRPD peaks of the forms. For example, when only three solid forms, e.g., Forms X and Y and Material N, are compared, if the Form X pattern shows a peak at an angle where no peaks appear in the Form Y or Material N pattern, then that peak, for that compound, distinguishes Form X from Form Y and Material N and further acts to characterize Form X. The collection of peaks that distinguish, e.g., Form X from the other known forms is a collection of peaks that characterize Form X. Those of ordinary skill in the art will recognize that there are often multiple ways, including multiple ways using the same analytical technique, to characterize solid forms. Additional peaks could also be used, but are not necessary, to characterize the form up to and including an entire diffraction pattern. Although all the peaks within an entire XRPD pattern may be used to characterize such a form, a subset of that data may, and typically is, used to characterize the form.

[0266] An XRPD pattern is an x-y graph with a diffraction angle (typically °20) on the x-axis and intensity on the y-axis. The peaks within this pattern may be used to characterize a crystalline solid form. As with any data measurement, there is variability in XRPD data. The data are often represented solely by the diffraction angle of the peaks rather than including the intensity of the peaks because peak intensity can be particularly sensitive to sample preparation (for example, particle size, moisture content, solvent content, and preferred orientation effects influence the sensitivity), so samples of the same material prepared under different conditions may yield slightly different patterns; this variability is usually greater than the variability in diffraction angles. Diffraction angle variability may also be sensitive to sample preparation. Other sources of variability come from instrument parameters and processing of the raw X-ray data: different X-ray instruments operate using different parameters. These may lead to slightly different XRPD patterns from the same solid form, and similarly different software packagesprocess X-ray data differently. This also leads to variability. These and other sources of variability are known to those of ordinary skill in the pharmaceutical arts. Due to such sources of variability, it is usual to assign a variability of ±0.2 °29 to diffraction angles in XRPD patterns.

[0267] The term “about”, “substantially” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to ± 20 %, preferably up to ± 10 %, more preferably up to ± 5 %, and more preferably still up to ± 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value. “Substantially as shown in” refers to any crystalline forms characterized by the graphical data in the identified figure, optionally having one or more of small variations, e.g., one or more variations described below or known to one of skill in the art. Such data may include, without limitation, powder X- ray diffractograms, differential scanning calorimetry curves, and thermogravimetric analysis curves, among others. As is known in the art, such graphical data may provide additional technical information to further define the crystal polymorph, amorphous solid form, or other composition. As is understood by one of skill in the art, such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity. Nonetheless, one of skill in the art will readily be capable of comparing the graphical data in the figures herein with graphical data generated for a crystal polymorph, amorphous solid form, or other composition and confirm whether the two sets of graphical data are characterizing the same material or two different materials.

[0268] For example, the term “substantially” when used in the context of A being “substantially free” of B means A contains less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5% of B. For example, if a particular crystalline form is described to be substantially free of other crystalline forms, it can be that the crystalline form contains less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5% by weight or by mole of other crystalline forms.

[0269] As used herein, “administering” refers to providing a compound or other therapy, remedy,or treatment such that an individual internalizes a compound. “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors.

[0270] “Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

[0271] The term “complex” as used herein, refers to a composite of two or more chemical entities where the chemical entities are associated in a non-covalent manner. Complexes can include cocrystals, salts, and other non-covalent composites, and solvates, and hydrates thereof. For example, in the context of “complex of xanomeline and quercetin”, the complex can be a cocrystal of xanomeline and quercetin, a salt of xanomeline and quercetin, or solvate or hydrate thereof.

[0272] The term “trospium pamoate” as used herein refers to a salt comprising one pamoate anion and at least one trospium cation e.g., one trospium cation or two trospium cations). For example, trospium pamoate disclosed herein may be trospium hemipamoate, which includes two trospium cations and one pamoate anion. In other examples, trospium pamoate as disclosedherein may be a salt comprising one pamoate anion, one trospium cation, and one additional cation as a counterion to the pamoate anion. Examples of the additional cation include, but are not limited to, an alkali cation, such as sodium cation (Na+) or potassium cation (K+). In some examples, the trospium pamoate can be a trospium alkali pamoate, such as a trospium sodium pamoate and trospium potassium pamoate.

[0273] As used herein, “disease” is generally synonymous and is used interchangeably with “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms and causes the human or animal to have a reduced duration or quality of life.

[0274] The term “movement disorders” includes, but is not limited to, Gilles de la Tourette’s syndrome, Friederich’s ataxia, Huntington’s chorea, restless leg syndrome and other diseases or disorders whose symptoms include excessive movements, ticks and spasms.

[0275] The term “addictive disorders” refers to diseases or conditions marked by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM-5). Such disorders are characterized by physical dependence, withdrawal and tolerance to a substance. Such substances include but are not limited to alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine and cannabis. Addictive disorders also encompass behaviors that a patient does compulsively or continually despite clear negative consequences. For instance, ludomania (gambling addiction, or compulsive gambling) is recognized by those skilled in the art as being an addictive behavior that often has devastating consequences. In certain embodiments, the addictive behavior may be Internet Gaming Disorder (gaming addiction), as defined in the DSM-5.

[0276] The term “pain” refers to physical suffering or discomfort caused by illness or injury. Pain is a subjective experience and the perception of pain is performed parts of the central nervous system (CNS). Usually noxious (peripheral) stimuli are transmitted to the CNS beforehand, but pain is not always associated with nociception. A broad variety of clinical pain exists, derived from different underlying pathophysiological mechanisms and needing different treatment approaches. Three major types of clinical pain have been characterized: acute pain, chronic pain, and neuropathic pain.

[0277] Acute clinical pain may result, for example, from inflammation or soft tissue injury. This type of pain is adaptive and has the biologically relevant function of warning and enabling healing and repair of an already damaged body part to occur undisturbed. A protective functionis achieved by making the injured or inflamed area and surrounding tissue hypersensitive to all stimuli so that contact with any external stimulus can be avoided. The neuronal mechanisms underlying this type of clinical pain are well understood and pharmacological control of acute clinical pain is available and effective, for example by means of nonsteroidal anti-inflammatory drugs (NSAIDs) up to opioids depending on type and extent of the sensation of pain.

[0278] Chronic clinical pain appears as sustained sensory abnormalities resulting from an ongoing peripheral pathology such as cancer or chronic inflammation (e.g., arthritis) or it can be independent of such initiating triggers. Chronic pain independent of initiating triggers is maladaptive, offering no survival advantage, and very often no effective treatment is available.

[0279] Neuropathic pain can be classified as peripheral or central. Peripheral neuropathic pain is caused by injury or infection of peripheral sensory nerves, whereas central neuropathic pain is caused by damage to the CNS and / or the spinal cord. Both peripheral and central neuropathic pain can occur without obvious initial nerve damage.

[0280] As used herein, “in need of treatment” and “in need thereof’ when referring to treatment are interchangeable to refer to a judgment made by a caregiver e.g., physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is based on a variety of factors in the realm of a caregiver’s expertise, but that includes the knowledge that the individual or animal is ill or will become ill as the result of a disease, condition, or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can alleviate, inhibit, or ameliorate the disease, condition, or disorder.

[0281] The term “mammal” is known in the art. Exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).

[0282] The term “muscarinic receptors” refers to G-protein linked receptors that bind the neurotransmitter acetylcholine. To date, five subtypes of muscarinic receptor have been identified. “Ml” means the subtype one muscarinic receptor. “M2” means the subtype two muscarinic receptor. “M3” means the subtype three muscarinic receptor. “M4” means the subtype four muscarinic receptor. “M5” means the subtype five muscarinic receptor.

[0283] The terms “parenteral administration” and “administered parenterally” are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection. These modes include without limitation intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.

[0284] A “patient,” “subject” or “host” to be treated by the subject method mean either a human or non-human mammal.

[0285] As used herein, “pharmaceutical composition” refers to a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0286] As used herein, “pure” means about 90-100%, such as 95-100%, 98-100% (wt / wt), or 99-100% (wt / wt) pure compound; e.g., less than about 10%, less than about 5%, less than about 2% or less than about 1% impurity is present. Such impurities include, e.g., degradation products, oxidized products, epimers, solvents, and / or other undesirable impurities.

[0287] When ranges of values are disclosed, and the notation “from m ... to n ” is used, where and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 M (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0288] As used herein, “room temperature” refers to a temperature between 68 °F and 86 °F (20 °C to 30 °C).

[0289] “ Solvate” as used herein refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0290] The term “therapeutic agent” is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance acting locally or systemically in a subject. Examples of therapeutic agents, also referred to as “drugs,” are described in well-known literature references such as the Merck Index (15th edition), the Physicians’ Desk Reference (71st edition), and The Pharmacological Basis of Therapeutics (14th edition). These therapeutic agents include without limitation medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.

[0291] As used herein, “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio and are effective for their intended use.

[0292] The term “therapeutically effective amount,” as used herein, is the amount of compound disclosed herein present in a formulation described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a formulation is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound disclosed herein, the specific activity of the formulation, the delivery device employed, the physical characteristics of the formulation, its intended use, as well as subject considerations such as severity of the disease state, subject cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.

[0293] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, formulations, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0294] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0295] The term “wt.%” is the weight percent based on the total weight, e.g., of the core, or enteric coating, or total bead, as described in context. Unless stated otherwise, the wt.% isintended to describe the weight percent based on dry weight (e.g., for a core following drying).

[0296] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter.

[0297] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[0298] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and all combinations or any two or more of the steps or features unless specifically stated otherwise.

[0299] The present invention(s) is not limited in scope by the specific embodiments described herein, which are intended for exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0300] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0301] All references, patents, or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.

[0302] Further embodiments include the embodiments disclosed in the following Examples, which is not to be construed as limiting in any way.EXAMPLES

[0303] The following examples are included to demonstrate some embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the disclosure. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain a like orsimilar result without departing from the spirit and scope of the disclosure; therefore, all matter set forth is to be interpreted as illustrative and not in a limiting sense.General Materials and MethodsA. Materials

[0304] Karuna Therapeutics provided the starting xanomeline (Frontier SSI, batch number: 2151 / 136) and trospium chloride (Procos, batch number: 322163). Quercetin was purchased from Sigma-Aldrich (Q4951 -100G). All other chemicals and solvents were purchased from either VWR, Fisher Scientific or Sigma Aldrich. HPLC-grade solvents were used for the HPLC and UPLC analyses.B. High-Throughput X-ray powder diffraction (HT- XRPD)

[0305] HT-XRPD patterns were obtained using the Ardena T2 high-throughput XRPD set-up. The plates were mounted on a Broker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector corrected for intensity and geometric variations. The calibration of the measurement accuracy (peaks position) was performed using NIST SRM1976 standard (Corundum).

[0306] Data were collected at room temperature using monochromatic Cu Ka radiation in the 20 region between 1.5° and 41.5°, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 20 ranges (1.5° < 20 < 21.5° for the first frame, and 19.5° < 20 < 41.5° for the second) with an exposure time of 90 seconds for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.C. High Resolution X-Ray Powder Diffraction (HR- XRPD)

[0307] The HR-XRPD data were collected on a D8 Advance diffractometer using Cu Kai radiation (1.54056 A) with a germanium monochromator at room temperature (296 K). Diffraction data were collected in the 20 range 1.5-41.5°. Detector scan on solid state LynxEye detector was performed using 0.01735° per step with 4 sec / step scan speed. The samples were measured in 8 mm long glass capillary with a 0.5-mm outer diameter.

[0308] Cell parameters as well as crystal system were obtained using LSI-Index indexing program. See Coelho, A. A. (2003). Indexing of powder diffraction patterns by iterative use of singular value decomposition. Journal of Applied Crystallography , 36, 86-95 Coelho, A. A. & Kem. A. (2005); Discussion of the indexing algorithms within TOPAS. CPD Newsletter, 32, 43-45. The space group was selected on reflections condition and density of the crystal. The cell parameters, purity as well as instrument parameters were refined using the whole powder pattern decomposition method. See Pawley, G. S. (1981), “Unit-cell refinement from powder diffraction scans.” J. Appl. Cryst., 14, 357- 361.D. TGA / SDTA and TGMS analysis

[0309] TGA determined mass loss due to solvent or water loss from the crystals. Monitoring the sample weight, during heating in a TGA / DSC 3+ STARe system equipped automatic sample robot (Mettler- Toledo GmbH, Switzerland), resulted in a weight versus temperature curve and a heat flow signal. The TGA / DSC 3+ was calibrated for temperature with samples of indium and aluminum. Samples (1-2 mg) were weighed in 100 jrL aluminum crucibles and hermetically sealed. The lids were pin-holed, and the crucibles heated in the TGA from 25 °C to 300 °C or 350 °C at a heating rate of 10 °C / min. Dry N2 gas was used for purging.

[0310] The gases coming from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 350 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer, which analyzes masses in the temperature range of 0-200 amu.E. DSC analysis

[0311] Thermal events were obtained from DSC thermograms, which were recorded with a heat flux DSC3+ STARe system equipped with an automatic sample robot (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6 °C; 6Hf = 28.45 J / g) and zinc (m.p. = 419.6 °C; 5Hf = 107.5 J / g). Samples (1-2 mg) were hermitically sealed in standard 40 pL aluminum pans, pin-holed and heated in the DSC from 25 °C to 300 °C or 350 °C, at a heating rate of 10 °C / min if not specified differently. Dry N2 gas, at a flow rate of 50 mL / min was used to purge the DSC equipment during measurement.F. NMR spectroscopy

[0312] 1H- and 13C- NMR spectroscopy was used to confirm compounds integrity stoichiometry of the crystalline forms. DMSO-de was used as a solvent. The spectra were recorded at room temperature on a 500 MHz instrument (Broker BioSpin GmbH) using standard pulse sequences. The data was processed with ACD Labs software Spectrus Processor 2016.2.2 (Advanced Chemistry Development Inc. Canada).G. Other Methods

[0313] Two HPLC methods were developed and used for these examples. Method 1 was used for the assessment of sample purity and Method 2 was used for the quantitative determination of low xanomeline-quercetin concentrations.Method 1 ParametersConcentration: appr. 1 mg / mL Solvent: MethanolMethod 2 ParametersConcentration: appr. 1 mg / mLSolvent: Methanol

[0314] Water sorption isotherms were collected on a DVS Adventure-I system from Surface Measurement Systems (London, UK). The relative humidity was cycled from 40% to 90% (sorption) and 90% to 40% (desorption) in steps of 10% at a constant temperature of 25°C. Weight equilibration was set with a dm / dt of 0.002% / min with a minimum holding time of 10 minutes and a maximum of six hours. Per the European Pharmacopeia Hygroscopicity classification, the solids can be classified based on the water uptake at 25 °C / 80%RH:1. Change in mass <0.2% — Non-hygroscopic2. Change in mass >0.2% & <2% — Slightly hygroscopic3. Change in mass >2% & <15% — Moderately hygroscopic4. Change in mass >15% — Very hygroscopic

[0315] Hot-stage microscopy measurements were performed on a Leica DM 2500M optical microscope. Measurements were carried out in the range of 25 °C to 350 °C with a heating rate of 5 °C / min. Pictures were taken every 1 °C.Example 1 - Xanomeline-Quercetin Complex Formation

[0316] The polymorphic behavior of the xanomeline-quercetin complexes revealed several crystalline forms. The identified solid phases were characterized by1H-NMR, DSC, TGMS, and LCMS. Form I was the most frequent form of the complex of xanomeline and quercetin, and crystallized from a variety of solvents (z.<?., water, alcohols, ketones, alkanes, esters, cyclic ethers as well as mixtures thereof).

[0317] The following experimental procedures describe the preparation of several batches of complexes of xanomeline and quercetin (also referred to herein as XQ complexes or XQ) that was used as a starting material for different experiments.A. XQ Form I preparation by evaporative crystallization

[0318] A 40 mL screw cap vial was charged with xanomeline (140.5 mg; 0.5 mmol) and quercetin (151 mg; 0.5 mmol) in 1: 1 molar ratio. Acetone (6.0 mL) was added to the mixture and stirred in an oven at 50 °C for one hour to achieve complete dissolution. Subsequently, theopen vial was stirred at ambient temperature to allow slow evaporation of acetone. Complete evaporation of acetone led to the obtainment of Form I as a solid in quantitative yield.

[0319] This solid was used as starting material for slurry conversion experiments and solubility assessment.B. XQ complex Form IV preparation by evaporative crystallization for polymorph screening

[0320] A 40 mL screw cap vial was loaded with xanomeline (422 mg; 1.5 mmol) and quercetin (453 mg; 1.5 mmol) in 1: 1 molar ratio. Then, acetone (20 mL) was added to the mixture.

[0321] The resulting slurry was placed into an oven and kept at 50 °C for one hour, to achieve complete dissolution. Subsequently, the vial was kept open at ambient temperature overnight, to allow acetone evaporation. The residue was dried for two hours under vacuum (10 mbar) to provide XQ Form IV as a solid in quantitative yield. This solid was used to prepare amorphous phase to be used as starting material for the polymorph screening experiments by thermocycling.

[0322] A 500 mL Erlenmeyer flask was charged with xanomeline (2.81 g; 10 mmol) and Quercetin (3.02 g; 10 mmol) in 1 : 1 molar ratio. Ethanol (160 mL) was added to the mixture. The resulting mixture was stirred at 50 °C for two hours to achieve complete dissolution. The mixture was allowed to cool down and was stirred at ambient temperature until ethanol evaporated. XRPD analysis of the residual solid revealed that XQ Form IA was obtained as a powder. The solid was suspended in 80 mL of acetone / water (95 / 5; v / v) mixture and stirred for 24 hours at ambient temperature. Subsequently, the slurry was filtered through a P4 filter to provide XQ Form I as a solid (4.36 g; 75%). XRPD analysis of the residual solid revealed that XQ Form I was obtained.D. Polymorphic Landscape Investigation

[0323] The solubility of XQ Form I was assessed in different solvents at ambient temperature. XQ Form I (5-7 mg) was placed into a vial. A solvent was added portion-wise (4 x 50 pL; 6 x 100 pL; 2 x 200 pL) until complete dissolution (determined by visual inspection) occurred or a maximum volume of 1.2 mL was reached. The experimental conditions and estimated solubility values are given in Table 1.Table 1. Summary of the estimated solubility determination of XQ Form I.

[0324] Slurry. Seven slurry experiments were performed to improve crystallinity of XQ Form I. A 1.8 mL vial was loaded with about 25 mg of XQ Form I and the corresponding solvent. Subsequently, the resulting slurry was stirred at ambient temperature for 72 hours. After equilibration, the solid phase was isolated by centrifugation, dried at ambient conditions and analyzed via HT-XRPD.

[0325] Attempts to generate amorphous complexes. Eighteen 1.8 mL vials were charged with about 45 mg of XQ complex of Form IV. THF / water (9: 1) mixture (0.5 mL) was added to dissolve the solid. The resulting solutions were frozen in liquid nitrogen placed in the freeze dryer (Alpha 2-4 LD, Christ), and freeze-dried at -70°C overnight. After freeze-drying, a reference sample of the obtained solids was analyzed by XRPD, DSC and TGMS, indicating a low-crystallinity complex of XQ of Form IV. The other vials were used as starting material for the thermocycling experiments.

[0326] Polymorphic landscape assessment by thermocycling. The solvents listed in Table2 were added to the 1.8 mL vials containing low crystallinity XQ Form IV obtained by freeze-drying. Subsequently, the resulting mixtures were placed in a crystallization platform (Crystal 16™) and subjected to a temperature profile. Three temperature cycles between 50 °C and 5 °C were applied to the samples while stirring. A constant heating rate of 10 °C / h was applied for heating, whereas variable cooling rates of -20 °C / h, -10 °C / h and -5 °C / h were used from the first to the third cycle, respectively. Afterwards, the samples were aged for 72 hours at 25 °C, without stirring.

[0327] After the temperature profiling and aging, the solid and liquid phases were separated by centrifugation. The solids were dried at ambient conditions overnight and under vacuum (10 mbar, RT) and analyzed by HT- XRPD as ambient-dried and vacuum-dried solids,respectively. The mother liquors were evaporated under ambient conditions. Solid residues obtained by evaporation of solvents were also analyzed by HT-XRPD.

[0328] Experimental details and results of the thermocycling experiments are given in Table 2. The solids were dried at ambient conditions (AD) and under vacuum (VD) at RT overnight and analyzed by XRPD. The solvents were evaporated and obtained solids were analyzed by XRPD. The notation (-) indicates that no solid material was recovered, whereas (ly) stands for “low yield.’’Table 2. Experimental details and results of the thermocycling experiments.Example 2 - XQ Form I

[0329] A three-neck reactor (2 L) was charged with xanomeline (90 g; 0.32 mol; 1 .02 eq; MW 281.42) and quercetin (94.76 g; 0.314 mol; 1.00 eq; MW 302.24) and acetone / water 95 / 5 (v / v) mixture (1600 mL) was added as a solvent. The resulting slurry was stirred for 72 hours at ambient temperature. Subsequently, the slurry was filtered through a P4 filter. The mother liquor was used to wash out the mixture to the filter.

[0330] The collected solid was dried in vacuum (10 mBar) overnight to provide XQ Form I as a solid (158 g; 83.6% isolated yield). The isolated XQ Form I was characterized by DSC, TGMS, LCMS, and 1H- and13C-NMR, and remained physically stable upon exposure to accelerated aging conditions (40 °C / 75% RH) for 48 hours.

[0331] The XPRD analysis of XQ Form I showed the Peaks in Table 3. (See also FIG. 1.)Table 3. Observed Peak Table for Xanomeline- Quercetin complex XQ1Bold: Characteristic peaks

[0332] Solid XQ Form 1 was further analyzed thermogravimetrically from 25-300 °C at a heating rate of 10 °C / min (FIG. 2). The TGA analysis showed a mass loss of 1.4% between 50- 150°C, due to water release, confirmed by MS. The recorded mass loss of 1.4% would correspond to 0.46 mol of water per mol of XQ Form I. Decomposition started above 160 °C. The DSC shows an endothermic event at Tpeak 134.7 °C (FIG. 3).

[0333] Form I remained physically stable upon exposure to accelerated aging conditions (40 °C / 75% RH) for 48 hours. The HPLC analyses confirmed that XQ Form I can be obtained with a purity of 99.9% by area. Signal detected at a retention time of 8.29 min corresponds to xanomeline (m / z of 282.3 corresponds to [M+H]+; MW of xanomeline is 281.4 g / mol). The quercetin residue was detected at a retention time of 4.77 min (m / z of 303.2 corresponds to[M+H]+; MW of quercetin of 302.2 g / mol).

[0334] NMR spectroscopy confirmed a xanomeline to quercetin ratio of 1 : 1.Thermogravimetric analysis indicated that XQ Form I is a non-stochiometric hydrate. The TGMS data collected with different samples indicated that the content of water varied from 0.5 to 1 mol per mol of xanomeline-quercetin complex. XQ Form I melted simultaneously with the water release at Tpeak from about 129 °C to 136°C. The DSC trace of XQ Form I showed its melting as a broad endothermic event, typically from 117 °C (Tonset) to 143 °C (Tendset). The DSC also showed an endothermic event at Tpeak 134.7 °C, likely due to the water loss and melting.

[0335] Sorption / desorption behavior of XQ Form I was studied by Dynamic Vapor Sorption (DVS). The results indicated that, per the European Pharmacopeia Hygroscopicity classification, XQ Form I was slightly hygroscopic. Mass uptake at 25° C / 80% RH was 0.57%. The water uptake and release were reversible with minimal hysteresis. HT-XRPD analysis conducted upon completion of the DVS measurement confirmed that the recovered solid corresponded to the initial XQ Form I. Thus, no form conversion occurred.Example 3 - XQ Form IA

[0336] An XRPD pattern slightly different from the pattern of XQ Form I was recorded upon the analysis of the solids obtained in two evaporative crystallization experiments from ethanol, as shown in Table 4. The pattern was designated as XQ Form IA, as it was similar to XQ Form I (FIG. 4).Table 4. Observed Peak table for XQ Form IABold: Characteristic peaks

[0337] Although XQ Form IA remained physically stable upon exposure to accelerated aging conditions (40 °C / 75% RH) for 48 hours, further investigations indicated that XQ Form IA instead corresponds to a kinetic form, which can be easily converted into XQ Form I by slurry equilibration. The initially isolated form underwent complete conversion into XQ Form I upon leaving its acetone / water (9 / 1 ; v / v) slurry incubation at ambient temperature for 24 hours. Moreover, the formation of XQ Form IA seemed difficult to control, as the majority of evaporative crystallization experiments from ethanol still led to the isolation of XQ Form I. Thus, likely a specific ethanol evaporation rate favors the formation of XQ Form IA.

[0338] HT-XRPD patterns of XQ Form IA and resulting XQ Form I recorded upon the XQ Form IA slurry in acetone / water (9 / 1; v / v) incubation at ambient temperature for 24 hours.

[0339] LCMS analysis of the obtained XQ Form IA confirmed its purity of 98.4% (by area) and the presence of xanomeline and quercetin. Signal detected at a retention time of 8.23 min corresponds to xanomeline (m / z of 282.3 corresponds to [M+H]+; MW of xanomeline is 281.4 g / mol). The quercetin residue was detected at a retention time of 4.71 min (m / z of 303. 1 corresponds to [M+H]+; MW of quercetin of 302.2 g / mol).

[0340] XQ Form IA was analyzed by DSC and TG between 25 °C and 300 °C at a heating rate of 10 °C / min. The TG analysis of the obtained material showed a mass loss of 1.8% between 40 °C and 140 °C (FIG. 5), likely due to a water loss. The mass loss would correspond to 0.58 mol of water per mol of the xanomeline-quercetin complex. Decomposition of the material was observed above 160 °C (FIG. 6).

[0341] The DSC trace showed an endothermic event at Tpeak 132 °C, likely due to water loss and melting. Collectively, the data indicated that the thermal behavior of XQ Form IA is similar to that of XQ Form I.Example 4 - XQ Form II

[0342] XQ Form II was identified in mixtures with XQ Form I and XQ Form III upon completion of the thermocycling experiments from acetone, acetonitrile, ethanol and isopropanol. Holding XQ Form IV for 10 minutes at 125 °C led to the isolation of XQ Form II as a pure phase. XRPD analysis for XQ Form II provided the peaks in Table 5 and the pattern of FIG. 7.Table 5. Observed Peaks for XQ Form IIBold: Characteristic peaks

[0343] Form II remained physically stable upon exposure to accelerated aging conditions (40775% RH) for 48 hours. HPLC analysis confirmed that XQ Form II was isolated with a purity of 98.9% (by area). LCMS analysis of the isolated XQ Form II confirmed its purity of 98.9 % (by area) and the presence of xanomeline and quercetin. Signal detected at a retention time of 8.30 min corresponds to xanomeline. The quercetin residue was detected at a retention time of 4.74 min.

[0344] NMR spectroscopy confirmed the xanomeline to quercetin ratio as 1 to 1.Thermogravimetric analysis indicated that XQ Form II contained only residual water, thus it islikely an anhydrous form (FIG. 8). DSC trace showed a sharp endothermic event likely due to XQ Form II melting at Tpeakof 158 °C (Tonset 157 °C and Tendset160 °C, FIG. 9).Example 5 - XQ Form III

[0345] XQ Form III was isolated upon slurry conversion experiments from methanol. A Syrris Atlas HD Reactor (IL) was charged with xanomeline (19.9 g; 71 mmol; 1.02 eq.; MW = 281.42) and quercetin (21.03 g; 69.6 mmol; 1.0 eq.; MW = 302). Methanol (200 mL) was added to the mixture. The resulting slurry was stirred for 72 hours at ambient temperature. Subsequently, the slurry was filtered through a P4 filter. An extra portion of methanol (50 mL) was added to permit the thick slurry to pass through the filter. The collected mother liquor was reused twice to wash out the remaining product from the reactor. The collected solid was dried in vacuum (10 mBar) overnight to provide XQ Form III as a powder (34.7 g; 85.7% isolated yield).

[0346] A large batch (30 g) of XQ Form III was prepared by slurry conversion in methanol. An amount of 34.7 g of XQ Form III was obtained in 85.7% isolated yield. The identity and purity of the obtained form was confirmed by means of HT- and HR-XRPD, TGMS, DSC, HPLC, SEM, DVS (including XRPD after DVS),1H-NMR and13C-NMR analyses. XRPD analysis for XQ Form III provided the peaks in Table 6 and the pattern of FIG. 10.Table 6. Observed Peaks for XQ Form III.Bold: Characteristic peaks

[0347] Form III remained physically stable upon exposure to accelerated aging conditions (40 °C / 75% RH) for 48 hours. LCMS analysis of the obtained XQ Form III confirmed its purity of 99.7% (by area) and the presence of both. Xanomeline (RT of 8.27 min; m / z of 282.3 corresponds to [M+H]+; MW of Xanomeline is 281.4 g / mol) and quercetin (Quercetin RT of 4.76 min; m / z of 303.2 corresponds to [M+H]+ matches with the MW of quercetin of 302.2 g / mol).

[0348] NMR spectroscopy confirmed the xanomeline to quercetin ratio as 1 to 1. No impurities were observed in the analyzed sample.

[0349] Thermogravimetric analysis indicated that XQ Form III is an anhydrous form of xanomeline-quercetin complex: 0.3 - 0.7% weight losses were recorded upon TGA / DSC analyses of different samples (FIG. 11). The DSC trace showed a sharp endothermic event due to XQ Form III melting which occurred at Tpeak of 162-166°C (Tonset 163 °C, FIG. 12). The collected HPLC data confirmed that XQ Form III can be obtained with a purity of 99.9% (by area).

[0350] DVS results indicated that, per the European Pharmacopeia Hygroscopicity classification, XQ Form III is slightly hygroscopic, with a mass uptake at 25 °C / 80% RH of 0.58%. The water uptake and release were reversible with minimal hysteresis.

[0351] HT-XRPD analysis conducted after the DVS measurement and confirmed that the recovered solid corresponded to the initial XQ Form III (FIG. 10). Thus, no form conversion occurred.Example 6 - XQ Form IV

[0352] XQ Form IV was obtained as a poorly crystalline solid upon crystallization experiments from acetone and acetonitrile. Traces of it were detected in mixtures with XQ Form I upon thermocycling crystallization experiments from ethyl acetate and methyl ethyl ketone. The obtained phase remained physically stable upon exposure to accelerated aging conditions(40 °C / 75% RH) for 48 hours. XRPD analysis for XQ Form IV provided the peaks in Table 7 and the pattern of FIG. 13.Table 7. Observed Peaks for XQ Form IV.Bold: Characteristic peaks

[0353] NMR spectroscopy confirmed the xanomeline to quercetin ratio of 1 : 1. The sample contained about 3 mol% of acetonitrile and other volatile impurities (resonating at 2.64-2.89 ppm), which were removed by simple heating to 125 °C.

[0354] TGA / DSC analysis showed a mass loss of 2.2% between 40 °C and 140 °C (FIG. 14), likely due to a water loss as indicated by the MS. The mass loss corresponded to 0.7 mol of water per mol of xanomeline-quercetin complex. More sensitive DSC trace revealed a temperature-induced XQ Form IV to XQ Form II phase transition recorded as consequent endothermic and exothermic events between 98 °C and 120 °C, followed by melting of the formed XQ Form II at Tpeak of 159 °C (FIG. 15).

[0355] HPLC analysis confirmed the isolated sample purity of 98.9% (by area). LCMS analysis of the isolated XQ Form IV confirmed its purity of 98.9% (by area) and the presence of xanomeline and quercetin. Signal detected at a retention time of 8.31 min corresponds to xanomeline, and the Quercetin residue was detected at a retention time of 4.75 min.Example 7 - XQ Form V

[0356] XQ Form V was isolated upon the thermocycling crystallization from TBME. The obtained solid remained physically stable upon exposure to accelerated aging conditions(40 °C / 75% RH) for 48 hours. NMR spectroscopy confirmed the xanomeline to quercetin ratioof 1 : 1 as well as about 0.5 mol of TBME. XRPD analysis for XQ Form V provided the peaks in Table 8 and the pattern of FIG. 16.Table 8. Observed Peaks for XQ Form V.Bold: Characteristic peaks

[0357] TGA / DSC data agreed with the NMR analysis: A mass loss of 7.3% was recorded between 80 °C and 160 °C in TGA (FIG. 17), corresponding to the release of about 0.5 mol of TBME as confirmed by MS. These results suggest that XQ Form V corresponds to a TBME solvate that contains about 0.5 mol TBME per mol of xanomeline-quercetin complex.

[0358] The DSC trace showed a sequence of events of unconfirmed nature (FIG. 18): (a) strong endothermic event at Tpeak of 135 °C likely due to the TBME release (possibly with melting); (b) a weak exothermic event at Tpeaj< of 141 °C, possibly due to a new phasecrystallization; and (c) a strong endotherm at Tpeak of 153 °C likely due to melting of the crystallized phase. HPLC analysis confirmed the isolated sample purity of 99.1% (by area).Example 8 - XQ Form VI

[0359] Xanomeline FB (Lot# BME0179A) and quercetin dihydrate (Thermal Fisher, 97 wt%) were used as starting materials to test the co-reactive crystallization process at low starting temperature (i.e., 25 °C vs 50 °C). 1.24 g of quercetin dihydrate was dissolved in 40 mL of aceione / ILO (95:5 v / v) and stirred to yield a 31 mg / mL solution. 1 g of xanomeline was dissolved in 10 mL of acetone / FLO (95:5 v / v) to yield a 100 mg / mL solution. 3 mL of the xanomeline solution was added to the quercetin solution, and after 15 minutes the mixture was seeded with 2 wt% seeds of 40 mg XQ Form 1 in 1 mL of acetone / FLO (95:5 v / v). After 1 hour, the remaining xanomeline solution was added over the course of 2 hours, then cooled to 5 °C and aged for 48 hours before filtering and vacuum drying.

[0360] The isolated solids gave an XRPD pattern different from the identified forms so far. This pattern was characterized by DSC, TGA, XRPD and 'H-NMR. The results suggest a likely hydrate of XQ, named XQ Form 6. XRPD analysis for XQ Form VI provided the peaks in Table 9 and the pattern of FIG. 38.Table 9. Observed Peaks for XQ Form VI.Bold: Characteristic peaksExample 9 -Stability and Solubility StudiesA. Solid State Stability Studies for XQ Forms I and III

[0361] Solid Process induced phase transformation. About 100 mg of XQ Form I and XQ Form III was milled in stainless steel grinding vials with two steel beads without solvent / water (dry milling to simulate jet milling) and with 20% of water (to simulate nano-milling). The vials were mounted in a Retsch MM301 ball mill and the API was milled at a frequency of 20 Hz for 5 minutes. The ground solids were analyzed by HT-XRPD, TGA, HPLC and SEM.

[0362] Short-term solid phase stability study. The short-term stability of the various forms of the xanomeline-quercetin complexes was determined by incubating solid samples under the following conditions:. 40 °C / 75% RH; 3 weeks. 75 °C / 75% RH; 3 weeks• 121 °C / saturated steam; 30 minutes• 160 °C / dry heat; 2 hours

[0363] Clear 1.8-mL borosilicate glass vials were loaded with about 20 mg of the corresponding solid form. Subsequently, open vials with the solids were incubated under above-listed conditions. Dry- milled and wet-milled samples stability was assessed identically to the scaled up XQ Form I and XQ Form III. Additionally, control samples for each solid phase were prepared identically, and incubated together with the experimental samples, but in closed containers. Upon completion of the incubation time, solids were analyzed by HT- XRPD, TGA and LCMS.

[0364] Photostability. Photostability of XQ Form I and XQ Form III was assessed by exposing the corresponding samples to artificial daylight for 24, 48 and 72 hours. Anindividual sample was conducted for each time point. Three solid samples of each form (about 20 mg) were weighed out in 20 mL transparent to daylight volumetric flask. Three control samples were prepared by weighing the corresponding forms (about 20 mg) in 20 mL amberglass volumetric flasks. For in-solution photostability assessment, solutions of each form (about 10 mg) at concentrations of about 0.5 mg / mL in methanol (i.e., HPLC diluent) were prepared in UV light transparent metric flasks. Control samples were prepared identically, but amber-glass volumetric flasks were used instead of UV-light transparent ones. Control samples were subjected to the corresponding light exposure together with the test samples. The samples were withdrawn after the corresponding time intervals of either 24, 36 or 72 hours.

[0365] Subsequently, the solid samples were dissolved using methanol (reaching concentrations of about 1 mg / mL) before HPLC analysis. The in-solution samples were directly subjected to HPLC analysis. The used irradiation level corresponds to 64800 kJ / m2 per 24 hours (about 3.2 million Lux*hr).

[0366] pH-dependent solubility and stability. An HPLC vial was charged with about 25 mg of XQ Form I or XQ Form III and buffer (1.5 mL) was added. The resulting suspension was stirred for 5 minutes at ambient temperature before its pH was measured. Subsequently, the suspension was equilibrated at 37 °C for 48 hours under continuous stirring. Upon completion of the equilibration time, the liquid and solid phases were separated by centrifugation. The pH- dependent solubility of xanomeline-quercetin complexes was determined by HPLC analysis of the liquid phase. The solid phase was analyzed by HT-XRPD.

[0367] In-vitro release study. The in-vitro release (IVR) experiments were performed in triplicate per the following protocol. XQ Form I or XQ Form III (about 100 mg) was suspended in 35 mL of PBS. At different time points (1, 2, 3, 7, 10, 14, 17, 21, 24, and 28 days), an aliquot (1 mL) of dissolution medium was taken for HPLC analysis and the remaining liquid phase (34 mL) was discarded. The solid sample was retained, and the vial was replenished with 35 mL of fresh PBS (equilibrated at 37 °C). The sample was then incubated at 37 °C until the next time point. After 28 days, the residual solids were analyzed by HT-XRPD.

[0368] Results of the HPLC analyses are given in Table 10. The given concentration values are in pg / mL; “AV” stands for “average7’ and corresponds to the concentration of the corresponding form measured on the specific day. Data represented as “Day 30” correspond to the data collected during the “verification experiment”.Table 10. Concentrations (pg / mL) of Xanomeline-Quercetin complex in the liquid phases determined by HPLC.

[0369] XQ Forms I and III have similar behavior regarding their stability, solubility, and in- vitro release kinetics. Nevertheless, differences between XQ Form I and III were observed in the particle size and morphology. XQ Form I appeared as larger agglomerates (200-300 pm) of “plate-like” particles (1-2 pm). XQ Form III was represented by smaller agglomerates (20-30 pm) of “needle-like” particles (1-2 pm).

[0370] Attempts of process induced transformation by milling resulted into smaller XQ Form I agglomerates (about 20 pm). No changes were observed with XQ Form III; the initial agglomerates (20-30 pm) were preserved. Both Forms remained stable upon incubation under stress conditions (i.e., 3 weeks at 40 °C / 75% RH and 75 °C / 75% RH), and under “wet sterilization conditions” (i.e., 30 minutes in saturated steam at 121 °C). Exposure of XQ Forms I and III to artificial daylight for up to 72 hours (irradiation level corresponds to 64800 kJ / m2 per 24 hours (appr. 3.2 million Lux*hr) indicated that both XQ Form I and III remained stable upon daylight exposure in solid-state, whereas both forms decomposed significantly in solution. Incubation of XQ Form I and XQ Form III as slurry in different pH-media (pH of 1. 1 ; 4.5; 6.5 and 7.4) revealed that both forms remain physically stable at pH levels from 4.6 to 7.4. However, in the assessed highly acidic medium (i.e., pH of 1.1) both XQ Form I and III converted into hydrochlorides. The in-vitro release assessment suggested that XQ Forms I and III have similar IVR behavior in PBS, and slow dissolution kinetics. The dissolution for 24 hours resulted in concentrations of about 2 pg / mL. A longer incubation of 72 hours resulted in higher concentration of the solutes, reaching 8 pg / mL level.B. Solubility Studies of Xanomeline and Quercetin Complex

[0371] Xanomeline free base and quercetin were formed into Xanomeline Quercetin (XQ) complexes as described herein for example in Examples 1 to 8 in various solvents / solvent mixtures at different crystallization conditions. Seven solid phases were observed. All were isolated and well characterized for their solid-state properties. From I (XQ1) was shown to be the most stable form in water and suitable for long-acting formulations. Form IA is very similar to Form 1 in terms of DSC and TGA. Without wishing to be bound by theory, Form IA could be a kinetic form that can be easily converted into Form I by slurry equilibration. Form II (XQ2) was obtained at high-temperature crystallization. Form III (XQ3) is an anhydrate. Form IV (XQ4) was less stable with poor crystallinity. Form V (XQ5) is a hemi-TBME solvate. Form VI (XQ6) is a hydrate.

[0372] Solubility of the various crystalline forms of the complex of xanomeline and quercetin in various aqueous buffers was studied at 37 °C and compared to the solubility of xanomeline free base, and xanomeline tartrate. The results are shown in Table 11 below.Table 11 - Solubility of Xanomeline Free Base, Xanomeline Tartrate and Xanomeline Quercetin Form I

[0373] As observed, Form I of the complex of xanomeline and quercetin was much less soluble compared to either the free base or the tartrate salt.Example 10 - Trospium Pamoate Crystal Forms

[0374] From the metathesis reaction with pamoic acid disodium a number of new crystalline phases of salts of trospium and pamoate were identified, designated Form A (TPaml), Form B (TPam2), Form C (TPam3), Form D (TPam4), Form E (TPam5), Form F (TPam6), and FormM. Form A was obtained after a cooling crystallization from ethanol. Form B was obtained after a cooling crystallization from water. Form C was observed after a cooling crystallization from water among other methods described in this Example. Form D was obtained after an evaporation crystallization from THF / water 90 / 10. Form E was obtained after being slurried at room temperature. Form F was obtained after being slurried at 50°C. All solids analyzed contained traces of sodium chloride (NaCl). Form M was observed from heating Form C as a solid sample at controlled humidity then cooling in a liquid nitrogen bath.Trospium Pamoate Form A

[0375] 30 mg of Trospium Chloride was dissolved at a concentration of 31 mg / mL in EtOH. 34.1 mg (1.1 Equiv) of pamoic acid disodium salt was added and stirred for 4 hours at 50°C to dissolve the solids, followed by aging at room temperature for 1 day and at 5 °C for 1 day.Upon completion of the aging time, the solids were separated by centrifugation from the liquid phases, dried under vacuum (10 mbar) at room temperature for 24 hours. The solids were Form A.

[0376] *H -NMR analysis of trospium pamoate Form A showed a trospium to pamoate ratio of 1 :1. The two hydroxylic and two carboxylic protons of the pamoate were not visible in the1H- NMR.

[0377] The UPLC chromatogram showed the peak of pamoic acid and the peak of trospium together covering 99.7% pure active pharmaceutical ingredient (API). The UPLC analysis of Form A+NaCl showed the API peak at 5.14 minutes with an area of 16.6% and the counterion pamoic acid at 3.30 minutes with an area of 83.1%. The impurities had a total area of 0.3%.

[0378] A summary of the UPLC method is as follows:

[0379] The XRPD analysis for trospium pamoate Form A is provided in FIG. 32.Table 12. Observed Peak Table for trospium pamoate Form ABold: Characteristic peaks

[0380] Thermal analysis by TGMS and DSC showed a mass loss of 1.8% likely to be ethanol or water. The TGMS curve of Form A+NaCl showed a mass loss of 1.8% between 25-200 °C due to the loss of ethanol and water based on the MS spectrum (FIG. 19). Thermal decomposition started above 280 °C. At about 300 °C the salt disproportionated and the melting / decomposition of the components took place.

[0381] Form A +NaCl was analyzed by TGMS and DSC at a maximum temperature of 400 °C, to investigate whether the endothermic event at about 300°C in the DSC was related to thermal decomposition or also melting (FIG. 20). A mass loss of 1.8% was observed in the TGMS between 25 °C and 200°C due to the loss of ethanol and water. Thermal decomposition started at about 300 °C. The DSC curve of Form A+NaCl showed one broad endothermal event visible with a Tpeak at 56.8 °C, followed by two less broad endothermal events at 308.9 °C and335.9 °C. Thermal decomposition started during the endothermal event at 308.9 °C.Trospium Pamoate Form B

[0382] 30 mg of Trospium Chloride was dissolved at a concentration of 60 mg / mL in Water. 34.0 mg (1 .1 Equiv) of pamoic acid disodium salt was added and stirred for 4 hours at 50°C to dissolve the solids, followed by aging at room temperature for 1 day and at 5 °C for 1 day.Upon completion of the aging time, the solids were separated by centrifugation from the liquid phases, dried under vacuum (10 mbar) at room temperature for 24 hours. The solids were Form B.

[0383] 1H-NMR analysis of trospium pamoate Form B showed a trospium to pamoate ratio of 1:1. The two hydroxy lie and the two carboxylic protons of Pamoate are not visible in the 'H- NMR.

[0384] The UPLC showed the peak of pamoic acid and the peak of trospium together covering 98. 1 % pure API. The UPLC analysis of Form B+NaCl showed the API peak at 5.14 minutes with an area of 16.1% and the counterion pamoic acid at 3.30 minutes with an area of 82.0%.The impurities had a total area of 1.9%. The XRPD analysis for trospium pamoate Form B is provided in FIG. 33.Table 13. Observed Peak Table for trospium pamoate Form BBold: Characteristic peaks

[0385] The TGMS curve of Form B+NaCl showed a mass loss of 4.8% between 25 °C and 200 °C due to the loss of water based on the MS spectrum (FIG. 21). As Form B+NaCl contains 4.8 % water, it is a dihydrate. Thermal decomposition started above 280 °C.

[0386] The DSC curve of Form B+NaCl showed three broad endothermal events at 78.5 °C, 101.8 °C, and 237.3 °C (FIG. 22). The first two were related to the loss of solvent, in this case water. The third endothermal event at 237.3 °C was the start of the decomposition, as suggested by the loss of CO2 in the MS. This event was followed by an exothermic event at 243.4°C and thermal decomposition.

[0387] Form B +NaCl was reanalyzed by TGMS and DSC at a maximum temperature of 400 °C, to investigate whether the endothermic event at about 300 °C in the DSC was related to thermal decomposition or also melting.Trospium Pamoate Form C

[0388] The salt of trospium pamoate of Form C was obtained using various methods as exemplified below.

[0389] Example Method 1 : 521.79 mg of Trospium chloride was dissolved in water. 594. 1 mg of pamoic acid disodium salt was added to the solution. The sample was stirred for 4 hours at 50°C, then at room temperature for 24 hours and at 5°C for another 24 hours. The solids were isolated via centrifugation and dried at 50°C under vacuum for 4 days. The material was subsequently washed with water to afford Form C. Although a 1:1.1 ratio of trospium to pamoate was used, the aging process allowed other less stable forms of salt of trospium and pamoate to equilibrate to the more stable Form C.

[0390] Example Method 2: Trospium chloride solution of 30 mg / mL in water was mixed with pamoic acid disodium salt solution in distilled water at 1: 0.55 molar ratio. The sample was stirred at 50 °C for a day. The solids were isolated via centrifugation to afford TPam3 (Form C).

[0391] Example Method 3 : 496 mg of Trospium Chloride was dissolved in 10 mL of 50:50 (vohvol) MeOH:water at 18 °C. 278 mg of Pamoic acid disodium salt (0.55 molarequivalence) was dissolved in 10 mL of 50:50 (vokvol) MeOH:water at 18 °C. The Pamoic acid disodium salt solution was added into Trospium chloride solution over 5 minutes. The resulting slurry was stirred for 1 hour at 18°C, affording Form C. The slurry was filtered, washed with 5 mL of 50:50 (vohvol) MeOH:water and then with 10 mL of water. The solids were dried at 35°C under vacuum overnight. The solids were Form C.

[0392] Form C is a trospium hemipamoate and a non-stoichiometric hydrate, which takes up 6.5% water at a RH of 10% and had a maximum water content of 9.2% at 95% RH.

[0393] One crystal was selected for a single crystal X-ray diffraction study. Trospium pamoate was crystallized with mono-ionized trospium cations, double ionized pamoate anions, and water molecules in the ratio 2: 1 :~7. The simulated XRPD analysis for trospium pamoate Form C is provided in FIG. 23.

[0394] Variable Temperature XRPD analysis was performed by heating the solid samples from 25 °C to 150 °C in a semi-closed system. Slow dry nitrogen flowed over the sample to prevent oxidation at high temperature. During the measurement, the humidity was not controlled, but because of the dry nitrogen flow, the humidity in the chamber was assumed to be low.Diffractograms were recorded at 25, 70, 100, 120 and 150 °C and after cooling at 25 °C again. Form C appeared to be physically stable until 100 °C. Above this temperature amorphization occurred, possibly due to water loss. The VT-XRPD data agreed with the DSC curve (FIG. 25). Upon cooling to 25 °C, the material did not recrystallize and hence remained amorphous.Table 14. Observed Peaks Table for Trospium Pamoate Form CBold: Characteristic peaks

[0395] The solubility of the trospium pamoate Form 3 was determined in water (demi- water and HPLC-grade water). A suspension was prepared with a total concentration of 60 mg / mL at room temperature T. After 5 minutes of equilibration and after 24 hours of equilibration, an aliquot of the mother liquor was taken and filtrated to remove any particulate matter. The cleared mother liquor was analyzed by UPLC and the concentration of trospium was determined against a pre-prepared calibration line. The sample in HPLC-grade water was only analyzed after 24 hours. The results are given in concentration of trospium, as summarized in Table 15.Table 15. Results of the solubility determination of trospium pamoate Form C

[0396] The solubility of Trospium Pamoate Form C (TPam3) was determined in a phosphate buffer with a pH of 6.8. Two suspensions were prepared with a concentration of about 8 mg / mL. One was kept at RT and the other one was incubated at 37 °C. An aliquot of the mother liquor was extracted and filtrated after 2 h and 48 h equilibration. The mother liquor was analyzed using HPLC and the concentration of Trospium was determined using a calibration line. The results are given in concentration of Trospium. The results are summarized in Table 16.

[0397] It was observed that Form C was a stable form compared to other forms. Form A and Form B converted to Form C upon slurrying in DI water under ambient conditions for 72 h. Further, Form F converted to Form C upon slurring in water at 20°C.Table 16. Results of the solubility determination of trospium pamoate Form C in a phosphate buffer.

[0398] The HT-XRPD of the Form C samples equilibrated for 48 h RT and 37 °C in phosphate buffer (pH 6.8) are shown in FIG. 39. The diffractograms were identical to the starting material TPam3. The TPam3 that had been suspended in water for 24 h at RT showed minor differences in its diffractogram and was therefore designated TPam3a. The differences might be related to a different water content of the Trospium Pamoate after being suspended in water for 24 hours.

[0399] The physical stability of trospium pamoate Form C was evaluated for three weeks at 40 °C / 75% RH and 75 °C / 75% RH. About 10 mg of Form C were weighed into a vial and placed into a climate chamber at 40 °C / 75% RH and 75 °C / 75%RH. The vials were removed after three weeks and analyzed by UPLC, TGMS and HT-XRPD. XRPD analysis of the solids after incubation at both stress conditions for three weeks showed that the material appeared physically stable.

[0400] UPLC analysis of the samples after three weeks incubation under stress conditions demonstrated the chemical stability of the solid as no impurities were detected in the spectra.

[0401] The TGMS analysis of Form C after stability test showed a small difference in mass loss (FIG. 24). The sample incubated at 40 °C / 75% RH lost 7.7% weight. The sample incubated at 75 °C / 75% RH lost 8.1 % weight. Thermal decomposition started for both samples above 240 °C.

[0402] Suspensions of trospium pamoate Form C in phosphate-buffered saline (PBS, pH = 7.4) were made and equilibrated at 37 °C. After different equilibration times (1, 2, 3, 7, 10, and l4 days) the samples were centrifuged, and the mother liquors were removed. The pH of the mother liquors was measured and the concentration of trospium pamoate in the solution was determined using UPLC analysis and calculated using a calibration line. A freshly prepared and preheated PBS solution was added to the remaining solids of Form C. After the last measurements the remaining solids were washed with water and dried.

[0403] The pH of the PBS remained stable over the experiment and was within the range given by the manufacturer (pH 7.3-7.5). The concentration of trospium pamoate was determined to be 0.08 mg / mL, whether calculated from the pamoate peak in the UPLC or the trospium peak. It was also the same result after an incubation of 1 day or 4 days. These results suggested that the solution was saturated well before 24 hours of equilibration, as shown in Table 17.Table 17. Results of the IVR study.Trospium Pamoate Form D

[0404] 30 mg of Trospium Chloride was dissolved at a concentration of 63 mg / mL in THF- water (9- 1 v / v). 34.5 mg (1.1 Equiv) of pamoic acid disodium salt was added and stirred for 4 hours at 50°C to dissolve the solids, followed by aging at room temperature for 1 day and at 5 °C for 1 day. The solution was left to evaporate at ambient conditions for 24 hours, followed by drying under vacuum (10 mbar) for 24 h. The solids were Form D.

[0405] ’ H -NMR analysis of trospium pamoate Form D showed a trospium to pamoate ratio of 1:1. The two hydroxy lie and the two carboxylic protons of pamoate were not visible in the1H- NMR.

[0406] The UPLC showed the peak of pamoic acid and the peak of trospium together covering 99.3% pure API. The UPLC analysis of Form D + NaCl showed the API peak at 5. 15 minutes with an area of 13.9 % and the counterion pamoic acid at 3.31 minutes with an area of 85.4 %. The impurities had a total area of 0.5%. The XRPD analysis for trospium pamoate Form D is provided in FIG. 35.Table 18. Observed Peak Table for trospium pamoate Form D

[0407] The TGMS curve of Form D+NaCl showed a mass loss of 8.1% in two steps between 25 °C and 220 °C due to the loss of THF and water based on the MS spectrum (FIG. 26). Thermal decomposition started above 280 °C. A THF monosolvate of trospium pamoate would contain 8.45% solvent. As trospium pamoate Form D contains 8.1 % solvent, it could be a THF monosolvate.

[0408] The DSC curve of Form D+NaCl showed two endothermic events at 130.8 °C and 266.8 °C, respectively (FIG. 27). The first one at 130.8 °C was related to the loss of THF, and the second at 266.8 °C was related to the starting decomposition of the material.Trospium Pamoate Forms E and F

[0409] Preparation of Form E: 1 g (1 equivalent) Trospium Chloride and 1.1 equivalent pamoic acid disodium salt were combined in water at room temperature with the Trospium Chloride concentration of 30mg / mL. The resulting slurry yielded Form E. After vacuum drying the form was Form B.

[0410] Preparation of Form F: 30 mg (1 equivalent) Trospium Chloride and 1.1 equivalent pamoic acid disodium salt were combined in water at 50°C with the Trospium Chlorideconcentration of 60mg / mL. The resulting slurry yielded Form F.

[0411] Initial investigations of the TPam2 (Form B) crystallization process led to the identification and characterization of five TPam polymorphs, with one anhydrous form and four hydrate forms. Two hydrate forms, TPam5 and TPam6, were identified as new forms (Forms E and F, respectively).

[0412] Trospium pamoate Form E is a metastable hexahydrate that can lose water and convert to TPam2 (Form B).1H-NMR analysis of trospium pamoate Form E showed a trospium to pamoate ratio of 1 : 1 . Trospium pamoate Form F is monohydrate. 'H-NMR analysis of trospium pamoate Form F showed a trospium to pamoate ratio of 1 : 1. The XRPD analysis for trospium pamoate Form E is provided in FIG. 36. The XRPD analysis for trospium pamoate Form F is provided in FIG. 37.

[0413] The TGMS curve of Form E showed a mass loss of 12.635 % in between 25 °C and 150 °C based on the MS spectrum (FIG. 28), which roughly correlates to the loss of six molecules of water by weight. Thermal decomposition started above 280 °C. The DSC curve of Form E showed six endothermic and exothermic events at 52.91 °C, 94.89 °C, 217.15°C, 233.40 °C, 297.46 °C, and 335.37 °C (FIG. 29).

[0414] The TGMS curve of Form F showed a mass loss of 2.255% in between 25 °C and 150 °C based on the MS spectrum (FIG. 30), which roughly correlates to the loss of one molecule of water by weight. Thermal decomposition started above 280 °C.

[0415] The DSC curve of Form F showed three endothermic events at 126.57 °C, 304.07 °C, and 335.35 °C (FIG. 31).Table 19. Observed Peak Table for trospium pamoate Form EBold: Characteristic peaksTable 20. Observed Peak Table for trospium pamoate Form FBold: Characteristic peaksTrospium Pamoate Form M

[0416] A powder sample of Form C was placed in a glove box filled with nitrogen. The relative humidity inside the glove box was controlled to around 10%. The sample was heated inside the glove box at 70 °C for 1 hour. The sample was then dispersed on a sample holder and submerged in a liquid nitrogen bath. The sample remained suspended in liquid nitrogen until characterized as Form M.Table 21. Observed Peak Table for trospium pamoate Form MBolded: characteristic peaks

[0417] Single crystal structure data of Form M was collected using a Thermo Scientific Glacios 200 kV cryo-TEM with a Thermo Scientific Ceta-D detector using a wavelength of 0.02508 Ang. Operating voltage was set to 200 kV with a vacuum of 10-7 Pa. The sample was held at 83 K during data collection. Data acquisition and processing were carried out using Thermo Scientific EPU-D and either XDS, SHELXT, OR SHELXL, respectively. The structures were solved by intrinsic phasing methods and refined by full-matrix least-squares approach using the SHELXTL software package (G. M. Sheldrick, SHELXTL v2018 / 3, Broker AXS, Madison, WI USA). Structure refinements involved minimization of the function defined by w(|Fo| - |Fc|)2, where w is an appropriate weighting factor based on errors in the observed intensities, Fo is the structure factor based on measured reflections, and Fc is the structure factor based on calculated reflections. Agreement between the refined crystal structure model and the experimental X-ray diffraction data is assessed by using the residual factors R = 2 ||FO|-|FC|| / 2 F°| and wR = [ w(|Fo|-|Fc|)2 / w|Fo|]l / 2. Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Data completeness was recorded as 89.5% complete. The coordinates of all H atoms were placed in idealized locations and then refined according to geometric constraints.Table 22. Single Crystal X-Ray Analysis Data trospium pamoate Form MSolubility Studies of Crystalline Forms of Trospium and Pamoate

[0418] Trospium Chloride and disodium pamoate were used to form Trospium Pamoate (TPam) salt in different solvents / solvent mixtures at varied conditions as described in Example 10. Six solid phases were observed, and all were isolated for thorough solid-state characterizations. At least Forms A to D were observed to have solubility in water or aqueous environment much lower than trospium chloride. Form C (TPam3) was characterized as the most stable form and the ratio of Trospium to Pamoate is 2:1 (hemi-salt). Form C was observed as a hydrate with a solubility about 100,000-fold lower than Trospium Chloride. Solubility was also observed to be very low compared to trospium chloride for all other crystalline forms of the trospium pamoate. Given the higher drug load in a hemi-salt, Form C is particularly suited for long-acting formulation development. The rest of the Trospium Pamoate salt forms were a 1 :1 ratio of Trospium to Pamoate. Form A (TPam 1) is an anhydrate. Form B (TPam2), Form E (TPam5), and Form F (TPam6) were hydrates. Form D (TPam4) was THF solvate.

[0419] Solubility of trospium chloride has been observed to be >160 mg / mL in water and has been reported to be > 100 mg / mL (MedChemExpress, Product Data Sheet for Trospium chloride). In contrast, the solubility of the most stable crystalline form, Form C, was observed to be 0.012 mg / mL in water.Example 11. Exposure after Four Weekly Intramuscular (IM) Injections of Xanomeline- Quercetin Complex in Guinea Pigs

[0420] The objective of Phase 1 of this study was to determine exposure of different Xanomeline test articles. Dunkin Hartley Guinea pigs were first administered with four weekly intramuscular (IM) injections of Xanomeline- Quercetin complex (Form I), Xanomeline freebase, or vehicle. This was followed by a challenge dose given at 2 weeks after plasma levels were below the limit of quantitation. The objective of Phase 2 of the study was to determine the exposure of test article(s) after a single IM administration followed by serial collection of plasma samples for analysis of plasma concentrations.

[0421] The doses of the complex of xanomeline and quercetin used in this Example are provided based on the equivalent amount in weight (e.g. mg) of xanomeline free base.Phase 1

[0422] The induction doses of test and control articles were administered via IM injection to the left hind limb at doses of 25 mg / animal Xanomeline-Quercetin (98 mg / mL); 25 mg / animal Xanomeline free base (98 mg / mL); and vehicle (vehicle, 1% CMC, 0.1% PS80, 246 mM Trehalose in water). The injection volume was 0.25 mL / injection. Due to severe injection site reactions after the first dose in all test article dose groups, the remaining injection doses were reduced to 6.255 mg / animal (25 mg / mL) and administered to the right hind limb.

[0423] Plasma concentrations of Xanomeline following IM administration of Xanomeline- Quercetin was detectable through Day 66. Detectable plasma levels were only observed through Day 31 following IM injections of Xanomeline free base. No test article was detected in the vehicle animals.Table 23. Means (SD) Xanomeline Plasma Concentrations During the Induction PhaseBLOQ: Below Limit of Quantitation (1 ng / ml), NM: Not Measured

[0424] Challenge injections were administered via IM injection (0.125 mL) to the left para lumbar muscle and SC injection (0.250 mL) at the scruff of the neck 2 weeks after the plasma levels of Xanomeline were below the limit of detection. Xanomeline free base animals received the challenge dose on Day 51. Xanomeline-Quercetin animals received the challenge dose on Day 93. The animals were subjected to external examination prior to necropsy at 24 or 48 hours post injection of the challenge dose.Phase 2

[0425] Xanomeline- Quercetin was administered via IM injection at a total volume of 0.25 mL to the right hind limb on Day 1 at a dose of 2.25 mg / animal Xanomeline-Quercetin (8.9 mg / mL).Table 24. Plasma Concentrations of Xanomeline (ng / mL) after Administration ofXanomeline-Quercetin, via IM Injection, 2.25 mg / animalBLOQ: Below Limit of Quantitation (1 ng / ml), NA: Not Applicable, *Values excluded from PK calculationsExample 12. Pharmacokinetics in Male and Female New Zealand White Rabbits Following Intramuscular (IM) and Intravenous (IV) Dose Administration

[0426] The objectives of this study were to determine the exposure to xanomeline after single administration of xanomeline tartrate at 0.2 mg / kg intramuscular (IM; Leg 1 Group 1) or intravenous (IV; Leg 1 Group 2); and after 4, once weekly IM administrations of complexes of xanomeline and quercetin at 3 mg / kg / week (Leg 2 Group 1, 12 mg / kg total dose) or after a single IM injection of xanomeline quercetin (Form I) at 12 mg / kg (Leg 2 Group 2). The vehicle for IM injections in Leg 1 and Leg 2 was 1% CMC, 0.1% PS80, 247 mM Trehalose in water (pH ~ 7.1), with an osmolarity 263 mOsm, while the vehicle for the IV group was 0.9% saline.

[0427] The doses of the complex of xanomeline and quercetin used in this Example are provided based on the equivalent amount in weight e.g. mg) of xanomeline free base.Similarly, the doses of xanomeline tartrate used in this Example are expressed in the equivalent amount of xanomeline free base.

[0428] All animals survived to the end of this phase of the study and there were no bodyweight effects noted after any of the treatments. For animals in Leg 1, there were no findingsafter IM injection while moderate salivation was noted at 5 minutes post IV dose administration. There were no sex- related differences in exposure after IM or IV administration with data summarized in the tables below.Table 25. Xanomeline Tartrate Exposure SummaryTable 26. Average xanomeline plasma concentrations (ng / mL) for Leg 1 Group 1 and Leg 1 Group 2BLQ: Below Limit of Quantitation, NA: Not Applicable,Table 27. Average xanomeline plasma concentrations (ng / mL) for rabbits dosed IM 3 mg / kg weekly for four weeks with Xanomeline- Quercetin Complex (Leg 2 Group 1)- no sampleTable 28. Xanomeline plasma concentrations (ng / mL) for rabbits dosed with single 12 mg / kg IM injection with Xanomeline-Quercetin Complex (Leg 2 Group 2)Table 29. Mean (+SD) Pharmacokinetic Parameters of Intramuscular Xanomeline Tartrate (Leg 1 Group 1) and Xanomeline Quercetin (Leg 2 Group 2)

[0429] FIG. 41 A plots the mean (±SD) plasma concentration vs time profile of xanomeline for Leg 1 Group 1, Leg 1 Group 2, and Leg 2 Group 2 for 672 hours (28 days) after dosing. FIG. 41B presents the same data for 120 hours (5 days) after dosing. Xanomeline-quercetin complex provided detectable xanomeline in plasma 28 days after dosing.Example 13. Trospium Chloride Single-Dose Intramuscular and Intravenous Exploratory Pharmacokinetic and Tolerability Study in New Zealand White Rabbits

[0430] The objective of the study was to determine the exposure of Trospium Chloride solution after a single 0.12 mg / kg intramuscular (IM) administration (Group 1) or 0. 18 mg / kg intravenous (IV) administration (Group 2) followed by serial collection of plasma samples for analysis of plasma concentrations in male and female New Zealand White rabbits. The results are presented in FIG. 42 and Table 29.

[0431] The doses of trospium chloride used in this Example are provided based on the equivalent amount in weight (e.g. mg) of trospium.Table 30. Mean (±SD) Plasma Concentration of Trospium Following a Single Intramuscular or Intravenous dose at ~0.2 mg / kg in New Zealand White RabbitBLQ- Below quantitation limit 0.100 ng / mLNA- Not applicable

[0432] Systemic exposures to trospium were independent of sex and are summarized in Table 30 below.Table 31. Mean (±SD) Pharmacokinetic Parameters of Trospium Chloride following Intramuscular and Intravenous DoseNA- Not applicable;Example 14. Xanomeline and Trospium: An 8-Week Single Dose Intramuscular Pharmacokinetic Study in New Zealand White Rabbit

[0433] The objective of this study was to determine the pharmacokinetics of xanomeline quercetin and salts of trospium and pamoate when given via single intramuscular injections to rabbits. Xanomeline quercetin (Form I) or trospium pamoate (Form C) was administered to groups of 5 rabbits / sex / group as single intramuscular injections in the right biceps femoris at 12 mg / kg. The contralateral biceps femoris was injected with the vehicle (saline). Dose volumes for all injections were 0.15 mL / kg.

[0434] The doses of the complex of xanomeline and quercetin used in this Example are provided based on the equivalent amount in weight (e.g. mg) of xanomeline free base. Similarly, the doses of trospium pamoate used in this Example are expressed as the equivalent amount in weight of trospium.Table 32. Mean Plasma Concentrations (ng / mL) following a Single Intramuscular Dose of Xanomeline Quercetin or Trospium Pamoate at 12 mg / kg in New Zealand White Rabbits*NA- Not applicable, samples collected prior to dosing on day -1 were BLQ

[0435] FIG. 43 presents mean (±SD) plasma concentration vs time profile of xanomeline following a single intramuscular dose of xanomeline quercetin. FIG. 44 presents mean (±SD) plasma concentration vs time profile of trospium following a single intramuscular dose of trospium pamoate. Systemic exposures to xanomeline and trospium were independent of sex and are summarized in the table below.Table 33: Mean (±SD) Pharmacokinetic Parameters of Xanomeline Quercetin and Trospium Pamoate in New Zealand White Rabbit Following a Single Intramuscular Dose of Xanomeline Quercetin or Trospium PamoateExample 15. Single Dose Intramuscular Pharmacokinetic High Dose Study in Rhesus Monkeys

[0436] The objective of this study was to evaluate the pharmacokinetics of xanomeline quercetin and trospium pamoate administered to Rhesus Monkeys by an intramuscular injection as a single dose.

[0437] The doses of the complex of xanomeline and quercetin used in this Example are provided based on the equivalent amount in weight (e.g. mg) of xanomeline free base. Similarly, the doses of trospium pamoate used in this Example are expressed as the equivalent amount in weight of trospium.

[0438] Xanomeline quercetin (Form I) and trospium pamoate (Form C) were administered alone or in combination, via intramuscular injection to groups of 3 monkey s / sex / group. The total dose for the combination groups were (all expressed as xanomeline / trospium) 12 / 3 mg / kg combination administration (Group 1), 16 / 4 mg / kg combination administration (Group 2), 20 / 5 mg / kg combination administration (Group 3), or 20 / 5 mg / kg single administration into separate dosage sites (Group 4) and were administered into right quadriceps. The vehicle (1% NaCMC, 5% Mannitol, 1.0% Tween 80) was injected into the contralateral left quadriceps, xanomeline or trospium alone were administered into the right or left quadriceps at 20 / 0 and 0 / 5 mg / kg, respectively. The dose volumes ranged from 0.16 to 0.25 mL / kg. Blood samples were collected on Week -2 and on Day 1 at the following time points: at approximately 0.167, 0.5, 1, 2, 4, 8, 12, 24, 72, 120, 240, 336, 408, 504, 576, 672, 744, 840, 912, 1008, 1080, 1176, 1320, and 1344 hours. Two animals / sex in the 12 / 3 mg / kg group were euthanized on Day 29 and the remaining 1 animal / sex were euthanized on Day 57. For the remaining groups, 2animals / sex / group were euthanized on Day 28 while the remaining 1 animal / sex / group were euthanized on Day 56. Systemic exposures to xanomeline and trospium were determined in samples collected throughout the 57- / 58-day study period.Table 34. Systemic exposures to xanomeline and trospium following administration of xanomeline quercetin and trospium pamoate administered to Rhesus Monkeys by an intramuscular injection as a single doseTable 35. Xanomeline Mean Plasma Concentration (ng / mL) vs Time Following a Single Intramuscular Dose of Xanomeline Quercetin and Trospium Pamoate in Rhesus MonkeyValues imposed as 0 were below quantitation limit NA = not applicable;- = no sampleTable 36. Trospium Mean Plasma Concentration (ng / mL) vs Time Following a Single Intramuscular Dose of Xanomeline and Trospium in Rhesus MonkeyValues imposed as 0 were below quantitation limitX / T = Xanomeline / trospiumNA = not applicable;- = no sample

[0439] The following pharmacokinetic results were observed when xanomeline quercetin and trospium pamoate were administered in combination: Cmaxand AUCo-648hr of 43.2 ng / mL and 7880 ng*h / mL for xanomeline, and 80.9 ng / mL and 3580 ng*h / mL for trospium, respectively. The following pharmacokinetic results were observed when xanomeline quercetin and trospium pamoate were administered separately: Cmax and AUCo-648hr of 21.6 ng / mL and 5910 ng*h / mL for xanomeline, and 155 ng / mL and 4970 ng*h / mL trospium, respectively.Table 37: Mean (±SD) Pharmacokinetic Parameters of Xanomeline Quercetin in Rhesus Monkey Following a Single Intramuscular Dose of Xanomeline and Trospium0440] FIG. 45 presents mean (±SD) xanomeline plasma concentration vs time profiles forGroups 1-4. FIG. 46 presents mean (+SD) trospium plasma concentration vs time profiles for Groups 1-4.Table 38: Mean (±SD) Pharmacokinetic Parameters of Trospium Pamoate in Rhesus Monkey Following a Single Intramuscular Dose of Xanomeline and TrospiumExample 16. Single Dose Intramuscular Pharmacokinetic Low Dose Study in Rhesus Monkeys

[0441] The objective of this study was to evaluate the pharmacokinetics of a combination of xanomeline quercetin and trospium pamoate when administered to rhesus monkeys by an intramuscular injection as a single dose.

[0442] The doses of the complex of xanomeline and quercetin used in this Example are provided based on the equivalent amount in weight (e.g. mg) of xanomeline free base. Similarly, the doses of trospium pamoate used in this Example are expressed as the equivalent amount in weight of trospium.

[0443] Xanomeline quercetin (Form I) and trospium pamoate (Form C) were administered in combination, via intramuscular injection to groups of 3 male monkeys / group. The total dose for the combination groups were 0 / 0, (Group 1 vehicle control), 15 / 3.75 (Group 2), 30 / 7.5 (Group 3), 45 / 11.25 (Group 4), or 60 / 15 (Group 5) mg (xanomeline / trospium) and were administered into the right quadricep. The vehicle (1% NaCMC, 5% Mannitol, 1.0% Tween 80) was injected into the left quadricep of animals administered xanomeline / trospium and was injected into the right quadricep of animals only receiving vehicle administration. Dose volumes were administered at 1 mL / injection. Blood samples were collected on Week -2 and on Day 1 at the following time points: at approximately 0.167, 0.5, 1, 2, 4, 8, 12, 24, 72, 120, 240, 336, 408, 504, 576, and 672 hours.

[0444] All animals were euthanized on Day 29. Criteria for evaluation included survival, clinical observations (including detailed and injection site observations), food consumption (qualitative), body weights, clinical pathology parameters (hematology, coagulation, and serum chemistry), organ weights, macroscopic pathology and microscopic pathology (injection sites and brain gross lesions). Systemic exposures to xanomeline and trospium were determined in plasma samples collected throughout the 29-Day study period.Table 39: Mean (±SD) Pharmacokinetic Parameters of Xanomeline Quercetin in Rhesus Monkey Following a Single Intramuscular Dose of Xanomeline and Trospiumpurposes.Table 40: Mean (±SD) Pharmacokinetic Parameters of Trospium Pamoate in Rhesus Monkey Following a Single Intramuscular Dose of Xanomeline and TrospiumNote: mean half-lives generated using less than 3 half-lives and reported for informational purposes.

[0445] FIG. 47A presents mean xanomeline plasma concentrations for Groups 2-5 for 672 hours. FIG. 47B presents the same data for 50 hours. FIG. 48 presents mean trospium plasma concentrations for Groups 2-5.

[0446] Mean Cmax values for xanomeline and trospium did not appear to consistently increase with increasing dose levels, whereas AUCiast values of xanomeline and trospium generally increased with increasing dose in an approximate dose proportional manner.

[0447] There were no unscheduled deaths.

[0448] In conclusion, the following pharmacokinetic results were calculated: Cmax and AUCO-last of 17.5 ng / mL and 4560 ng-h / mL for xanomeline, and 67.0 ng / mL and 2260 ng-h / mL for trospium, respectively.

Claims

WHAT IS CLAIMED IS1 . A complex of xanomeline and quercetin.

2. The complex of claim 1 , wherein the complex is a crystalline form, optionally the crystalline form is chosen from Form I, Form IA, Form II, Form III, Form IV, and Form V, and Form VI.

3. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.4+0.2, 8.9+0.2, 13.3+0.2, 18.2+0.2, 25.3+0.2, and 26.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 1; a thermogravimetric analysis showing a mass loss of about 1.4% at between about 50 °C and about 150 °C; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 3; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 117 °C and about 143 °C; a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeak between about 129 °C and about 136 °C; and a differential scanning calorimetry trace substantially as shown in FIG 2.

4. The complex of claim 3, which is a hydrate comprising about 0.5 to about 1 mole of water per mole of xanomeline-quercetin complex.

5. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.5+0.2, 9.0+0.2, 12.7+0.2, 13.6+0.2, 25.1+0.2, and 26.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 4; a thermogravimetric analysis showing a mass loss of about 1.8% at between about 40°C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 5; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 113 and about 142 °C; and a differential scanning calorimetry trace substantially as shown in FIG 6.

6. The complex of claim 5, which is a hydrate comprising about 0.5 to about 0.6 mole of water per mole of xanomeline-quercetin complex.

7. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 7.4+0.2, 8.6+0.2, 12.6+0.2, 19.1+0.2, 23.6+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray pow der diffraction pattern substantially as shown in FIG. 7; a thermogravimetric analysis showing a mass loss of about 0.35% at between about 40 °C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 8; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 160 °C; and a differential scanning calorimetry trace substantially as shown in FIG 9.

8. The complex of claim 7, which is anhydrous.

9. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 8. 1+0.2, 24.2+0.2, 25.0+0.2, 25.3+0.2, 26.1+0.2, and 27.1+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 10; a thermogravimetric analysis showing a mass loss of about 0.3% at between about 25°C and about 150 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 11; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 161 and about 168 °C; a differential scanning calorimetry profile having a melt at a Tpeak between about 162 °C and about 166 °C; and a differential scanning calorimetry trace substantially as shown in FIG 12.

10. The complex of claim 9, which is anhydrous.

11. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.8+0.2, 13.0+0.2, 19.5+0.2, 23.7+0.2, 24.5+0.2, and 25.5+0.2 with radiation Cu Ka; an X-ray pow der diffraction pattern substantially as shown in FIG. 13; a thermogravimetric analysis showing a mass loss of about 2.2% at between about 40 °C and about 140 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 14; a differential scanning calorimetry profile having an endotherm / exotherm event at between about 157 and 161 °C; a differential scanning calorimetry profile showing a phase transition to Form II followed by a melt of the Form II; and a differential scanning calorimetry trace substantially as shown in FIG 15.

12. The complex of claim 11, which is a hydrate comprising about 0.7 mole of water per mole of xanomeline-quercetin complex.

13. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020,chosen from 6.1+0.2, 7.9+0.2, 14.2+0.2, 20.2+0.2, 24.8+0.2, and 25.8+0.2 with radiation Cu Ka; an X-ray powder diffraction patern substantially as shown in FIG. 16; a thermogravimetric analysis showing a mass loss of about 7.3% at between about 80 °C and about 160 °C due to a loss of tert- butyl methyl ether as indicated by mass spectroscopy; a thermogravimetric analysis coupled with a differential scanning calorimetry profile substantially as shown in FIG. 17; a differential scanning calorimetry profile having endotherm / exotherm events at between about 125 and 139 °C, about 141 °C, and between about 149 and 156 °C; and a differential scanning calorimetry trace substantially as shown in FIG 18.

14. The complex of claim 13, which is a tert-butyl methyl ether (TBME) solvate comprising about 0.5 mole of TBME per mole of xanomeline-quercetin complex.

15. The complex of claim 1 or 2, wherein the complex is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 4.6+0.2, 9.2+0.2, 13.0+0.2, and 13.9+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 38; a thermogravimetric analysis showing a mass loss of about 1.9% at between about 120 °C and about 140 °C due to a loss of tert- butyl methyl ether as indicated by mass spectroscopy; a differential scanning calorimetry profile having endotherm / exotherm events at between about 120 and 140 °C; a differential scanning calorimetry profile having a melt simultaneous with water release at a Tpeak between about 122 °C and about 126 °C; and a differential scanning calorimetry trace substantially as shown in FIG 40.

16. The complex of claim 15, which is a hydrate comprising about 0.5 to about 1 mole of water per mole of xanomeline-quercetin complex.

17. The complex of any one of claims 1 to 16, wherein the stoichiometry of xanomeline to quercetin is about 1 : 1 as demonstrated by proton nuclear magnetic resonance spectroscopy.I l l18. The complex of any one of the claims 1 to 17, which is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours.

19. The complex of claim 18, which is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks.

20. The complex of claim 19, which is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks.

21. The complex of any one of claims 1 to 20, wherein the complex has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%, optionally by high-performance liquid chromatography.

22. The complex of any one of claims 1 to 21, wherein the complex has total chemical impurities of not more than about 0.5% by high-performance liquid chromatography.

23. A crystalline form of trospium pamoate.

24. The crystalline form of claim 23, wherein the crystalline form chosen from Form C, Form A, Form B, Form D, Form E, Form F and Form M.

25. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, chosen from 6.5+0.2, 9.8+0.2, 10.1+0.2, 10.6+0.2, 14.2+0.2, 18.2+0.2, 19.8+0.2, 20.8+0.2, and 21.4+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 34; a thermogravimetric analysis showing a mass loss of about 7.4% at between about 40 °C and about 200 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 24; a differential scanning calorimetry profile having endotherm / exotherm events at between about 40 °C and about 113 °C and between about 120 °C and about 135 °C; anda differential scanning calorimetry trace substantially as shown in FIG 25.

26. The crystalline form of claim 25, which is a hemipamoate hydrate comprising about 1 mole of pamoate and up to about 7 moles of water per 2 moles of trospium.

27. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 10.39+0.2, 12.31+0.2, 13.11+0.2, 13.61+0.2, and 16.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 32; a thermogravimetric analysis showing a mass loss of between about 1.8% at between about 25 °C and about 200 °C due to a loss of ethanol and water as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 19; a differential scanning calorimetry profile having endotherm / exotherm events at between about 31 °C and about 82 °C, between about 301 °C and about 312 °C, and between about 312 °C and about 338 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 20.

28. The salt of claim 27, which is anhydrous and wherein the stoichiometry of trospium to pamoate is 1 :1 as demonstrated by proton nuclear magnetic resonance spectroscopy.

29. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 5.4+0.2, 9.9+0.2, 13.2+0.2, 14.8+0.2, 15.4+0.2, 18.9+0.2, 20.3+0.2, 20.4+0.2, and 25.3+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 33; a thermogravimetric analysis showing a mass loss of about 4.8% at between about 25 °C and about 200 °C due to a water loss as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 21;a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 60 °C and about 85 °C, between about 93 °C and about 113 °C, between about 226 °C and about 247 °C, between about 300 °C and about 308 °C, and between about 329 °C and about 337 °C; and a differential scanning calorimetry trace substantially as shown in FIG 22.

30. The crystalline form of claim 29, which is a hydrate comprising about 2 to 3 moles of water per 1 mole of trospium and 1 mole of pamoate.

31. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 8.3+0.2, 16.8+0.2, 20.0+0.2, and 20.7+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 35; a thermogravimetric analysis showing a mass loss of about 8% at between about 25 °C and about 220 °C due to a loss of tetrahydrofuran as indicated by mass spectroscopy; a thermogravimetric analysis coupled with mass spectroscopy substantially as shown in FIG. 26; a differential scanning calorimetry profile having endotherm / exotherm events at between about 115 °C and about 141 °C, and between about 258 °C and about 273 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 27.

32. The crystalline form of claim 31, which is a tetrahydrofuran solvate comprising about 1 mole of tetrahydrofuran per 1 mole of trospium and 1 mole of pamoate.

33. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from: an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 4.6+0.2, 9.3+0.2, and 19.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 36; a thermogravimetric analysis showing a mass loss of about 12% at between about 25 °C and about 150 °C; a thermogravimetric analysis substantially as shown in FIG. 28;a differential scanning calorimetry profile having endotherm / exotherm events between about 40 °C and about 75 °C, between about 75 °C and about 125 °C, between about 195 °C and about 250 °C, between about 280 °C and about 318 °C, and between about 319 °C and about 360 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 29.

34. The crystalline form of claim 33, which is a hexahydrate comprising about 6 moles of water per 1 mole of trospium and 1 mole of pamoate.

35. The crystalline form of claim 23, wherein the salt is characterized by one or more properties chosen from an X-ray powder diffraction pattern comprising three or more peaks, in terms of020, at 7.8+0.2, 10.8+0.2, 14.0+0.2, 15.6+0.2, 17.5+0.2, 18.4+0.2, and 20.5+0.2 with radiation Cu Ka; an X-ray powder diffraction pattern substantially as shown in FIG. 37; a thermogravimetric analysis showing a mass loss of about 2.25% at between about 25 °C and about 150 °C; a thermogravimetric analysis substantially as shown in FIG. 30; a differential scanning calorimetry profile having one or more endotherm / exotherm events between about 110 °C and about 150 °C, between about 290 °C and about 320 °C, and between about 321 °C and about 360 °C; and a differential scanning calorimetry trace substantially as shown in FIG. 31.

36. The crystalline form of claim 35, which is a monohydrate comprising about 1 moles of water per 1 mole of trospium and 1 mole of pamoate.

37. The crystalline form of claim 23, wherein the salt is characterised by an XRPD pattern comprising three or more peaks at 5.3+0.2° 20, 7.0+0.2° 20, 8.6+O.2020, 10.7+0.2° 20, 19.0+0.2° 20, or 21.3+0.2° 20.

38. The crystalline form of claim 37, wherein the XRPD pattern is substantially as shown in FIG. 49.

39. The crystalline form of claim 37 or 38, wherein the salt is anhydrous.

40. The crystalline form of any one of claims 37 to 39, wherein the salt comprises 2 moles of trospium to 1 mole of pamoate.

41. The crystalline form of any one of the claims 23 to 40, which is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for 48 hours.

42. The crystalline form of claim 41, which is physically stable upon exposure to accelerated aging conditions of 40 °C at 75% relative humidity for three weeks.

43. The crystalline form of claim 41 or 42, which is physically stable upon exposure to accelerated aging conditions of 75 °C at 75% relative humidity for 3 weeks.

44. The crystalline form of any one of claims 23 to 43, wherein the salt has a chemical purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by high-performance liquid chromatography.

45. The crystalline form of any one of claims 23 to 44, wherein the salt has total chemical impurities of not more than about 0.5% by high-performance liquid chromatography.

46. A pharmaceutical composition comprising a complex of xanomeline and quercetin of any one of claims 1 to 22.

47. The pharmaceutical composition of claim 46, further comprising a trospium salt.

48. The pharmaceutical composition of claim 47, wherein the trospium salt is a crystalline form of trospium pamoate as defined in any one of claims 23 to 45.

49. The pharmaceutical composition of claim 48, wherein the complex of xanomeline and quercetin is set forth in claim 3 or 4; and wherein the trospium pamoate salt is set forth in claim 25 or 26.

50. A method of treating or reducing the symptoms of a disorder ameliorated byactivating muscarinic receptors in a subject in need thereof, comprising administering to the subject:(a) a complex of xanomeline and quercetin as defined in any one of claims 1 to 22;(b) a salt of trospium and pamoate as defined in any one of claims 23 to 45; or(c) a pharmaceutical composition of any one of claims 46 to 48; optionally wherein the subject is administered both (a) and (b).51 . The method of claim 50, wherein the disorder is selected from schizophrenia, autism, Alzheimer’s disease (optionally Alzheimer’s disease with agitation, and / or Alzheimer’s disease with cognitive impairment), bipolar, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction or addictive disorder, schizoaffective disorder, tauopathy, and synucleinopathy.

52. The method of claim 50 or 51, wherein the disorder is schizophrenia.

53. The method of claim 50 or 51, wherein the disorder is Alzheimer’s disease.

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