Trospium hydrogen pamoate salt and crystal forms thereof

Abstract

The present disclosure relates to a hydrogen pamoate salt of trospium, and crystalline forms thereof. For example, the present disclosure relates to the hydrogen pamoate salt of trospium (compound of Formula I) and crystalline Forms G to L thereof.

Description

Attorney Docket No. 055920-813001WOTROSPIUM SALTS AND CRYSTAL FORMS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the filing date of US Provisional Application No.63 / 759,857, filed on February 18, 2025, the entire contents of which are incorporated by reference herein.FIELD

[0002] The present disclosure relates generally to trospium salts and crystal forms thereof. For example, the present disclosure relates to trospium hydrogen pamoate salts and crystalline Forms G to L thereof.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] Similarly, different salt form of compounds can lead to different properties and different utilities of the compound.

[0005] 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.Attorney Docket No. 055920-813001WOThis approach has the potential to provide a differentiated therapy, and to beneficially impact the lives of millions of people with serious mental illness.

[0006] Xanomeline and trospium both have defined pharmacokinetic properties that may not be suitable for all types of formulations and administration routes. Therefore, there is a need to develop new salt and solid forms of these compounds, for example, forms with desired features for use in specific types of formulations and administration routes.SUMMARY

[0007] The present disclosure generally relates to hydrogen pamoate salt of trospium, and various crystal forms thereof (for example Forms G to L), and pharmaceutical compositions thereof. The present disclosure also relates to methods of preparing the salt and the crystal forms, and to methods of treatment using the hydrogen pamoate salt of trospium of the present disclosure, for example in combination with xanomeline or a salt thereof. In particular, it has been shown here that some crystalline forms of the present disclosure, such as Form G, have very low solubility compared to other salts of trospium (such as trospium chloride and trospium sodium pamoate) and other crystalline forms. As such, the salt and crystalline forms of the present disclosure can be particularly suitable for certain formulations such as long-acting formulations, for example long-acting injectable formulations.

[0008] In one aspect, the present disclosure includes a hydrogen pamoate salt of trospium having a structure of Formula IOI.

[0009] In some embodiments, the hydrogen pamoate salt of trospium of Formula I is in a crystalline form, for example, Form G, Form H, Form I, Form J, Form K, and Form L as disclosed herein. For example, the crystalline form can be Form G. For example, the crystalline form can be Form H. For example, the crystalline form can be Form I. For example, theAttorney Docket No. 055920-813001WOcrystalline form can be Form J. For example, the crystalline form can be Form K. For example, the crystalline form can be Form L.

[0010] In some embodiments, the crystalline form is Form G., Such a crystalline form can be characterized by an X-ray Powder Diffraction (XRPD) pattern comprising three or more (e.g., four or more, or five or more) peaks at 4.9± 0.2° 29, 5.5± 0.2° 29, 6.4± 0.2° 29, 7.9± 0.2° 29, 8.5± 0.2° 29, 10.3± 0.2° 29, 13.7± 0.2° 29, 17.8± 0.2° 29, 18.1± 0.2° 29, and 19.7± 0.2° 29. In some examples, the XRPD pattern includes peaks at 4.9± 0.2° 29, 5.5± 0.2° 29, 6.4± 0.2° 2 9, 7.9± 0.2° 29, 8.5± 0.2° 29, 10.3± 0.2° 29, 13.7± 0.2° 29, 17.8± 0.2° 29, 18.1± 0.2° 29, and 19.7± 0.2° 29. In some instances, the XRPD pattern may further include one or more peaks at 8.2± 0.2° 29, 9.5± 0.2° 29, 9.8± 0.2° 29, 11.1± 0.2° 29, 11.4± 0.2° 29, 13.0± 0.2° 2 9, 14.1± 0.2° 29, 14.7± 0.2° 29, 15.0± 0.2° 29, 15.8± 0.2° 29, 16.1± 0.2° 29, 16.6± 0.2° 29, 17.1± 0.2° 29, 18.6± 0.2° 29, 19.2± 0.2° 29, 20.2± 0.2° 29, 20.6± 0.2° 29, 20.9± 0.2° 29, 21.2± 0.2° 29, 22.0± 0.2° 29, 22.3± 0.2° 29, 23.2± 0.2° 29, 24.0± 0.2° 29, 24.8± 0.2° 29, 25.5± 0.2° 29, 26.2± 0.2° 29, 27.1± 0.2° 29, 29.4± 0.2° 29, and 30.8 ± 0.2° 29.

[0011] In a specific example, the XRPD pattern of Form G can be substantially as shown in FIG. 1

[0012] In some instances, the crystalline form of Form G can be characterized by a differential scanning calorimetry (DSC) thermogram including at least one endotherm with an onset of about 217 °C. The endotherm with an onset of about 217 °C can have a peak at about 219 °C. The thermogram can further comprise a broad endothermic event at about 90 °C. For example, the DSC thermogram can be substantially as shown in FIG. 2.

[0013] Alternatively, or in addition, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing a mass loss of about 1.8 wt% from room temperature to about 175 °C. For example, the TGA can be characterized by a curve substantially as shown in FIG. 3.

[0014] Alternatively, or in addition, the crystalline form is characterized by a vapour sorption of about 2.3 wt% water uptake from 0% up to 95% relative humidity (RH). For example, the vapour sorption can be substantially as shown in FIG. 4.

[0015] In some examples, the crystalline form is a hydrate.

[0016] In some embodiments, the crystalline form can be Form H. Such a crystalline form can be characterized by an X-ray Powder Diffraction (XRPD) pattern including three or more (e.g., four or more, or five or more) peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 2 9, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29. For example, the XRPDAttorney Docket No. 055920-813001WOpattern may include peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 9.2° 29, 12.2± 9.2° 29, 13.0± 9.2° 29, 15.1± 9.2° 29, 18.0± 9.2° 29, and 19.5± 9.2° 29. In some examples,the XRPD pattern can further include one or more peaks at 9.3± 9.2° 29, 11.1± 9.2° 29, 14.0± 9.2° 29, 14.7± 9.2° 29, 15.7± 9.2° 29, 16.1± 9.2° 29, 17.3± 9.2° 29, 18.9± 9.2° 29, 29.4± 9.2° 29, 21.6± 9.2° 29, 23.2± 9.2° 29, 24.6± 9.2° 29, 25.5± 9.2° 29, 26.3± 9.2° 29, 27.5± 9.2° 29, 29.2± 9.2° 29, and 39.9± 9.2° 29.

[0017] In a specific example, the XRPD pattern of Form H can be substantially as shown in FIG. 5

[0018] In some instances,, the crystalline form of Form H can be characterized by a differential scanning calorimetry (DSC) thermogram including at least one endotherm with an onset of about 169 °C. The endotherm with an onset of about 169 °C can have a peak at about 181 °C. The DSC thermogram can further include a broad endothermic event at about 39 °C. For example, the DSC thermogram can be substantially as shown in FIG. 6.

[0019] Alternatively, or in addition, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing substantially no mass loss from room temperature to about 200 °C. for example, the TGA can be characterized by a curve substantially as shown in FIG. 7

[0020] In some embodiments, the crystalline form can be Form I. Such a crystalline form can be characterized by an X-ray Powder Diffraction (XRPD) pattern including three or more (e.g.. four or more, or five or more) peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 2 9, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0± 0.2° 29. In some examples, the XRPD pattern includes peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 29, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0± 0.2° 29. In some instances, the XRPD pattern can further include one or more peaks at 7.1± 0.2° 29, 12.0± 0.2° 29, 16.8± 0.2° 29, 17.9± 0.2° 29, 19.8± 0.2° 2 9, 20.5± 0.2° 29, 22.3± 0.2° 29, 22.9± 0.2° 29, and 24.2°± 0.2° 29.

[0021] In a specific example, the XRPD pattern of Form I can be substantially as shown in FIG. 8

[0022] In some examples, the crystalline form of Form I can be acetonitrile solvate.

[0023] In some embodiments, the crystalline form can be Form J. Such a crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern including three or more(e.g., four or more, or five or more) peaks at 8.2± 0.2° 29, 8.7± 0.2° 29, 9.9± 0.2° 29, 10.6± 0.2° 2 9, 11.5± 0.2° 29, 12.8± 0.2° 29, 17.3± 0.2° 29, 21.2± 0.2° 29, and 22.5± 0.2° 29. For example, the XRPD pattern can include peaks at 8.2± 0.2° 29, 8.7± 0.2° 29, 9.9± 0.2° 29, 10.6± 0.2° 29, 11.5± 0.2° 29, 12.8± 0.2° 29, 17.3± 0.2° 29, 21.2± 0.2° 29, and 22.5± 0.2° 2Attorney Docket No. 055920-813001WO9. In some instances, the XRPD pattern can further include one or more peaks at 9.2± 0.2° 29, 9.5± 0.2° 2θ, 10.3± 0.2° 2θ, 13.8± 0.2° 2θ, 14.3± 0.2° 2θ, 14.9± 0.2° 2θ, 15.5± 0.2° 2θ, 16.1± 0.2° 2θ, 16.4± 0.2° 2θ, 16.9± 0.2° 2θ, 18.0± 0.2° 2θ, 18.6± 0.2° 2θ, 19.6± 0.2° 2θ, 20.5± 0.2° 2θ, 20.8± 0.2° 2θ, 22.1± 0.2° 2θ, 23.2± 0.2° 2θ, 23.8± 0.2° 2θ, 24.2± 0.2° 2θ, 24.9± 0.2° 2θ, 25.5± 0.2° 2θ, 26.3± 0.2° 2θ, and 28.5± 0.2° 2θ.

[0024] In a specific example, the XRPD pattern of Form J can be substantially as shown in FIG. 9

[0025] In some instances, crystalline form of Form J can be characterized by a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 162 °C or 213 °C. The DSC endotherm can include an endotherm with an onset of about 162 °C and an endotherm at an onset of about 213 °C. The endotherm with an onset of about 162 °C can have a peak at about 176 °C. The endotherm with an onset of about 213 °C can have a peak at about 218 °C. For example, the DSC thermogram can be substantially as shown in FIG. 10

[0026] Alternatively, or in addition, the crystalline form can be characterized by a thermogravimetric analysis (TGA) showing substantially a mass loss of about 7.5 wt% from about 100 °C to about 200 °C. For example, the TGA can be characterized by a curve substantially as shown in FIG. 11.

[0027] In some examples, the crystalline form is a tetrahydrofuran (THF) solvate.

[0028] For example, in some embodiments, the crystalline form can be Form K. Such a crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern including three or more (e.g., four or more, or five or more) peaks at 7.7± 0.2° 29, 9.0± 0.2° 29, 9.5± 0.2° 29, 11.1± 0.2° 29, 12.8± 0.2° 29, 14.3± 0.2° 29, and 17.2 ± 0.2° 29. For example, the XRPD pattern can include peaks at 7.7± 0.2° 29, 9.0± 0.2° 29, 9.5± 0.2° 29, 11.1± 0.2° 29, 12.8± 0.2° 29, 14.3± 0.2° 29, and 17.2 ± 0.2° 29. In some instances, the XRPD pattern can further include one or more peaks at 7.1± 0.2° 29, 11.9± 0.2° 29, 12.3± 0.2° 29, 13.4± 0.2° 2 9, 14.9± 0.2° 29, 15.7± 0.2° 29, 18.5± 0.2° 29, 19.4± 0.2° 29, 19.8± 0.2° 29, 20.3± 0.2° 29, 20.6± 0.2° 29, 21.4± 0.2° 29, 22.3± 0.2° 29, 22.8± 0.2° 29, 23.2± 0.2° 29, 23.5± 0.2° 29, 26.3± 0.2° 29, 28.4± 0.2° 29, and 30.0 ± 0.2° 29.

[0029] In a specific example, the XRPD pattern of Form K can be substantially as shown in FIG. 12

[0030] In some examples, the crystalline form of Form K can be characterized by a differential scanning calorimetry (DSC) thermogram including at least one endotherm with an onset of about 140 or 215 °C., For example, the crystalline form can be characterized by a differentialAttorney Docket No. 055920-813001WOscanning calorimetry (DSC) thermogram including one endotherm with an onset of about 140 and one endotherm with an onset of 215 °C. The endotherm with an onset of about 140 °C can have a peak at about 151 °C. The endotherm with an onset of about 215 °C can have a peak at about 219 °C. For example, the DSC thermogram can further include a broad endothermic event at about 39 °C. For example, the DSC thermogram can be substantially as shown in FIG.13

[0031] Alternatively, or in addition, the crystalline form can be characterized by a thermogravimetric analysis (TGA) showing substantially a mass loss of about 8.2 wt% from about 100 °C to about 175 °C. For example, the TGA can be characterized by a curve substantially as shown in FIG. 14.

[0032] In some instances, the crystalline form is an ethanol solvate.

[0033] In some embodiments, the crystalline form can be Form L. Such a crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern including three or more (e.g., four or more, or five or more) peaks at 7.5± 0.2° 29, 8.7± 0.2° 29, 9.3± 0.2° 29, 14.4± 0.2° 2 9, 17.0± 0.2° 29, 19.2± 0.2° 29, and 22.8 ± 0.2° 29. For example, the XRPD pattern can include peaks at 7.5± 0.2° 29, 8.7± 0.2° 29, 9.3± 0.2° 29, 14.4± 0.2° 29, 17.0± 0.2° 29, 19.2± 0.2° 29, and 22.8 ± 0.2° 29. In some instances, the XRPD pattern can further include one or more peaks at 11.0± 0.2° 29, 11.9± 0.2° 29, 12.6± 0.2° 29, 15.5± 0.2° 29, 18.4± 0.2° 2 9, 20.4± 0.2° 29, 21.2± 0.2° 29, 24.9± 0.2° 29, 26.1± 0.2° 29, 28.5± 0.2° 29, 29.0± 0.2° 29, 29.8± 0.2° 29, and 30.4 ± 0.2° 29.

[0034] In a specific example, the XRPD pattern of Form L can be substantially as shown in FIG. 15

[0035] In some examples, the crystalline form of Form L can be a tetrahydrofuran (THF) solvate.

[0036] In another aspect, the present disclosure provides a pharmaceutical composition comprising a salt of Formula I of the present disclosure, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a muscarinic agonist, such as xanomeline or a salt or prodrug thereof. For example, the muscarinic agonist can produce xanomeline under physiological conditions. In some instances, the muscarinic agonist can be xanomeline or a salt thereof. For example, the xanomeline or salt thereof is in a crystalline form.

[0037] Crystalline form of xanomeline can include a complex of xanomeline and a coformer. Such suitable coformer includes for example quercetin. For example, the composition canAttorney Docket No. 055920-813001WOcomprise a complex of xanomeline and quercetin, such as a cocrystal of xanomeline and quercetin.

[0038] The pharmaceutical composition is formulated for various routes of administration. For example, the pharmaceutical composition can be formulated for injection such as a long-acting injection.

[0039] In another aspect, the present disclosure includes a pharmaceutical composition of the present disclosure for use in therapy. In another aspect, the present disclosure includes a method of treating a disease or disorder ameliorated by activating muscarinic receptors comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0040] In another aspect, the present disclosure includes a pharmaceutical composition of the present disclosure for use in the treatment of a disease or disorder ameliorated by activating muscarinic receptors.

[0041] In another aspect, the present disclosure includes a use of a pharmaceutical composition of the present disclosure in the treatment of a disease or disorder ameliorated by activating muscarinic receptors comprising administering to a subject in need thereof.

[0042] In another aspect, the present disclosure includes a use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease or disorder ameliorated by activating muscarinic receptors.

[0043] The disease or disorder ameliorated by activating muscarinic receptors can be a central nervous system (CNS) disorder. For example, the CNS disorder can be selected from schizophrenia, Alzheimer’s disease, bipolar disorder, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy. For example, the CNS disorder can include schizophrenia, Alzheimer’s disease, bipolar disorder or autism.

[0044] The pharmaceutical composition of the present disclosure can be administered by any suitable means of administration. For example, the pharmaceutical composition can be administered to the subject by injection. For instance, the injection can be intravenous injection, intramuscular, or subcutaneous injection. The pharmaceutical composition can be administered to the subject once every two days to once every six months.

[0045] In another aspect, the present disclosure includes a method of preparing a hydrogen pamoate salt of trospium of Formula I. In some embodiments, the method includes reacting trospium or a salt thereof with alkali hydrogen pamoate to produce the salt of Formula I. For example, the reacting comprises or consists essentially of a salt metathesis reaction. TheAttorney Docket No. 055920-813001WOreacting can be carried out at a molar ratio of trospium to pamoate of about 1: 1. In some embodiments, the trospium or salt thereof is trospium chloride and the method includes reacting trospium chloride with alkali hydrogen pamoate. The alkali hydrogen pamoate can be potassium hydrogen pamoate or sodium hydrogen pamoate.

[0046] In some instances, the trospium or salt thereof can be comprised in a first aqueous solution. Similarly, in some instances, the alkali hydrogen pamoate can be comprised in a second aqueous solution. For example, the second aqueous solution can include THF: water as a solvent. Optionally, the THF: water can be at a volume ratio of about 5:1 to about 9:1. The reacting can include contacting the first aqueous solution with the second aqueous solution to obtain a trospium pamoate solution. The reacting can be carried out with stirring.

[0047] In some embodiments, the method can further include drying the trospium pamoate solution. The method can further include providing the alkali hydrogen pamoate. For example, the alkali hydrogen pamoate can be provided by reacting pamoic acid and alkali hydroxide at a molar ratio of pamoic acid to alkali hydroxide of about 1:1. For example, the reacting of pamoic acid and alkali hydroxide can be carried out in a solvent of THF: water. The THF: water can be at a volume ratio of about 5:1 to about 9:1. Alternatively, the alkali hydrogen pamoate can be provided by reacting pamoic acid and disodium pamoate at a molar ratio of pamoic acid to disodium pamoate of about 1:1. For example, the reacting of pamoic acid and disodium pamoate can be carried out in a solvent of THF: water. The THF: water can be at a volume ratio of about 1.5:1.

[0048] In another aspect, the present disclosure includes a method of preparing a crystalline form of the salt of Formula I. In some embodiments, the method includes crystallising a hydrogen pamoate salt of trospium of Formula I in a solvent to obtain the crystalline form. The solvent can be selected from water and an organic solvent:water mixture.

[0049] The organic solvent: water can be acetone: water, acetonitrile: water, THF: water, or ethanol: water, or other suitable organic solvent mixtures as described herein. The acetone:water can be at a volume ratio of about 1:1. The acetonitrile:water can be at a volume ratio of about 1:1.

[0050] In some embodiments, the crystallising can be carried out with stirring. The crystallising can also be carried out at room temperature, or elevated temperature such as about 40 °C to about 70 °C. For example, the crystallising can be at about 40 °C. For example, the crystallising can be at about 50 °C. For example, the crystallising can be at about 60 °C. For example, the crystallising can be at about 70 °C.Attorney Docket No. 055920-813001WO

[0051] The method can further include drying the crystalline form obtained, such as in vacuo. The drying can be carried out at room temperature, or elevated temperature such as about 40 °C to about 70 °C. For example, the drying can be at about 40 °C. For example, the drying can be at about 50 °C. For example, the drying can be at about 60 °C. For example, the drying can be at about 70 °C.

[0052] The method of preparing a crystalline form of the present disclosure can include seeding.

[0053] The method of preparing the crystalline form of the present disclosure using seeding can include seeding a solution of the hydrogen pamoate salt of trospium in a first mixture of organic solvent and water with a first amount of a seed crystalline form to obtain a first slurry. The first slurry can be filtered to obtain a first solid. The first solid can be suspended in a second mixture of organic solvent and water. The first solid is a crystalline form of the present disclosure. The method of preparing a crystalline form of the present disclosure can include suitably a second round of seeding. As such, the method can further include seeding the resulting mixture with a second amount of the seed crystalline form to obtain a second slurry. The second slurry can be filtered to obtain a second solid. The second solid can comprise the crystalline form. Optionally, the method can include drying of the second solid. The drying can be carried out in vacuo. The drying can be carried out at about room temperature or at an elevated temperature, such as at about 30 °C to about 50 °C. For example, the drying can be carried out at about 40 °C.

[0054] The second mixture of organic solvent and water can include about 20% v / v or less than 20% v / v organic solvent. The organic solvent can be selected from THF, ethanol, acetonitrile, acetone and combinations thereof.

[0055] Since the present disclosure also provides method of preparing a crystalline form of the present disclosure including crystallising the hydrogen pamoate salt of trospium in a solvent without seeding. The seed crystalline form can be prepared using appropriate methods described in this disclosure.

[0056] In some embodiments, the seed crystalline form can be Form G, Form H, Form I, Form J, Form K, or Form L as described herein, which can be used to obtain the crystalline form of Form G. In some embodiments, the seed crystalline form can be Form H as described herein, which can be used to obtain a crystalline form of Form I. In some embodiments, the seed crystalline form can be Form G as described herein, which can be used to obtain a crystalline form of Form J. In some embodiments, the seed crystalline form can be Form G as described herein, which can be used to obtain a crystalline form of Form K. In some embodiments, theAttorney Docket No. 055920-813001WOseed crystalline form can be Form G as described herein, which can be used to obtain a crystalline form of Form L. The method of the present disclosure can be adjusted as described herein to obtain the desired crystalline form.

[0057] 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 DRAWINGS

[0058] 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.

[0059] FIG. 1 shows the XRPD pattern of Form G.

[0060] FIG. 2 shows the DSC thermogram of Form G.

[0061] FIG. 3 shows the TGA thermogram of Form G.

[0062] FIG. 4 shows vapour sorption of Form G.

[0063] FIG. 5 shows the XRPD pattern of Form H.

[0064] FIG. 6 shows the DSC thermogram of Form H.

[0065] FIG. 7 shows the TGA thermogram of Form H.

[0066] FIG. 8 shows the XRPD pattern of Form I.

[0067] FIG. 9 shows the XRPD pattern of Form J.

[0068] FIG. 10 shows the DSC thermogram of Form J.

[0069] FIG. 11 shows the TGA thermogram of Form J.

[0070] FIG. 12 shows the XRPD pattern of Form K.

[0071] FIG. 13 shows the DSC thermogram of Form K.

[0072] FIG. 14 shows the TGA thermogram of Form K.

[0073] FIG. 15 shows the XRPD pattern of Form L.

[0074] FIG. 16 shows the 1H NMR spectrum of the hydrogen pamoate salt of trospium of Formula I.

[0075] FIGs. 17A-17B show in panel A the plasma concentration (ng / mL) of trospium cation and in panel B the plasma concentration (ng / mL) of xanomeline free base between 0 to 240 hours after injection in the animals injected in Example 7. The insets show plasma concentration (ng / mL) between 0 to 24 hours.Attorney Docket No. 055920-813001WODETAILED DESCRIPTION

[0076] The present disclosure is based, at least in part, on the development of a hydrogen pamoate salt of trospium (Formula I),OI.and various crystal forms (for example Forms G to L) thereof, which exhibit superior features, for example, low solubility, which can be beneficial for certain formulations such as long-acting formulations. As such, the hydrogen pamoate salt of trospium, including the various crystal forms thereof as provided herein, are expected to be useful in controlled- or delayed-release formulations such as long-acting formulation (e.g. long acting injection).

[0077] The present disclosure also includes pharmaceutical compositions of the salt or crystalline form thereof. The present disclosure also relates to methods of preparing the salt and the crystal forms, and to methods of treatment using the hydrogen pamoate salt of trospium of the present disclosure, for example in combination with xanomeline or a salt thereof.Definitions

[0078] As used in the present specification, the following words, phrases and symbols 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.

[0079] The term “about” 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 orderAttorney Docket No. 055920-813001WOof 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. In some embodiments, the hinge domain is a hinge domain of a naturally occurring protein. “Substantially as shown in” refers to any crystal or solid form of the salt of Formula I 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.

[0080] “Substantially free of’ refers to a crystalline or solid form of the salt of Formula I containing no significant amount of such other crystalline or solid forms of the salt of Formula I. For example, a first crystalline form can be substantially free of a second crystalline form when the first crystalline form constitutes at least about 95% by weight of the crystalline Compound I present, or at least about 96%, 97%, 98%, 99%, or at least about 99.5% by weight of the crystalline salt of Formula I present.

[0081] “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.

[0082] A “subject” or “patient” is meant to describe a human or vertebrate animal including a dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, and mouse. A “pocket pet” refers to a group of vertebrate animals capable of fitting into a commodious coat pocket such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits and sugar gliders.

[0083] “ 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 symptomsAttorney Docket No. 055920-813001WOresulting 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.

[0084] 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.

[0085] “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.

[0086] “ 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 orAttorney Docket No. 055920-813001WOminutes. 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.

[0087] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. The disease may be an autoimmune, inflammatory, cancer, infectious (e.g., a viral infection), metabolic, developmental, cardiovascular, liver, intestinal, endocrine, neurological, or other disease. In some embodiments, the disease is cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0088] “ 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.

[0089] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of pharmaceutically acceptable carriers and pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.I. Salt of Formula I and Crystalline Forms Thereof

[0090] Disclosed herein are, among other things, a hydrogen pamoate salt of trospium of Formula IAttorney Docket No. 055920-813001WOI.

[0091] The salt of Formula I 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 G, Form H, Form I, Form J, Form K, and Form L. The salt of Formula I can comprise a mixture of two or more crystalline forms. Alternatively, the salt of Formula I can comprise substantially one specific crystalline form as disclosed herein. In other instances, the salt of Formula I can be substantially free of one or more specific crystalline forms.

[0092] In some embodiments, the present disclosure includes a crystalline form of the salt of Form I. For example, the crystalline form can be Form G, Form H, Form I, Form J, Form K, or Form L, or those having substantially the same essential features as any of these specific crystalline forms.

[0093] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 4.9± 0.2° 29, 5.5± 0.2° 29, 6.4± 0.2° 29, 7.9± 0.2° 29, 8.5± 0.2° 29, 10.3± 0.2° 29, 13.7± 0.2° 29, 17.8± 0.2° 29, 18.1± 0.2° 2 9, and 19.7± 0.2° 29.

[0094] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29.

[0095] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 29, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0± 0.2° 29.

[0096] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 8.2± 0.2° 29, 8.7± 0.2° 29, 9.9± 0.2° 29, 10.6± 0.2° 29, 11.5± 0.2° 29, 12.8± 0.2° 29, 17.3± 0.2° 29, 21.2± 0.2° 29, andAttorney Docket No. 055920-813001WO22.5± 0.2° 26.

[0097] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 7.7± 0.2° 29, 9.0± 0.2° 29, 9.5± 0.2° 29, 11.1± 0.2° 2θ, 12.8± 9.2° 29, 14.3± 9.2° 29, and 17.2 ± 0.2° 29.

[0098] In some embodiments, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern including three or more peaks at 7.5± 0.2° 29, 8.7± 0.2° 29, 9.3± 0.2° 29, 14.4± 0.2° 29, 17.0± 0.2° 29, 19.2± 0.2° 29, and 22.8 ± 0.2° 29.Form G

[0099] In some embodiments, the crystalline form can be Form G as described herein. In some exemplary embodiments of the crystalline form G, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form G are shown in Examples 2 and 6.

[0100] In some examples, the crystalline form is characterised by an X-ray Powder Diffraction (XRPD) pattern comprising three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more peaks at 4.9± 0.2° 29, 5.5± 0.2° 29, 6.4± 0.2° 29, 7.9± 0.2° 2 9, 8.5± 0.2° 29, 10.3± 0.2° 29, 13.7± 0.2° 29, 17.8± 0.2° 29, 18.1± 0.2° 29, and 19.7± 0.2° 2 9. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising peaks at 4.9± 0.2° 29, 5.5± 0.2° 29, 6.4± 0.2° 29, 7.9± 0.2° 29, 8.5± 0.2° 29, 10.3± 0.2° 29, 13.7± 0.2° 29, 17.8± 0.2° 29, 18.1± 0.2° 29, and 19.7± 0.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising three or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising four or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising five or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising six or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising seven or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 2Attorney Docket No. 055920-813001WO9, 17.8± 0.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising eight or more peaks at 4.9± 0.2° 29, 5.5± 9.2° 29, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the crystalline form is characterised by an XRPD pattern comprising nine or more peaks at 4.9± 9.2° 29, 5.5± 9.2° 2 9, 6.4± 9.2° 29, 7.9± 9.2° 29, 8.5± 9.2° 29, 10.3± 9.2° 29, 13.7± 9.2° 29, 17.8± 9.2° 29, 18.1± 9.2° 29, and 19.7± 9.2° 29. In some embodiments, the XRPD pattern further comprises one or more peaks at 8.2± 9.2° 29, 9.5± 9.2° 29, 9.8± 9.2° 29, 11.1± 9.2° 29, 11.4± 9.2° 29, 13.0± 9.2° 29, 14.1± 9.2° 29, 14.7± 9.2° 29, 15.0± 9.2° 29, 15.8± 9.2° 29, 16.1± 9.2° 29, 16.6± 9.2° 29, 17.1± 9.2° 29, 18.6± 9.2° 29, 19.2± 9.2° 29, 29.2± 9.2° 29, 29.6± 9.2° 29, 20.9± 9.2° 29, 21.2± 9.2° 29, 22.9± 9.2° 29, 22.3± 9.2° 29, 23.2± 9.2° 29, 24.9± 9.2° 29, 24.8± 9.2° 29, 25.5± 9.2° 29, 26.2± 9.2° 29, 27.1± 9.2° 29, 29.4± 9.2° 29, and 39.8 ± 9.2° 2 9. In some embodiments, the XRPD pattern of Form G comprises ten or more peaks at positions described above in this section.

[0101] In some embodiments, the XRPD pattern is substantially as shown in FIG. 1.

[0102] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 217 °C. In some embodiments, the endotherm with an onset of about 217 °C has a peak at about 219 °C. In some embodiments, the thermogram further comprises a broad endothermic event at about 90 °C. In some embodiments, the DSC thermogram is substantially as shown in FIG. 2

[0103] In some embodiments, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing a mass loss of about 1.8 wt% from room temperature to about 175 °C.In some embodiments, the TGA is characterized by a curve substantially as shown in FIG. 3.

[0104] In some embodiments, the crystalline form is characterized by a vapour sorption of about 2.3 wt% water uptake from 0% up to 95% relative humidity (RH). In some embodiments, the vapour sorption is substantially as shown in FIG. 4.

[0105] In some embodiments, the crystalline form Form G is a hydrate. For example, the crystalline form Form G can comprise about 0.7 to about 1 mole of water per mole. In some embodiments, the crystalline form Form G comprises about 1 mole of water per mole.

[0106] In some embodiments, the crystalline form has a solubility of about 1 pg trospium per mL in water, where the crystalline form was incubated in water at a target concentration of about 5 mg of trospium / mL at about 37°C over 24 hours with gentle agitation (about 200 rpm). The resulting solution of the crystalline form in water can have a pH of about 5.9. In someAttorney Docket No. 055920-813001WOembodiments, the crystalline form has a solubility of about 2.7 pg trospium per mL in phosphate buffered saline (PBS), where the crystalline form was incubated in the PBS buffer at a target concentration of about 5 mg of trospium / mL at about 37°C over 24 hours with gentle agitation (about 200 rpm). The resulting solution of the crystalline form in the PBS buffer can have a pH of about 6.9.Form H

[0107] For example, the crystalline form can be Form H as described herein. In some exemplary embodiments of Form H, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form H are shown in Example 3.

[0108] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising four or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 2 9, and 19.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising five or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising six or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 29, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 2 9, 18.0± 0.2° 29, and 19.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising seven or more peaks at 6.6± 0.2° 29, 9.0± 0.2° 2 9, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29. In some embodiments, the XRPD pattern comprises peaks at 6.6± 0.2° 29, 9.0± 0.2° 2 9, 10.8± 0.2° 29, 12.2± 0.2° 29, 13.0± 0.2° 29, 15.1± 0.2° 29, 18.0± 0.2° 29, and 19.5± 0.2° 29. In some embodiments, the XRPD pattern can further include one or more peaks at 9.3± 0.2° 29, 11.1± 0.2° 29, 14.0± 0.2° 29, 14.7± 0.2° 29, 15.7± 0.2° 29, 16.1± 0.2° 29, 17.3± 0.2° 29, 18.9± 0.2° 29, 20.4± 0.2° 29, 21.6± 0.2° 29, 23.2± 0.2° 29, 24.6± 0.2° 29, 25.5± 0.2° 29, 26.3± 0.2° 29, 27.5± 0.2° 29, 29.2± 0.2° 29, and 30.0± 0.2° 29. In some embodiments, the XRPD pattern of Form H comprises ten or more peaks at positions described above in this section.

[0109] In some embodiments, the XRPD pattern is substantially as shown in FIG. 5.Attorney Docket No. 055920-813001WO

[0110] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 169 °C. In some embodiments, the endotherm with an onset of about 169 °C has a peak at about 181 °C. In some embodiments, the DSC thermogram further comprises a broad endothermic event at about 39 °C. In some embodiments, the DSC thermogram is substantially as shown in FIG. 6.[OHl] In some embodiments, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing substantially no mass loss from room temperature to about 200 °C. In some embodiments, the TGA is characterized by a curve substantially as shown in FIG. 7.Form I

[0112] For example, the crystalline form can be Form I as described herein. In some exemplary embodiments of Form I, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form I are shown in Example 3.

[0113] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more, four or more, five or more, six or more peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 29, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 29, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising four or more peaks at 6.4± 9.2° 29, 9.8± 9.2° 29, 13.2± 9.2° 2 9, 14.3± 9.2° 29, 15.6± 9.2° 29, 18.5± 9.2° 29, and 21.0± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising five or more peaks at 6.4± 9.2° 29, 9.8± 9.2° 29, 13.2± 9.2° 29, 14.3± 9.2° 29, 15.6± 9.2° 29, 18.5± 9.2° 29, and 21.0± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising six or more peaks at 6.4± 9.2° 29, 9.8± 9.2° 29, 13.2± 9.2° 29, 14.3± 9.2° 29, 15.6± 9.2° 29, 18.5± 9.2° 29, and 21.0± 9.2° 29. In some embodiments, the XRPD pattern comprises peaks at 6.4± 9.2° 29, 9.8± 9.2° 29, 13.2± 9.2° 29, 14.3± 9.2° 29, 15.6± 9.2° 29, 18.5± 9.2° 29, and 21.0± 9.2° 29. In some embodiments, the XRPD pattern further comprises one or more peaks at 7.1± 9.2° 29, 12.0± 9.2° 29, 16.8± 9.2° 29, 17.9± 9.2° 29, 19.8± 9.2° 2 9, 29.5± 9.2° 29, 22.3± 9.2° 29, 22.9± 9.2° 29, and 24.2° 29, ± 9.2° 29. In some embodiments, the XRPD pattern of Form I comprises ten or more peaks at positions describedAttorney Docket No. 055920-813001WOabove in this section. In some embodiments, the XRPD pattern is substantially as shown in FIG. 8

[0114] In some embodiments, the crystalline form of Form I is an acetonitrile solvate.Form J

[0115] For example, the crystalline form can be Form J as described herein. In some exemplary embodiments of Form J, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form J are shown in Example 4.

[0116] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more, four or more, five or more, six or more, seven or more, or eight or more peaks at 8.2± 0.2° 26, 8.7± 0.2° 26, 9.9± 0.2° 26, 10.6± 0.2° 26, 11,5± 0.2° 26, 12.8± 0.2° 29, 17.3± 0.2° 29, 21.2± 0.2° 29, and 22.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more peaks at 8.2± 0.2° 29, 8.7± 0.2° 29, 9.9± 0.2° 29, 10.6± 0.2° 29, 11.5± 0.2° 29, 12.8± 0.2° 29, 17.3± 0.2° 2 9, 21.2± 0.2° 29, and 22.5± 0.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising four or more peaks at 8.2± 9.2° 29, 8.7± 9.2° 2 9, 9.9± 9.2° 29, 10.6± 9.2° 29, 11.5± 9.2° 29, 12.8± 9.2° 29, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising five or more peaks at 8.2± 9.2° 29, 8.7± 9.2° 29, 9.9± 9.2° 29, 19.6± 9.2° 2 9, 11.5± 9.2° 29, 12.8± 9.2° 29, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising six or more peaks at 8.2± 9.2° 29, 8.7± 9.2° 29, 9.9± 9.2° 29, 10.6± 9.2° 29, 11.5± 9.2° 29, 12.8± 9.2° 2 9, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising seven or more peaks at 8.2± 9.2° 29, 8.7± 9.2° 29, 9.9± 9.2° 29, 10.6± 9.2° 29, 11.5± 9.2° 29, 12.8± 9.2° 29, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 29. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising eight or more peaks at 8.2± 9.2° 29, 8.7± 9.2° 29, 9.9± 9.2° 2 9, 19.6± 9.2° 29, 11.5± 0.2° 29, 12.8± 9.2° 29, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 2 9. In some embodiments, the XRPD pattern comprises peaks at 8.2± 9.2° 29, 8.7± 9.2° 29, 9.9± 9.2° 29, 10.6± 9.2° 29, 11.5± 9.2° 29, 12.8± 9.2° 29, 17.3± 9.2° 29, 21.2± 9.2° 29, and 22.5± 9.2° 29. In some embodiments, the XRPD pattern can further include one or more peaks at 9.2± 9.2° 29, 9.5± 9.2° 29, 10.3± 9.2° 29, 13.8± 9.2° 29, 14.3± 9.2° 29, 14.9± 9.2° 29, 15.5± 9.2° 29, 16.1± 9.2° 29, 16.4± 9.2° 29, 16.9± 9.2° 29, 18.0± 9.2° 29, 18.6± 9.2° 29,29Attorney Docket No. 055920-813001WO19.6± 0.2° 26, 20.5± 0.2° 26, 20.8± 0.2° 26, 22.1± 0.2° 26, 23.2± 0.2° 26, 23.8± 0.2° 26, 24.2± 0.2° 26, 24.9± 0.2° 26, 25.5± 0.2° 26, 26.3± 0.2° 26, and 28.5± 0.2° 26. In some embodiments, the XRPD pattern of Form J comprises ten or more peaks at positions described above in this section. In some embodiments, the XRPD pattern is substantially as shown in FIG. 9

[0117] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 162 °C or 213 °C. In some embodiments, the DSC endotherm comprises an endotherm with an onset of about 162 °C and an endotherm at an onset of about 213 °C. In some embodiments, the endotherm with an onset of about 162 °C has a peak at about 176 °C. In some embodiments, the endotherm with an onset of about 213 °C has a peak at about 218 °C. In some embodiments, the DSC thermogram is substantially as shown in FIG. 10.

[0118] In some embodiments, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing substantially a mass loss of about 7.5 wt% from about 100 °C to about 200 °C. In some embodiments, the TGA is characterized by a curve substantially as shown in FIG. 11.

[0119] In some embodiments, the crystalline form of Form J is a tetrahydrofuran (THF) solvate.Form K

[0120] For example, the crystalline form can be Form K as described herein. In some exemplary embodiments of Form K, the crystalline form is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form K are shown in Example 5.

[0121] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more, four or more, five or more peaks, or six or more peaks at 7.7± 0.2° 2 e, 9.0± 0.2° 2 e, 9.5± 0.2° 26, 11.1± 0.2° 26, 12.8± 0.2° 26, 14.3± 0.2° 26, and 17.2 ± 0.2° 2 9. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more peaks at 7.7± 0.2° 2θ, 9.0± 0.2° 2θ, 9.5± 0.2° 2θ, 11.1± 0.2° 2θ, 12.8± 0.2° 2θ, 14.3± 0.2° 2θ, and 17.2 ± 0.2° 2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising four or more peaks at 7.7± 0.2° 2θ, 9.0± 0.2° 2θ, 9.5± 0.2° 2θ, 11.1± 0.2° 2θ, 12.8± 0.2° 2θ, 14.3± 0.2° 2θ, and 17.2 ± 0.2° 2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising five or more peaks at 7.7± 0.2° 2θ, 9.0± 0.2° 2θ, 9.5± 0.2° 2θ, 11.1± 0.2° 2θ, 12.8± 0.2° 2θ, 14.3±Attorney Docket No. 055920-813001WO0.2° 2θ, and 17.2 ± 0.2° 2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising six or more peaks at 7.7± 0.2° 2θ, 9.0± 0.2° 2θ, 9.5± 0.2° 2θ, 11.1± 0.2° 2θ, 12.8± 0.2° 2θ, 14.3± 0.2° 2θ, and 17.2 ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 7.7± 0.2° 2θ, 9.0± 0.2° 2θ, 9.5± 0.2° 2θ, 11.1± 0.2° 2θ, 12.8± 0.2° 2θ, 14.3± 0.2° 2θ, and 17.2 ± 0.2° 2θ. In some embodiments, the XRPD pattern further comprises one or more peaks at 7.1± 0.2° 2θ, 11.9± 0.2° 2θ, 12.3± 0.2° 2θ, 13.4± 0.2° 2θ, 14.9± 0.2° 2θ, 15.7± 0.2° 2θ, 18.5± 0.2° 2θ, 19.4± 0.2° 2θ, 19.8± 0.2° 2θ, 20.3± 0.2° 2θ, 20.6± 0.2° 2θ, 21.4± 0.2° 2θ, 22.3± 0.2° 2θ, 22.8± 0.2° 2θ, 23.2± 0.2° 2θ, 23.5± 0.2° 2θ, 26.3± 0.2° 2θ, 28.4± 0.2° 2θ, and 30.9 ± 0.2° 2θ. In some embodiments, the XRPD pattern is substantially as shown in FIG. 12. In some embodiments, the XRPD pattern of Form K comprises ten or more peaks at positions described above in this section.

[0122] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 140 or 215 °C. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram comprising one endotherm with an onset of about 140 and one endotherm with an onset of 215 °C. In some embodiments, the endotherm with an onset of about 140 °C has a peak at about 151 °C. In some embodiments, the endotherm with an onset of about 215 °C has a peak at about 219 °C. In some embodiments, the DSC thermogram further comprises a broad endothermic event at about 39 °C. In some embodiments, the DSC thermogram is substantially as shown in FIG. 13.

[0123] In some embodiments, the crystalline form is characterized by a thermogravimetric analysis (TGA) showing substantially a mass loss of about 8.2 wt% from about 100 °C to about 175 °C. In some embodiments, the TGA is characterized by a curve substantially as shown in FIG. 14.

[0124] In some embodiments, the crystalline form of Form K is an ethanol solvate.Form L

[0125] For example, the crystalline form can be Form L as described herein. In some exemplary embodiments of Form L, the crystalline form, is characterised by one or more of the properties described below in this section. Exemplary embodiments of Form L are shown in Example 2.

[0126] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising three or more, four or more, or five or more peaks at 7.5± 0.2° 29, 8.7± 0.2° 29, 9.3± 0.2° 29, 14.4± 0.2° 29, 17.0± 0.2° 29, 19.2± 0.2° 29, and 22.8 ± 0.2° 29. In someAttorney Docket No. 055920-813001WOembodiments, the crystalline form is characterized by an XRPD pattern comprising three or more peaks at 7.5± 0.2° 2θ, 8.7± 0.2° 2θ, 9.3± 0.2° 2θ, 14.4± 0.2° 2θ, 17.0± 0.2° 2θ, 19.2± 0.2° 2θ, and 22.8 ± 0.2° 2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising four or more peaks at 7.5± 0.2° 2θ, 8.7± 0.2° 2θ, 9.3± 0.2° 2θ, 14.4± 0.2° 2θ, 17.0± 0.2° 2θ, 19.2± 0.2° 2θ, and 22.8 ± 0.2° 2θ. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising five or more peaks at 7.5± 0.2° 2θ, 8.7± 0.2° 2θ, 9.3± 0.2° 2θ, 14.4± 0.2° 2θ, 17.0± 0.2° 2θ, 19.2± 0.2° 2θ, and 22.8 ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 7.5± 0.2° 2θ, 8.7± 0.2° 2θ, 9.3± 0.2° 2θ, 14.4± 0.2° 2θ, 17.0± 0.2° 2θ, 19.2± 0.2° 2θ, and 22.8 ± 0.2° 2θ. In some embodiments, the XRPD pattern further comprises one or more peaks at 11.0± 0.2° 2θ, 11.9± 0.2° 2θ, 12.6± 0.2° 2θ, 15.5± 0.2° 2θ, 18.4± 0.2° 2θ, 20.4± 0.2° 2θ, 21.2± 0.2° 2θ, 24.9± 0.2° 2θ, 26.1± 0.2° 2θ, 28.5± 0.2° 2θ, 29.9± 0.2° 2θ, 29.8± 0.2° 2θ, and 30.4 ± 0.2° 2θ. In some embodiments, the XRPD pattern of Form L comprises ten or more peaks at positions described above in this section.

[0127] In some embodiments, the XRPD pattern is substantially as shown in FIG. 15.

[0128] In some embodiments, the crystalline form of Form L is a tetrahydrofuran (THF) solvate.II. Methods of Preparing the Salt and Crystalline Forms

[0129] In one aspect, the present disclosure includes a method of preparing a hydrogen pamoate salt of trospium of Formula I of the present disclosure, the method comprising reacting trospium or a salt thereof with alkali hydrogen pamoate to produce the salt of Formula I.

[0130] In some embodiments, the reacting is carried out at a molar ratio of trospium to pamoate of about 1:1.

[0131] In some embodiments, the method comprises reacting trospium chloride with the alkali hydrogen pamoate. For example, the trospium or a salt thereof is trospium chloride. In some embodiments, the trospium or salt thereof is comprised in a first aqueous solution.

[0132] In some embodiments, the alkali hydrogen pamoate is potassium hydrogen pamoate or sodium hydrogen pamoate. In some embodiments, the alkali hydrogen pamoate is comprised in a second aqueous solution. For example, the second aqueous solution can comprise THF:water as a solvent. In some embodiments, the THF: water of the second aqueous solution is at a volume ratio of about 5:1 to about 9:1. For example, the volume ratio can be about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1. In some embodiments, the reacting comprises contacting the first aqueous solution with the second aqueous solution to obtain a trospium pamoate solution. In some embodiments, the contacting can be carried out with stirring. In some embodiments, the method further comprises filtering and / or drying the trospium pamoate solution.

[0134] It is contemplated that the alkali hydrogen pamoate can be from a commercial source or prepared. In some embodiments, the method further comprises providing the alkali hydrogen pamoate. For example, the providing of the alkali hydrogen pamoate can be carried out by reacting pamoic acid and a base of suitable strength to deprotonate the pamoic acid, in an amount of about 1: 1 molar ratio with the pamoic acid such that only one carboxylic acid of the pamoic acid is deprotonated. The preparation of alkali hydrogen pamoate can be carried in a solvent with suitable solubility for pamoic acid, the base and the resulting alkali hydrogen pamoate. For example, it can be carried out in a solvent of THF:water. In some embodiments, the THF:water is at a volume ratio of about 5: 1 to about 9:1. For example, the volume ration can be about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1.

[0135] In some embodiments, the base is alkali hydroxide, and the alkali hydroxide is used at a molar ratio of pamoic acid to alkali hydroxide of about 1:1. For example, the alkali hydroxide can be potassium or sodium hydroxide.

[0136] It is contemplated that other suitable bases can be used. In some embodiments, the base is disodium pamoate. In some embodiments, the providing the alkali hydrogen pamoate is carried out by reacting pamoic acid and disodium pamoate at a molar ratio of pamoic acid to disodium pamoate of about 1:1. In some embodiments, the reacting of pamoic acid and disodium pamoate is carried out in a solvent of THF:water, such as at a volume ratio of about 1.5:1.III. Methods of Preparing the Crystalline Forms

[0137] In another aspect, the present disclosure includes a method of preparing a crystalline form of the hydrogen pamoate salt of trospium of Formula I, the method comprising crystallising a hydrogen pamoate salt of trospium of Formula I in a solvent to obtain the crystalline form, wherein the solvent is selected from water and an organic solvent:water mixture. In some embodiments, the organic solvent water mixture is a mixture of water and an organic solvent selected from THF, ethanol, acetone, acetonitrile, methanol, isopropanol, DMSO, DMF, NMP, DMA, and combinations thereof. In some embodiments, the solvent is selected from acetone: water, acetonitrile:water, water, THF:water, and ethanol: water. In someAttorney Docket No. 055920-813001WOembodiments, the acetone:water is at a volume ratio of about 1: 1. In some embodiments, the acetontrile: water is at a volume ratio of about 1:1.

[0138] The methods of the present disclosure can prepare different crystalline forms using for example different solvent choices and crystallization conditions. The resulting crystalline forms can be used as seeds or seed crystalline forms in the preparation of the same or different crystalline forms.

[0139] In some instances, the methods of preparing the crystalline forms of the present disclosure use the hydrogen pamoate salt of trospium of Formula I of the present disclosure as a starting material. In some embodiments, the hydrogen pamoate salt of trospium of Formula I of the present disclosure can be prepared using a method of preparing a hydrogen pamoate salt of trospium of Formula I of the present disclosure as described herein. Accordingly, in some embodiments, the methods of preparing a crystalline form of the hydrogen pamoate salt of trospium of Formula I of the present disclosure further comprises preparing the hydrogen pamoate salt of trospium of Formula I using methods of the present disclosure.Form G

[0140] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form G of the hydrogen pamoate salt of trospium of Formula I, the method comprising crystallising a hydrogen pamoate salt of trospium of Formula I in a solvent to obtain the crystalline form, and drying the crystalline form in vacuo, wherein the solvent is acetone: water. In some embodiments, the acetone:water is at a volume ratio of about 1:1. In some embodiments, the drying is carried out overnight at about room temperature to about 60 °C, optionally at room temperature.

[0141] In some embodiments, the crystallising comprises providing a solution of the hydrogen pamoate salt of trospium of Formula I in acetone: water, stirring the solution at about 50 °C to about 60 °C, for overnight, and cooling the solution to room temperature. For example, the stirring is carried out at about 40 °C.

[0142] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form G of the hydrogen pamoate salt of trospium of Formula I using a seeding technique. In some embodiments, the method of preparing a crystalline form of Form G of the hydrogen pamoate salt of trospium of Formula I comprises:(i) seeding a solution of the salt in a first mixture of organic solvent and water with a first amount of a seed crystalline form of the salt of Formula I (e.g. Form G) to obtain a first slurry,Attorney Docket No. 055920-813001WO(ii) filtering the first slurry to obtain a first solid,(iii)suspending the first solid in a second mixture of organic solvent and water, and seeding with a second amount of a seed crystalline form of Form G to obtain a second slurry, wherein the second mixture comprises about 35% v / v or less than 35% v / v organic solvent,(iv)filtering the second slurry to obtain a second solid, and(v) drying the second solid in vacuo at about 30 °C to about 50 °C, to obtain the crystalline form of the salt of trospium and hydrogen pamoate of Form G.

[0143] In some embodiments, the drying is at about 40 °C. In some embodiments, the organic solvent is selected from THF, ethanol, acetonitrile, acetone and combinations thereof. In some embodiments the organic solvent is THF. In some embodiments, the second mixture comprises about 30% v / v or less than 30% v / v of THF:water. In some embodiments, the second mixture comprises about 25% v / v or less than 25% v / v of THF: water. In some embodiments, the second mixture comprises about 20% v / v or less than 20% v / v of THF: water. In some embodiments, the second mixture comprises about 15% v / v of THF: water. In some embodiments, the second mixture comprises about 10% v / v of THF: water. In some embodiments, the second mixture comprises about 5% v / v of THF:water.

[0144] In step (i), the first amount of the seed crystalline form of the salt of Formula I can be a crystalline form of Form G. In some embodiments, the first amount of the seed crystalline form and the second amount of the seed crystalline form are both Form G.

[0145] In some embodiments, step (i) is carried out at room temperature. In some embodiments, step (i) is carried out overnight.

[0146] In some embodiments, the method further comprises after step (ii) and / or before step (iii) washing the first solid. In some embodiments, the washing is carried out with 10% v / v THF: water and / or water.

[0147] In some embodiments, step (iii) is carried out at room temperature for about 30 hours to about 50 hours. In some embodiments, step (iii) is carried out for about 40 hours.

[0148] In some embodiments, the method further comprises after step (iv) and prior to step (v) washing the second solid. In some embodiments, the washing is carried out with 10% v / v THF: water and / or water.

[0149] In some embodiments, step (v) is carried out for overnight.

[0150] It can be understood that the seed crystalline form of Form G can be prepared using methods as described herein.Attorney Docket No. 055920-813001WOForm H

[0151] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form H of the hydrogen pamoate salt of trospium of Formula I, the method comprising crystallising a hydrogen pamoate salt of trospium of Formula I in a solvent to obtain the crystalline form, and drying the crystalline form in vacuo at about 50 °C to about 70 °C, wherein the solvent is acetonitrile:water. In some embodiments, the acetonitrile: water is at a volume ratio of about 1:1. In some embodiments, the drying is at about 60 °C. In some embodiments, Form H is obtained by isolating and drying a crystalline form of Form I (prepared as described herein).Form I

[0152] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form I of the hydrogen pamoate salt of trospium of Formula I, the method comprising crystallising a hydrogen pamoate salt of trospium of Formula I in a solvent to obtain the crystalline form, wherein the solvent is acetonitrile:water. In some embodiments, the acetonitrile: water is at a volume ratio of about 1:1.

[0153] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form I of the hydrogen pamoate salt of trospium of Formula I using a seeding technique. In some embodiments, the method preparing a crystalline form of Form I of the hydrogen pamoate salt of trospium of Formula I comprises(i) seeding a solution of the hydrogen pamoate salt of trospium of the present disclosure in acetonitrile: water with a seed crystalline form of Form H to obtain a slurry, the slurry comprising the crystalline form of Form I.

[0154] In some embodiments, the method further comprises isolating the crystalline form from the slurry. In some embodiments, step (i) is carried out overnight.

[0155] It can be understood that the seed crystalline form of Form H can be prepared using methods as described herein.Form J

[0156] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form J of the hydrogen pamoate salt of trospium of Formula I using a seeding technique. In some embodiments, the method preparing a crystalline form of Form J of the hydrogen pamoate salt of trospium of Formula I comprisesAttorney Docket No. 055920-813001WO(i) seeding a solution of the salt with a seed crystalline form of Form G in water to allow for formation of the crystalline form of Form J.

[0157] In some embodiments, the method further comprises isolating the crystalline form from the slurry.

[0158] In some embodiments, the method further comprises drying the crystalline form of Form J in vacuo at about 50 °C to about 70 °C. In some embodiments, the drying is carried out at about 60 °C. In some embodiments, the drying is carried out for about 3 days to about 5 days. In some embodiments, the drying is carried out for about 4 days.

[0159] It can be understood that the seed crystalline form of Form G can be prepared using methods as described herein.Form K

[0160] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form K of the hydrogen pamoate salt of trospium of Formula I using a seeding technique. In some embodiments, the method preparing a crystalline form of Form K of the hydrogen pamoate salt of trospium of Formula I comprises(i) seeding a solution of the salt with a seed crystalline form of Form G in ethanol: water to allow for formation of the crystalline form of Form K.

[0161] In some embodiments, the method further comprises isolating the crystalline form from the slurry. In some embodiments, step (i) is carried out at room temperature. In some embodiments, step (i) is carried out for about one or two hours.

[0162] In some embodiments, the method further comprises drying the crystalline form of Form K in vacuo at about 40 °C to about 60 °C. In some embodiments, the drying is carried out at about 50 °C. In some embodiments, the drying is carried out for overnight.

[0163] It can be understood that the seed crystalline form of Form G can be prepared using methods as described herein.Form L

[0164] In another aspect, the present disclosure includes a method of preparing a crystalline form of Form L of the hydrogen pamoate salt of trospium of Formula I using a seeding technique. In some embodiments, the method preparing a crystalline form of Form L of the hydrogen pamoate salt of trospium of Formula I comprises(i) seeding a solution of the hydrogen pamoate salt of trospium of Formula I of the present disclosure in THF:water with a first amount of a seed crystalline form ofAttorney Docket No. 055920-813001WOForm G to obtain a first slurry,(ii) filtering the first slurry to obtain a first solid as Form L, and(iii)suspending the first solid in 10% v / v THF: water and seeding with a second amount of the seed crystalline form of Form G to obtain a second slurry, and (iv)filtering the second slurry to obtain a second solid, the second solid being the crystalline form of Form G.

[0165] It can be understood that the seed crystalline form of Form G can be prepared using methods as described herein.IV. Pharmaceutical Compositions

[0166] Also disclosed herein are pharmaceutical compositions comprising a salt of Formula I of the present disclosure, and a pharmaceutically acceptable excipient. In some embodiments, the salt of Formula I is a crystalline form, such as crystalline forms of Forms G to L as described herein. In some embodiments, the pharmaceutical composition further comprises a muscarinic agonist, such as xanomeline or a salt or prodrug thereof.

[0167] In some embodiments, the muscarinic agent comprises or is xanomeline or a salt thereof. In some embodiments, the xanomeline or the salt thereof is in a crystalline form. In some embodiments, the xanomeline or the salt thereof is a complex of xanomeline and quercetin, such as a cocrystal of xanomeline and quercetin. Complexes of xanomeline and quercetin can be those described in PCT application WO 2025 / 255488, the relevant content of which is incorporated herein by reference for the subject matter and purpose referenced herein.

[0168] In some embodiments, the muscarinic agonist produces xanomeline under physiological conditions. For example, the muscarinic agonist can be a prodrug of xanomeline that releases or provides xanomeline under physiological conditions.

[0169] In some embodiments, the pharmaceutical composition of the present disclosure is formulated for injection.

[0170] It is understood that trospium is capable of reducing or alleviating one or more side effects caused by xanomeline in the subject treated. (WO 2011 / 011060, WO 2020 / 069301, both content incorporated herein by reference in its entirety for the subject matter and purpose referenced herein.) For instance, trospium is capable of reducing, ameliorating or alleviate at least one side effect associated with the use of xanomeline in a subject in need thereof, the side effect can include one or more of nausea, vomiting, diarrhea, sweating, or excess salivation. Accordingly, in some embodiments, when the pharmaceutical composition of the present disclosure comprises the xanomeline or a salt or prodrug thereof, and the salt of the presentAttorney Docket No. 055920-813001WOdisclosure or a crystalline form thereof of the present disclosure, the salt of the present disclosure or a crystalline form thereof of the present disclosure is present in an amount equivalent to an amount of trospium capable of alleviating at least one side effect associated with the use of xanomeline.

[0171] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can contain, for instance, excipients, glidants, fillers, binders, or a combination thereof. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Exemplary excipients include, but are not limited to, those set forth in the “HANDBOOK OF PH RMACEUTICAL EXCIPIENTS” (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and combinations thereof. In some embodiments, the compounds can be dispersed in aqueous or lipid excipients as the suspension for administration. In some embodiments, the compounds and compositions herein can be formulated in oil-based formulations.

[0172] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for different routes of administration of the compounds. Formulations suitable for administration can, for instance, 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 or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered, for instance, as a bolus, electuary, or paste.

[0173] A tablet can be made by compression or molding, optionally with at least accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as, for instance, a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active, dispersing agent, or a combination thereof. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0174] The choice of suitable oils or fats for the formulation can be based on achieving the desired cosmetic or functional properties. In some embodiments, the cream can be a non-greasy, non-staining, and washable product with suitable consistency to avoid leakage from tubes or other containers.Attorney Docket No. 055920-813001WO

[0175] In some embodiments, the compounds disclosed herein are administered alone or as fixed dose combo. In some embodiments, the compounds disclosed herein are administered in pharmaceutical compositions. In some embodiments, the pharmaceutical compositions are for veterinary use. In some embodiments, the pharmaceutical compositions are for human use. In some embodiments, the pharmaceutical compositions disclosed herein include at least one additional therapeutic agent. In some embodiments, the pharmaceutical compositions disclosed herein include one or more additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is independently a chemotherapeutic agent, a psychiatric agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenesis agent.

[0176] Pharmaceutical compositions disclosed herein can be in any form suitable for the intended method of administration. The pharmaceutical compositions disclosed herein can be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Exemplary techniques and formulations can be found, for instance, in REMINGTON’S PHARMACEUTICA SCIENCES (Mack Publishing Co., Easton, PA). Such methods can include the step of bringing into association a compound disclosed herein with the carrier that constitutes at least accessory ingredients. In general, the formulations can be 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.

[0177] When used for oral or parenteral use for example, as needed, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs can be prepared. Formulations intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such formulations can contain at least agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non -toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a waxAttorney Docket No. 055920-813001WOcan be employed.

[0178] Formulations for oral use can be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0179] Aqueous suspensions can contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can include, for instance, a suspending agent, dispersing or wetting agents, pH modifiers, and tonicity agents. The aqueous suspension can also contain, for example, preservatives, one or more coloring agents, one or more flavoring agents, one or more sweetening agents (such as sucrose or saccharin), or combinations thereof.

[0180] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, glyceride excipient, a mineral oil such as liquid paraffin, or a combination thereof. The oral suspensions can contain, for instance, a thickening agent, or a combination thereof. In some embodiments, sweetening agents, such as those set forth above, and / or flavoring agents, are added to provide a palatable oral preparation. In some embodiments, the formulations disclosed herein are preserved by the addition of an antioxidant such as ascorbic acid.

[0181] Dispersible powders and granules suitable for preparation of an aqueous or oil suspension by the addition of water or glyceride excipient can provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, a preservative, and combinations thereof. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0182] The pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, a mineral oil, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, naturally-occurring phosphatides, esters or partial esters derived from fatty acids and hexitol anhydrides, and condensation products of these partial esters with ethylene oxide. The emulsion can also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, such as for instance, glycerol, sorbitol or sucrose. Such formulations can also contain, for instance, a demulcent, a preservative, a flavoring, a coloring agent, or a combination thereof.

[0183] The pharmaceutical compositions can be in the form of a sterile injectable or intravenous preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing orAttorney Docket No. 055920-813001WOwetting agents and suspending agents which have been mentioned above. The sterile injectable or intravenous preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, or prepared as a lyophilized powder.

[0184] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0185] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that can contain anti-oxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that can include suspending agents and thickening agents.

[0186] The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit-dosage formulations are those containing a daily to monthly dose or unit daily to monthly sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0187] It should be understood that in addition to the ingredients particularly mentioned above the formulations can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavoring agents.

[0188] Further provided are veterinary formulations comprising a compound disclosed herein together with a veterinary carrier therefor.

[0189] Veterinary carriers are materials useful for the purpose of administering the formulation and can be solid, liquid, suspension or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary formulations can be administered orally, parenterally, or by any other desired route.

[0190] Compounds herein are used to provide controlled release pharmaceutical compositions containing as active ingredient one or more of the compounds (“controlled or sustained release formulations”) in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0191] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or againstAttorney Docket No. 055920-813001WOan active disease, the method of delivery, and the pharmaceutical composition, and will be determined by the clinician using conventional dose escalation studies. In some embodiments, the effective dose of the salt of Formula I is from 0.0001 mg to 500 mg, for instance from 0.001 mg to about 500 mg, or about 0.001 mg to about 300 mg.V. Kits

[0192] Also provided herein are kits that includes a salt of Formula I or a crystalline form disclosed herein, or a pharmaceutical composition of the present disclosure. In some embodiments the kits described herein can comprise a label and / or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof. In some embodiments, the disease or condition is cancer.

[0193] In some embodiments, the kit can also comprise one or more additional therapeutic agents and / or instructions for use of additional therapeutic agents in combination with the compound disclosed herein in the treatment of the disease or condition in a subject (e.g., human) in need thereof.

[0194] In some embodiments, the kits provided herein comprise individual dose units of the salt of Formula I or the crystalline forms of the present disclosure, or a pharmaceutical composition of the present disclosure. Examples of individual dosage units can include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers etc., each comprising a therapeutically effective amount of the salt of Formula I or the crystalline forms of the present disclosure, or a pharmaceutical composition of the present disclosure in question. In some embodiments, the kit can contain a single dosage unit and in others multiple dosage units are present, such as the number of dosage units required for a specified regimen or period. In some embodiments, the pharmaceutical composition of the present disclosure can be packaged separately from the vehicle and / or diluent. As such, in some embodiments, the kits provided herein comprise the pharmaceutical composition of the present disclosure and a vehicle or diluent and instructions for reconstitution of the pharmaceutical composition to obtain a dose unit for administration.

[0195] Also provided are articles of manufacture that include the salt of Formula I or the crystalline forms of the present disclosure, or a pharmaceutical composition of the present disclosure; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, an intravenous bag, an inhaler, or a nebulizer.Attorney Docket No. 055920-813001WOV. Administration and Methods of Use

[0196] The salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be dosed orally.

[0197] The salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0198] The dosage or dosing frequency of the salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0199] The salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure is administered once daily.

[0200] The salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous, subcutaneous, or intramuscular) administration. Therapeutically effective amounts of the salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure may include from about 0.00001 mg to about 500 mg, such as from about 0.0001 mg to about 300 mg, or such as from about 0.001 mg to about 100 mg.

[0201] A salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure may be combined with one or moreAttorney Docket No. 055920-813001WOadditional therapeutic agents in any dosage amount of salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure (e.g., from about 0.0001 mg to about 1000 mg of compound). Therapeutically effective amounts may include from about 0.001 mg per dose to about 1000 mg per dose, such as from about 0.001 mg per dose to about 500 mg per dose, or such as from about 0.01 mg per dose to about 400 mg per dose, or such as from about 0.1 mg per dose to about 350 mg per dose, or such as from about 0.1 mg per dose to about 300 mg per dose. A single dose can be administered hourly, daily, or weekly. In some embodiments, a single dose can be administered once about every week. A single dose can also be administered once about every month.

[0202] The frequency of dosage of the salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure can be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration continues for as long as necessary to treat the disease or condition. For example, a salt of Formula I, the crystalline forms of the present disclosure and the pharmaceutical compositions of the present disclosure can be administered to a human for a period of from about 20 days to about 180 days or, from about 1 month to about 5 years.

[0203] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the salt of Formula I, the crystalline forms of the present disclosure or the pharmaceutical compositions of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

[0204] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of an active ingredient from subcutaneous, intravenous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. As shown herein, the salt and crystalline forms of the present disclosure have a lower solubility compared to other salt forms of trospium and thus can be used in a long-acting formulation.

[0205] In another aspect, the present disclosure includes a pharmaceutical composition of the present disclosure for use in therapy. The disclosure further relates to the use of the salt of Formula I, the crystalline forms thereof, and the pharmaceutical compositions disclosed herein for the treatment a disease or disorder ameliorated by activating muscarinic receptors InAttorney Docket No. 055920-813001WOanother aspect, the present disclosure includes a method of treating a disease or disorder ameliorated by activating muscarinic receptors comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0206] In another aspect, the present disclosure includes a pharmaceutical composition of the present disclosure for use in the treatment of a disease or disorder ameliorated by activating muscarinic receptors.

[0207] In another aspect, the present disclosure includes a use of a pharmaceutical composition of the present disclosure in the treatment of a disease or disorder ameliorated by activating muscarinic receptors comprising administering to a subject in need thereof.

[0208] In another aspect, the present disclosure includes a use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease or disorder ameliorated by activating muscarinic receptors.

[0209] Medicaments as referred to herein can be prepared by conventional processes, including the combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0210] In some embodiments, provided herein is a method of activating muscarinic receptors in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0211] In some embodiments, the disease or disorder is a central nervous system (CNS) disorder. In some embodiments, the CNS disorder is selected from schizophrenia, Alzheimer’s disease, bipolar disorder, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy, optionally wherein the CNS disorder is schizophrenia, Alzheimer’s disease, bipolar disorder or autism. In some embodiments, the pharmaceutical composition is administered to the subject by injection, optionally intravenous injection or subcutaneous injection.

[0212] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference for the purposes or subject matter referenced herein.Attorney Docket No. 055920-813001WOEXAMPLES

[0213] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit, and scope of the present disclosure. All such modifications are intended to be within the scope of the disclosure.Example A: Abbreviations

[0214] Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table A contains a list of many of these abbreviations and acronyms.Table A. List of Abbreviations and AcronymsAbbreviation Meaning°C degree(s) Celsiuspg or ug microgram(s)pL or uL microliter(s)pm or um micron(s)pmol or umol micromole(s)aq AqueousDCM DichloromethaneDMA DimethylacetamideDMF DimethylformamideDMSO Dimethyl sulfoxideEtOAc Ethyl acetateg gram(s)h hour(s)HPLC high-performance liquid chromatographyIPA or iPrOH Isopropyl alcoholLCMS liquid chromatography mass spectrometryM MolarityMeCN AcetonitrileMeOH Methanolmg milligram(s)Attorney Docket No. 055920-813001WOmin minute(s)mL milliliter(s)mm millimeter(s)mmol millimole(s)NMR nuclear magnetic resonanceNMP N-Methyl-2-pyrrolidonert room temperatureTHF Tetrahydrofuranv / v volume / volumewt WeightExample B: General Methodology and MaterialsSingle Crystal X-Ray Diffraction

[0215] Single crystal X-ray data of Form G was collected using a Bruker D8-Venture diffractometer equipped with a Photon III detector and monochromatic Cu Ka radiation. The single crystals were held at 100K during data collection. Indexing and processing of the measured intensity data were carried out with the APEX3 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the full data set. 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, Bruker AXS, Madison, WI USA). Structure refinements involved minimization of the function defined by Xw(|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 = XI |F°|-|Fc| | / X|Fo| and wR = [Xw(|Fo|-|Fc|)2 / Xw|Fo|]l / 2. Difference Fourier maps were examined at all stages of refinement. All nonhydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms on carbon atoms were introduced using idealized geometry with isotropic temperature factors and included in structure factor calculations with fixed parameters. Hydrogen atoms on heteroatoms were located from residual electron density and either refined with constrained distances (0.84A, O-H) only or with full geometric constraints in idealized geometry (01).

[0216] Single crystal X-ray data of Forms I and J were collected using a Bruker D8-Venture diffractometer equipped with a Photon III detector and monochromatic Cu Ka radiation. The single crystals were held at 100K during data collection. Indexing and processing of theAttorney Docket No. 055920-813001WOmeasured intensity data were carried out with the APEX3 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the full data set. 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, Bruker AXS, Madison, WI USA). Structure refinements involved minimization of the function defined by Xw(|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 = XI |Fo|-|Fc| | / X|Fo| and wR = [Xw(|Fo|-|Fc|)2 / Xw|Fo|]l / 2. Difference Fourier maps were examined at all stages of refinement. All nonhydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms on heteroatoms were located from residual electron density and freely refined. Hydrogen atoms on carbon atoms were introduced using idealized geometry with isotropic temperature factors and included in structure factor calculations with fixed parameters.X-Ray Powder Diffraction (XRPD)

[0217] XRPD data for Forms G, H, J, and K were obtained using Bruker D8 Discover DaVinci with XYZ Stage. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation). Incident beam optics included Montel mirrors with a 0.3 mm collimator. Photons were counted using an Eiger2 R 500K Detector in 2D, 29 optimized mode. The sample-to-detector distance was 137.7 mm. Each sample was loaded into a glass capillary (1 mm diameter). Data were collected over a 29 range of approximately 3-33° with an exposure time of 1000 s and an approximate step size of 0.01°.

[0218] XRPD data for Forms I, and L were obtained using Bruker D8 Discover DaVinci. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation).Incident beam optics included Montel mirrors with a 0.3 mm collimator. Photons were counted using an VANTEC500 Detector. The sample-to-detector distance was 197.8 mm. Each sample was loaded into a 96 or 384 well-plate. Data were collected over a 29 range of approximately 3-33° with an exposure time of 60 s and an approximate step size of 0.01°.Differential Scanning Calorimetry (DSC)

[0219] The differential scanning calorimetry (DSC) experiments for Form G were performed using a TA Instruments - Discovery DSC 2500 with RCS90. Sample (~1-5 mg) was placed inAttorney Docket No. 055920-813001WOa TZero aluminum DSC pan with a TZero lid, and the weight was accurately recorded. Data were collected between room temperature and a maximum temperature of approximately 300 °C to 400 °C, for example 300 °C or 350°C at a heating rate of 10°C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.

[0220] The differential scanning calorimetry (DSC) experiments for Forms H, J and K were performed using a TA Instruments - Discovery DSC 2500 with RCS90. Sample (~1-5 mg) was placed in a TZero aluminum DSC pan with a TZero Hermetic, pinholed lid and the weight was accurately recorded. Data were collected between -20°C and a maximum temperature of approximately 300°C at a heating rate of 10°C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.Thermal Gravimetric Analysis (TGA)

[0221] The thermal gravimetric analysis (TGA) experiments for Forms G and H were performed using a TA Instruments - Discovery TGA model 5500. The sample (~10 mg) was placed in a previously cleaned and tarred platinum pan then loaded into the instrument furnace. The furnace was heated under nitrogen gas. Data were collected between room temperature and approximately 400°C at a heating rate of 10°C / min.

[0222] The thermal gravimetric analysis (TGA) experiments for Forms J and K were performed using a TA Instruments - Discovery TGA model 5500. The sample (~10 mg) was placed in a previously cleaned and tarred platinum pan then loaded into the instrument furnace. The furnace was heated under nitrogen gas. Data were collected between room temperature and approximately 300°C at a heating rate of 10°C / min.Vapor Sorption

[0223] The vapor sorption experiment for Form G was performed using a TA Instrument VTI-SA+ Vapor Sorption Analyzer. Sample (~10 mg) was placed in a previously cleaned and tarred platinum pan then loaded into the instrument chamber. Sample was dried RT until the loss rate of 0.005 wt % / min was obtained for 10 minutes. The sample was then held isothermally at 25°C while the %RH of the system was stepped between 4, 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, 85, 75, 65, 55, 45, 35, 25, 15, 5, 4 %RH. Equilibration criteria was + / - 0.01 wt% for 35 min with a maximum equilibration time of 600 min at each step.NMR Spectroscopy

[0224] 1H- NMR spectroscopy was used to confirm compounds integrity and stoichiometry of the counterions (e.g. trospium and hydrogen pamoate). DMSO-d6 was used as a solvent. TheAttorney Docket No. 055920-813001WOspectra were recorded at room temperature on 500 MHz instrument (Bruker). The data was processed with ACD Labs software Spectrus Processor 2018.1 (Advanced Chemistry Development Inc. Canada).Example 1: Preparation of Hydrogen Pamoate Salt of Trospium of Formula I

[0225] Salt metathesis was used to exchange the counterions from a mixed salt system. In one example, 42 mg (97 pmol) of trospium chloride was dissolved in 0.2 mL of water. 38 mg (97 pmol) of pamoic acid was suspended in 0.42 mL of 9: 1 THF: Water. 12.2 pL (97.6 pmol) of 8 N KOH was charged to the pamoic acid suspension to generate a solution of monopotassium pamoate. The two solutions were combined. The resulting solution has a balanced amount of K and Cl ions to produce the side product KC1 and the desired hydrogen pamoate salt of trospium. The side product KC1 was removed, for example upon subsequent crystallization of hydrogen pamoate salt of trospium as it remained dissolved in solution.

[0226] In another example, 20.1 g of trospium chloride (46.8 mmol) was dissolved in 125 mL of water. 9.6 g of pamoic acid (24.57 mmol) and 9.53 g of disodium pamoate (25.74 mmol) were combined in 225 mL of THF and 25 mL of water to generate a solution of monosodium pamoate. The two solutions were combined. The resulting solution had a balance of Na and Cl ions to produce the side product NaCl, and the desired product hydrogen pamoate salt of trospium. The side product NaCl was removed for example upon subsequent crystallization of hydrogen pamoate salt of trospium as it remained dissolved in solution.

[0227] 1H-NMR analyses on isolated dried solids (e.g. Forms G, H, J and K) showed a trospium to pamoate ratio of 1: 1. 1H NMR spectrum is shown in FIG. 16. 1H NMR (500 MHz, DMSO-d6 ) 88.41 - 8.26 (s, 2H), 8.24 - 8.11 (d, 2H), 7.85 - 7.71 (d, 2H), 7.43 - 7.34 (m, 7H), 7.34 - 7.29 (m, 2H), 7.18 - 7.06 (t, 2H), 6.84 - 6.68 (s, 1H), 5.15 - 5.03 (t, 1H), 4.83 - 4.65 (s, 2H), 3.78 - 3.65 (s, 2H), 3.62 - 3.53 (t, 2H), 3.35 - 3.29 (t, 4H), 2.57 - 2.52 (d, 1H), 2.13-2.07 (s, 0.5), 2.05 - 1.94 (t, 4H), 1.94 - 1.84 (m, 2H), 1.84 - 1.70 (d, 2H), 1.60 - 1.47 (d, 2H)Example 2: Forms G and L

[0228] Form G was prepared using a variety of methods described below.(a) Form G

[0229] 42 mg of trospium chloride was dissolved in 0.2 mL of water. 38 mg of pamoic acid was suspended in 0.42 mL of 9:1 THF:water. 12.2 pL of 8 N KOH was charged to the Pamoic acid suspension to fully dissolve the counterion. The two solutions were combined, and the resulting solution was evaporated to dryness on a Genevac. 1 mL of 50:50 Acetone: Water wasAttorney Docket No. 055920-813001WOcharged and stirred overnight at 40 °C. Sample was cooled to ambient temperature, solids were isolated in a centrifuge tube and dried overnight under vacuum at RT to afford Form G.(b) Form G and Form L by slurry with seeds

[0230] 5.15 g of trospium chloride was dissolved in 25 mL of water. 4.67 g of pamoic acid was dissolved in 65 mL of THF, 12 mL of water and 1.5 mL of 8 N KOH. The two solutions were combined and the resulting solution was polish filtered, and the filter and flask were rinsed with 10 mL of 50:50 THF:water, which was added to the polish filtered solution. 75 mL of water was added, followed by 1 mL of THF. 25 mg of Form G seeds (as prepared for example as described in Example 2a) were suspended in 1 mL of water with a drop of THF and the suspension was added to the solution. Slurry was stirred for 15 minutes. 100 mL of water was added, and the slurry was stirred overnight. The solids were isolated, washed with 100 mL of 10 vol% THF in water and then 100 mL of water. The isolated solids, isolated as form L as determined by XRPD, were charged back into the reactor and suspended in 200 mL of 10% THF in water. 25 mg of Form G seeds were added and stirred for 40 hours at ambient temperature. The slurry was wet-milled for 2 minutes. The slurry was filtered and the sample was washed with 100 mL of 10% THF in water followed by an additional wash with 100 mL of water. The wet sample yielded Form G as determined by XRPD. The sample was dried in vacuum oven at 40 °C overnight to yield Form G.(c) Form G by slurry with seeds

[0231] 20.1 g of trospium chloride (46.8 mmol) was dissolved in 125 mL of water. 9.6 g of pamoic acid (24.57 mmol) and 9.53 g of disodium pamoate (25.74 mmol) were dissolved in 225 mL of THF and 25 mL of water. The two solutions were combined and the resulting solution was polish filtered, and the filter was rinsed with 10 mL of 4: 1 THF:water, which was added to the polish filtered solution. 215 mL of water was added, followed by addition of 20 mg of Form G seeds (as prepared for example as described in Example 2a). The slurry was stirred for 1 hour. 435 mL of water was added slowly and further 20 mg of Form G seeds were added. The slurry was stirred at room temperature for 6 days. The solids were isolated, washed with 200 mL of water. The sample was dried in vacuum oven at 50 °C overnight to yield Form G.(d) Single Crystal Analysis Data and XRPD for Form G

[0232] Form G harvested from the above examples was submitted to XRPD analysis. TheAttorney Docket No. 055920-813001WOresults for single crystal analysis are shown below in Table 1. The XRPD pattern for Form G is shown in FIG. 1. Major peaks and observed peaks in the XRPD pattern of Form G are listed in Table 2. Form G was observed as a hydrate.Table 1 - Single Crystal Analysis Data for Form G77K 100Crystal System TriclinicSpace Group P-1Unit CellDimensions:a = 13.76 ± 0.10 A a = 81.7 ± 1.0°b = 16.00 ± 0.10 A y5 = 88.o ± 1.0°c = 18.10 ± 0.10 A y = 88.7 ± 1.0°Volume 3943 ± 20 A3Z’ 2DcalcJ g cm’31.344Table 2 - Major peaks and Observed Peaks for Form GMajor Peaks (°20) Observed Peaks (°20) 4.9 ± 0.2 4.9 ± 0.25.5 ± 0.2 5.5 ± 0.26.4 ± 0.2 6.4 ± 0.27.9 ± 0.2 6.8 ± 0.28.5 ± 0.2 7.9 ± 0.210.3 ± 0.2 8.2 ± 0.213.7 ± 0.2 8.5 ± 0.217.8 ± 0.2 9.5 ± 0.218.1 ± 0.2 9.8 ± 0.219.7 ± 0.2 10.3 ± 0.211.1 ± 0.211.4 ± 0.213.0 ± 0.213.7 ± 0.214.1 ± 0.214.7 ± 0.215.0 ± 0.215.8 ± 0.216.1 ± 0.216.6 ± 0.217.1 ± 0.217.8 ± 0.218.1 ± 0.218.6 ± 0.219.2 ± 0.219.7 ± 0.2Attorney Docket No. 055920-813001WO20.2 ± 0.220.6 ± 0.220.9 ± 0.221.2 ± 0.222.0 ± 0.222.3 ± 0.223.2 ± 0.224.0 ± 0.224.8 ± 0.225.5 ± 0.226.2 ± 0.227.1 ± 0.229.4 ± 0.230.8 ± 0.2(e) DCS, TGA, and VTI analysis of Form G

[0233] Form G was assessed using DSC, TGA and VTI. The results are shown in FIGs.2, 3, and 4 respectively and summarized in Table 3. Dehydration was observed during DSC. Form G was moderately hygroscopic.Table 3 - Characterization of Form GTechniques Experimental ResultsBruker D8-VentureSingle with a Photon IIISee Table 1crystal detector and Cu KaradiationBruker D8 DiscoverCrystalline,XRPD DaVinci with XYZSee Table 2StageBroad endothermic eventwith peak at approximatelyTA Instruments - 90 °C;DSC Discovery DSC 2500 Endotherm onset atwith RCS90 approximately 217 °C,peak at approximately 219°Capproximately 1.8 wt%TA Instruments loss from roomTGADiscovery TGA 5500 temperature to about 175°CTA Instrument VTI- approximately 2.3% waterVTI SA± Vapor Sorptionuptake up to 95% RHAnalyzerAttorney Docket No. 055920-813001WO(f) XRPD for Form L

[0234] Form L harvested from the above examples was submitted to XRPD analysis. The XRPD pattern for Form L is shown in FIG. 15. Major peaks and observed peaks in the XRPD pattern of Form L are listed in Table 4. Form L was identified as a THF solvate.Table 4 - Major peaks and Observed Peaks for Form LMajor Peaks (°20) Observed Peaks (°20)7.5 ± 0.2 7.5 ± 0.28.7 ± 0.2 8.7 ± 0.29.3 ± 0.2 9.3 ± 0.214.4 ± 0.2 11.0 ± 0.217.0 ± 0.2 11.9 ± 0.219.2 ± 0.2 12.6 ± 0.222.8 ± 0.2 14.4 ± 0.215.5 ± 0.217.0 ± 0.218.4 ± 0.219.2 ± 0.220.4 ± 0.221.2 ± 0.222.8 ± 0.224.9 ± 0.226.1 ± 0.228.5 ± 0.229.0 ± 0.229.8 ± 0.230.4 ± 0.2Example 3: Forms H and I

[0235] Forms H and I were prepared using a variety of methods described below.(a) Forms H and I

[0236] 42 mg of trospium chloride was dissolved in 0.2 mL of water. 38 mg of pamoic acid was suspended in 0.42 mL of 90:10 THF: Water. 12.2 pL of 8 N KOH was charged to the pamoic acid suspension to fully dissolve the pamoic acid. The two solutions were combined and the resulting solution was evaporated to dryness on a Genevac. 50:50 Acetonitrile: Water was charged and stirred overnight at 40 °C. Sample was cooled to ambient temperature. The slurry yielded Form I. The solids were isolated in a centrifuge tube and dried overnight under vacuum at RT to afford Form H.Attorney Docket No. 055920-813001WO(b) Forms Hand I

[0237] 388 mg of pamoic acid was dissolved in 5 mL of THF, 1 mL of water and 125 pL of 8 N KOH. 429 mg of trospium Cl was dissolved in 2.5 mL of water. The two solutions were combined. 7.5 mL of MeCN and 10 mL of water were added. 2 mg of Form H seeds (as prepared for example using the method in Example 3a) were added. The slurry was stirred for 1 hour, followed by addition of 10 mL of water. Slurry was stirred overnight at ambient temperature. The slurry yielded Form I. The slurry was filtered, and sample was washed with 10 mL of water. The sample was dried overnight at 60 °C in a vacuum oven to afford Form H.(c) XRPD for Form H

[0238] Form H harvested from the above examples was submitted to XRPD analysis. The XRPD pattern for Form H is shown in FIG. 5. Major peaks and observed peaks in the XRPD pattern of Form H are listed in Table 5. Form H was observed as non-hydrate, non-solvate.Table 5 - Major peaks and Observed Peaks for Form HMajor Peaks (°20) Observed Peaks (°20)6.6 ± 0.2 6.6 ± 0.29.0 ± 0.2 9.0 ± 0.210.8 ± 0.2 9.3 ± 0.212.2 ± 0.2 10.8 ± 0.213.0 ± 0.2 11.1 ± 0.215.1 ± 0.2 12.2 ± 0.218.0 ± 0.2 13.0 ± 0.219.5 ± 0.2 14.0 ± 0.214.7 ± 0.215.1 ± 0.215.7 ± 0.216.1 ± 0.217.3 ± 0.218.0 ± 0.218.9 ± 0.219.5 ± 0.220.4 ± 0.221.6 ± 0.223.2 ± 0.224.6 ± 0.225.5 ± 0.226.3 ± 0.227.5 ± 0.229.2 ± 0.230.0 ± 0.2Attorney Docket No. 055920-813001WO(d) DCS and TGA analysis of Form H

[0239] Form H was assessed using DSC and TGA. The results are shown in FIGs. 6, and 7 respectively and summarized in Table 6.Table 6 - Characterisation of Form HTechniques Experimental ResultsBruker D8 DiscoverCrystallineXRPD DaVinci with XYZSee Table 4StageBroad endotherm withpeak at approximatelyTA Instruments - 39°C;DSC Discovery DSC 2500Endotherm onset atwith RCS90approximately 169°C, pealat approximately 181 °CNegligible weight lossTA InstrumentsTGA between RT andDiscovery TGA 5500approximately 200°C(e) Single Crystal Analysis Data and XRPD for Form I

[0240] Form I harvested from the above examples was submitted to XRPD analysis. The results for single crystal analysis are shown below in Table 7. The XRPD pattern for Form I is shown in FIG. 8. Major peaks and observed peaks in the XRPD pattern of Form I are listed in Table 8. Form I was observed as an acetonitrile solvate. A summary of results can be found in Table 9.Table 7 - Single Crystal Analysis Data for Form I77K 100Crystal System MonoclinicSpace Group P2i / cUnit CellDimensions:a = 13.76 ± 0.10 A a = 90 ± 1.0°b = 14.23 ± 0.10 A y5 = 93.4 ± 1.0°c = 22.55 ± 0.10 A y = 90 ± 1.0°Volume 4407 ± 20 A3Z’ 1DcalcJ g cm’31.299Attorney Docket No. 055920-813001WOTable 8 - Major peaks and Observed Peaks for Form IMajor Peaks (°20) Observed Peaks (°20) 6.4 ± 0.2 6.4 ± 0.29.8 ± 0.2 7.1 ± 0.213.2 ± 0.2 9.8 ± 0.214.3 ± 0.2 12.0 ± 0.215.6 ± 0.2 13.2 ± 0.218.5 ± 0.2 14.3 ± 0.221.0 ± 0.2 15.6 ± 0.216.8 ± 0.217.9 ± 0.218.5 ± 0.219.8 ± 0.220.5 ± 0.221.0 ± 0.222.3 ± 0.222.9 ± 0.224.2 ± 0.2Table 9 - Characterisation of Form ITechniques Experimental ResultsBruker D8- VentureSingle with a Photon IIISee Table 6crystal detector and Cu KaradiationBruker D8 Discover CrystallineXRPDDaVinci See Table 7Example 4: Form J

[0241] Forms J was prepared as described below.

[0242] 2,15 g trospium chloride was dissolved in 8 mL water. 1.94 g pamoic acid was dissolved in 50 mL of 90: 10 THF: Water and 0.63 mL of 8 N KOH. The two solutions were combined and ~20 mL of the resulting solvent was removed by evaporation. After adding 20 mL acetone, 20 mL solvent was removed by evaporation. 35 mL of water was added, followed by addition of Form G seeds (as prepared for example as described in Example 2a) and a sequential addition of 25 mL of water. The slurry was stirred overnight. The sample was filtered and the cake was washed with 50 mL of 90% water- 10% acetone. The cake was dried over 4 days in vacuum oven at 60 C to afford Form J.(a) Single Crystal Analysis Data and XRPD for Form J

[0243] Form J harvested from the above examples was submitted to XRPD analysis. TheAttorney Docket No. 055920-813001WOresults for single crystal analysis are shown below in Table 10. The XRPD pattern for Form J is shown in FIG. 9. Major peaks and observed peaks in the XRPD pattern of Form J are listed in Table 11. Form J was observed as a THF solvate.Table 10 - Single Crystal Analysis Data for Form JT / K 100Crystal System MonoclinicSpace Group P21 / nUnit CellDimensions:a = 13.11 ± 0.10 A a = 90 ± 1.0°b = 18.65 ± 0.10 A P = 93.6 ± 1.0°c = 17.26 ± 0.10 A y = 90 ± 1.0°Volume 4212 ± 20 A3Z’ 1Deale. / g cm-3 1.344Table 11 - Major peaks and Observed Peaks for Form JMajor Peaks (°20) Observed Peaks (°20)8.2 ± 0.2 8.2 ± 0.28.7 ± 0.2 8.7 ± 0.29.9 ± 0.2 9.2 ± 0.210.6 ± 0.2 9.5 ± 0.211.5 ± 0.2 9.9 ± 0.212.8 ± 0.2 10.3 ± 0.217.3 ± 0.2 10.6 ± 0.221.2 ± 0.2 11.5 ± 0.222.5 ± 0.2 12.8 ± 0.213.8 ± 0.214.3 ± 0.214.9 ± 0.215.5 ± 0.216.1 ± 0.216.4 ± 0.216.9 ± 0.217.3 ± 0.218.0 ± 0.218.6 ± 0.219.6 ± 0.220.5 ± 0.220.8 ± 0.221.2 ± 0.222.1 ± 0.222.5 ± 0.223.2 ± 0.2Attorney Docket No. 055920-813001WO23.8 ± 0.224.2 ± 0.224.9 ± 0.225.5 ± 0.226.3 ± 0.228.5 ± 0.2(b) DCS and TGA analysis of Form J

[0244] Form J was assessed using DSC and TGA. The results are shown in FIGs. 10, and 11 respectively and summarized in Table 12. Desolvation was observed during DSC.Table 12 - Characterisation of Form JTechniques Experimental ResultsBruker D8-VentureSingle with a Photon IIISee Table 6crystal detector and Cu KaradiationBruker D8 DiscoverDaVinci with XYZ CrystallineXRPDStage See Table 9Endotherm onset atapproximately 162°C, peakTA Instruments - at approximately 176 °C;DSC Discovery DSC 2500 Endotherm onset atwith RCS90 approximately 213 °C,peak at approximately 218°CApproximately 7.5%TA InstrumentsTGA weight loss between aboutDiscovery TGA 5500100 and 200°CExample 5: Form K

[0245] Forms K was prepared as described below.

[0246] 6.1 g of trospium chloride was dissolved in 35 mL of water. The solution was polish filtered. 3 mL of water was added to rinse the filter. 5.5 g pamoic acid was dissolved in 70 mL THF and 14 mL water and 1.8 mL of 8 N KOH (in water). The solution was polish filtered and 5 mL of THF was added to rinse the filter. The two solutions were combined and stirred.100 mL of EtOH was added to the resulting solution, followed by 100 mL of water.Approximately 10 mg of Form G seeds (as prepared for example as described in Example 2a) were added and slurry was stirred for 1 hour at ambient temperature. The sample was isolatedAttorney Docket No. 055920-813001WOand washed with 100 mL water. The sample was dried in vacuum oven at 50 °C overnight to yield Form K.(a) XRPD for Form K

[0247] Form K harvested from the above examples was submitted to XRPD analysis. The XRPD pattern for Form K is shown in FIG. 12. Major peaks and observed peaks in the XRPD pattern of Form K are listed in Table 13.Table 13 - Major peaks and Observed Peaks for Form KMajor Peaks (°20) Observed Peaks (°20)7.7 ± 0.2 7.1 ± 0.29.0 ± 0.2 7.7 ± 0.29.5 ± 0.2 9.0 ± 0.211.1 ± 0.2 9.5 ± 0.212.8 ± 0.2 11.1 ± 0.214.3 ± 0.2 11.9 ± 0.217.2 ± 0.2 12.3 ± 0.212.8 ± 0.213.4 ± 0.214.3 ± 0.214.9 ± 0.215.7 ± 0.217.2 ± 0.218.5 ± 0.219.4 ± 0.219.8 ± 0.220.3 ± 0.220.6 ± 0.221.4 ± 0.222.3 ± 0.222.8 ± 0.223.2 ± 0.223.5 ± 0.226.3 ± 0.228.4 ± 0.230.0 ± 0.2(b) DCS and TGA analysis of Form K

[0248] Form K was assessed using DSC and TGA. The results are shown in FIGs. 13, and 14 respectively and summarized in Table 14. Desolvation was observed during DSC.Attorney Docket No. 055920-813001WOTable 14 - Characterisation of Form KTechniques Experimental ResultsBruker D8 DiscoverCrystalline, agrees withXRPD DaVinci with XYZsimulated patternStageBroad endotherm withpeak at approximately39°C;TA Instruments - Endotherm onset atDSC Discovery DSC 2500 approximately 140°C, pealwith RCS90 at approximately 151°C;Endotherm onset atapproximately 215°C, pealat approximately 219°CApproximately 8.2%TA InstrumentsTGA weight loss between aboutDiscovery TGA 5500100 and 175°CExample 6: Solubility of Form G

[0249] Form G was assessed for its solubility in different aqueous conditions. The ability of Form G to dissolve in aqueous conditions was also compared to a different crystalline form of a trospium hemipamoate salt (trospium: pamoate at 2: 1). The trospium hemipamoate salt and crystal form was prepared according to US Provisional Application No. 63 / 656,787, the relevant content of which is incorporated herein by reference for the subject matter and purpose referenced herein.

[0250] The solubility of the trospium hemipamoate crystal form and Form G of the present disclosure was determined in water (Milli-Q water). A suspension was made with a target trospium concentration over 5 mg / mL if all dissolved. The samples were then prepared with a vigorous vortexing followed by 24 hours of gentle agitation (200 rpm) at 37 °C. A 1 mL aliquot of the mother liquor was taken and spun down (at 1400 ref) to separate the solution from the undissolved solid. The supernatant was then analyzed by UPLC and the concentration of trospium was determined against a pre-prepared calibration line. The results are given in concentration of trospium, as summarized in Table 15. Trospium chloride was dissolved inAttorney Docket No. 055920-813001WOwater in example methods (e.g. Example 2c) where a solubility of above 160 mg / mL was observed. The literature reported value of trospium chloride in water is > 100 mg / mL (MedChemExpress, Product Data Sheet for Trospium chloride)Table 15 - Solubility of Form G in WaterSolubility (Trospium) pH of the resulting Sample and Medium(pg / mL) solutionForm G in H2O 1.0 5.9Trospium hemipamoate in H₂O 8.5 6.8Trospium Chloride in H2O >1.6 x 105

[0251] The solubility of the trospium hemipamoate crystal form and Form G of the present disclosure was determined in phosphate buffered saline (PBS). A suspension was made with a target trospium concentration over 5 mg / mL if all dissolved. The samples were then prepared with a vigorous vortexing followed by 24 hours of gentle agitation (200 rpm) at 37 °C. A 1 mL aliquot of the mother liquor was taken and spun down (at 1400 ref) to separate the solution from the undissolved solid. The supernatant was then analyzed by UPLC and the concentration of trospium was determined against a pre-prepared calibration line. The results are given in concentration of trospium, as summarized in Table 16.Table 16 - Solubility of Form G in PBSSolubility (Trospium)Sample and Medium pH(pg / mL)Form G in H2O 2.7 6.9Trospium hemipamoate in25.7 7.2H2O

[0252] The XRPD of the Form G samples equilibrated for 24 h at 37 °C in water and PBS were collected. The diffractograms were identical to the starting material Form G. As such, Form G was stable when incubated in aqueous conditions at physiological temperature.Example 7: Chemical and Physical Stability and Pharmacokinetic (PK) Properties of Form G

[0253] Form G and a complex of xanomeline and quercetin were formulated in a composition containing 0.6% w / w aqueous polysorbate 80, xanomeline quercetin at a concentration of 60 mg / mL and Form G at a concentration of 15 mg / mL. The composition was administered to male Sprague-Dawley rats (body weight over 350 g) at a dose equivalent to 3 mg xanomelineAttorney Docket No. 055920-813001WOfree base and 0.75 mg trospium cation per rat, via a single injection. The injection was made intramuscularly in the rear quadricep muscle of the rats to ensure consistent IM placement across animals. The volume of the injection was 50 pL. A 1 mL syringe with a 25-gauge needle was used. A vehicle of 1% w / w sodium carboxymethyl cellulose (NaCMC), 0.6% w / w PS80 (aq) was used as control.

[0254] After the IM administration, the following mean pharmacokinetic parameters were investigated over the course of 240 hours. Overall, exposure of trospium (AUC0-240h) was 864.74 + / - 136.98 ng*h / mL, maximal concentration (Cmax) was 50.64 + / - 6.12 ng / mL, and final concentration was 0.02 + / - 0.01 ng / mL. Overall, exposure of xanomeline (AUC0-240h) was 314.81 + / - 75.04 ng*h / mL, maximal concentration (Cmax) was 2.22 + / - 0.34 ng / mL, and final concentration was 1.12 + / - 0.28 ng / mL. FIG. 17 shows plasma concentration of trospium cation and xanomeline free base after injection.

[0255] Additionally, Form G was found to be chemically and physically stable when monitored using high performance liquid chromatography (HPLC) and powder x-ray diffraction (XRPD) for a total of 4 weeks at the following storage conditions: 25 °C / 60 %RH closed, 40 °C / 75 %RH open, 40 °C / 75 %RH closed, 50 °C / 20 %RH closed, and 5 °C closed. Samples stored in closed configurations were stored in colorless, glass screw cap vials with parafilmed caps.

[0256] The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.EQUIVALENTS

[0257] While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize, or be able to ascertain using noAttorney Docket No. 055920-813001WOmore than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0258] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0259] All references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may encompass the entirety of the document.

[0260] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0261] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0262] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly oneAttorney Docket No. 055920-813001WOelement of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0263] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0264] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

Claims

Attorney Docket No. 055920-813001WOCLAIMS1. A hydrogen pamoate salt of trospium having a structure of Formula IOI.

2. The salt of claim 1, wherein the salt is in a crystalline form.

3. The salt of claim 2, wherein the crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern as set forth below:(i) comprising three or more, optionally four or more, or five or more, peaks at 4.9± 0.2° 26, 5.5± 0.2° 26, 6.4± 0.2° 26, 7.9± 0.2° 26, 8.5± 0.2° 26, 10.3± 0.2° 2 e, 13.7± 0.2° 26, 17.8± 0.2° 26, 18.1± 0.2° 26, and 19.7± 0.2° 26, (ii) comprising three or more, optionally four or more, or five or more, peaks at 6.6± 0.2° 26, 9.0± 0.2° 26, 10.8± 0.2° 26, 12.2± 0.2° 26, 13.0± 0.2° 26, 15.1± 0.2° 26, 18.0± 0.2° 26, and 19.5± 0.2° 26,(iii) comprising three or more, optionally four or more, or five or more, peaks at 6.4± 0.2° 26, 9.8± 0.2° 26, 13.2± 0.2° 26, 14.3± 0.2° 26, 15.6± 0.2° 26, 18.5± 0.2° 26, and 21.0± 0.2° 26,(iv) comprising three or more, optionally four or more, or five or more, peaks at 8.2± 0.2° 26, 8.7± 0.2° 26, 9.9± 0.2° 26, 10.6± 0.2° 26, 11.5± 0.2° 26, 12.8± 0.2° 26, 17.3± 0.2° 26, 21.2± 0.2° 26, and 22.5± 0.2° 26,(v) comprising three or more, optionally four or more, or five or more, peaks at 7.7± 0.2° 26, 9.0± 0.2° 26, 9.5± 0.2° 26, 11.1± 0.2° 26, 12.8± 0.2° 26, 14.3± 0.2° 26, and 17.2 ± 0.2° 26, or(vi) comprising three or more, optionally four or more, or five or more, peaks at 7.5± 0.2° 26, 8.7± 0.2° 26, 9.3± 0.2° 26, 14.4± 0.2° 26, 17.0± 0.2° 26, 19.2± 0.2° 26, and 22.8 ± 0.2° 26.Attorney Docket No. 055920-813001WO4. The salt of claim 3, wherein the XRPD pattern comprises peaks at 4.9± 0.2° 2θ, 5.5± 0.2° 2θ, 6.4± 0.2° 2θ, 7.9± 0.2° 2θ, 8.5± 0.2° 2θ, 10.3± 0.2° 2θ, 13.7± 0.2° 2θ, 17.8± 0.2° 2θ, 18.1± 0.2° 2θ, and 19.7 ± 0.2° 2θ.

5. The salt of claim 4, wherein the XRPD pattern is substantially as shown in FIG. 1.

6. The salt of claim 4 or 5, wherein the crystalline form is characterized by one or more of the following features:(a) a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 217 °C, optionally the endotherm with an onset of about 217 °C has a peak at about 219 °C, optionally wherein the thermogram further comprises a broad endothermic event at about 99 °C; (b) a thermogravimetric analysis (TGA) showing a mass loss of about 1.8 wt% from room temperature to about 175 °C; and(c) a vapour sorption of about 2.3 wt% water uptake from 9% up to 95% relative humidity (RH).

7. The salt of claim 6, wherein the crystalline form has one or more of the following features:(a) the DSC thermogram that is substantially as shown in FIG. 2;(b) the TGA is characterized by a curve substantially as shown in FIG. 3; and; (c) the vapour sorption is substantially as shown in FIG. 4.

8. The salt of any one of claims 4 to 7, wherein the crystalline form is a hydrate.

9. The salt of any one of claims 4 to 8, wherein the crystalline form is Form G.

19. The salt of claim 3, wherein the crystalline form is characterized by the XRPD pattern comprising peaks at 6.6± 0.2° 2θ, 9.0± 0.2° 2θ, 10.8± 0.2° 2θ, 12.2± 0.2° 2θ, 13.0± 0.2° 2θ, 15.1± 0.2° 2θ, 18.0± 0.2° 2θ, and 19.5± 0.2° 2θ.

11. The salt of claim 10, wherein the XRPD pattern substantially as shown in FIG. 5.

12. The salt of claim 10 or 11, wherein the crystalline form is characterized by one or more of the following features:(a) a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 169 °C, optionally the endotherm with anAttorney Docket No. 055920-813001WOonset of about 169 °C has a peak at about 181 °C, optionally the DSC thermogram further comprises a broad endothermic event at about 39 °C; (b) a thermogravimetric analysis (TGA) showing substantially no mass loss from room temperature to about 200 °C.

13. The salt of claim 12, wherein the crystalline form has one or more of the following features(a) the DSC thermogram is substantially as shown in FIG. 6; and(b) the TGA is characterized by a curve substantially as shown in FIG. 7.

14. The salt of any one of claims 10 to 13, wherein the crystalline form is Form H.

15. The salt of claim 3, wherein the crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern comprising peaks at 6.4± 0.2° 29, 9.8± 0.2° 29, 13.2± 0.2° 29, 14.3± 0.2° 29, 15.6± 0.2° 29, 18.5± 0.2° 29, and 21.0 ± 0.2° 29.

16. The salt of claim 15, wherein the XRPD pattern is substantially as shown in FIG. 8.

17. The salt of claim 15 or 16, wherein the crystalline form is an acetonitrile solvate.

18. The salt of any one of claims 15 to 17, wherein the crystalline form is Form I.

19. The salt of claim 3, wherein the crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern comprising peaks at 8.2± 0.2° 29, 8.7± 0.2° 29, 9.9± 0.2° 29, 10.6± 0.2° 29, 11.5± 0.2° 29, 12.8± 0.2° 29, 17.3± 0.2° 29, 21.2± 0.2° 29, and 22.5 ± 0.2° 29.

20. The salt of claim 10, wherein the XRPD pattern is substantially as shown in FIG. 9.

21. The salt of claim 10 or 20, wherein the crystalline form is characterized by one or more of the following features:(a) a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 162 or 213 °C, optionally wherein the endotherm with an onset of about 162 °C has a peak at about 176 °C, optionally wherein the endotherm with an onset of about 213 °C has a peak at about 218 °C; andAttorney Docket No. 055920-813001WO(b) a thermogravimetric analysis (TGA) showing substantially a mass loss of about 7.5 wt% from about 100 °C to about 200 °C.

22. The salt of claim 21, wherein the crystalline form has one or more of the following features:(a) the DSC thermogram is substantially as shown in FIG. 10; and(b) the TGA is characterized by a curve substantially as shown in FIG. 11.

23. The salt of any one of claims 19 to 22, wherein the crystalline form is a THF solvate.

24. The salt of any one of claims 19 to 23, wherein the crystalline form is Form J.

25. The salt of claim 3, wherein the crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern comprising peaks at 7.7± 0.2° 29, 9.0± 0.2° 29, 9.5± 0.2° 29, 11.1± 0.2° 2θ, 12.8± 0.2° 29, 14.3± 0.2° 29, and 17.2 ± 0.2° 29.

26. The salt of claim 25, wherein the XRPD pattern is substantially as shown in FIG. 12.

27. The salt of claim 25 or 26, wherein the crystalline form is characterized by one or more of the following features:(a) a differential scanning calorimetry (DSC) thermogram comprising at least one endotherm with an onset of about 149 or 215 °C, optionally wherein the endotherm with an onset of about 149 °C has a peak at about 151 °C, optionally wherein the endotherm with an onset of about 215 °C has a peak at about 219 °C, and optionally wherein the DSC thermogram further comprises a broad endothermic event at about 39 °C; and(b) a thermogravimetric analysis (TGA) showing substantially a mass loss of about 8.2 wt% from about 199 °C to about 175 °C.

28. The salt of claim 27, wherein the crystalline form has one or more of the following features:(a) the DSC thermogram is substantially as shown in FIG. 13; and(b) the TGA is characterized by a curve substantially as shown in FIG. 14.

29. The salt of any one of claims 25 to 28, wherein the crystalline form is an ethanol solvate.Attorney Docket No. 055920-813001WO30. The salt of any one of claims 25 to 29, wherein the crystalline form is Form K.

31. The salt of claim 3, wherein the crystalline form is characterized by an X-ray Powder Diffraction (XRPD) pattern comprising peaks at 7.5± 0.2° 29, 8.7± 0.2° 29, 9.3± 0.2° 29, 14.4± 0.2° 29, 17.0± 0.2° 29, 19.2± 0.2° 29, and 22.8 ± 0.2° 29.

32. The salt of claim 31, wherein the XRPD pattern is substantially as shown in FIG. 15.

33. The salt of claim 31 or 32, wherein the crystalline form is a THF solvate.

34. The salt of any one of claims 31 to 33, wherein the crystalline form is Form L.

35. A pharmaceutical composition comprising the salt of any one of claims 1 to 34, and a pharmaceutically acceptable excipient.

36. The pharmaceutical composition of claim 35, further comprising a muscarinic agonist.

37. The pharmaceutical composition of claim 36, wherein the muscarinic agonist produces xanomeline under physiological conditions.

38. The pharmaceutical composition of claim 37, wherein the muscarinic agonist is xanomeline or a salt thereof, optionally wherein the xanomeline or the salt thereof is in a crystalline form.

39. The pharmaceutical composition of claim 38, wherein the crystalline form of the xanomeline or the salt thereof is a complex of xanomeline and quercetin.

49. The pharmaceutical composition of any one of claims 35 to 39, wherein the composition is formulated for injection.

41. A method of treating a disease or disorder ameliorated by activating muscarinic receptors comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 35 to 49.

42. The method of claim 41, wherein the disease or disorder is a central nervous system (CNS) disorder.Attorney Docket No. 055920-813001WO43. The method of claim 42, wherein the CNS disorder is selected from schizophrenia, Alzheimer’s disease, bipolar disorder, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy, optionally wherein the CNS disorder is schizophrenia, Alzheimer’s disease, bipolar disorder or autism.

44. The method of any one of claims 41 to 43, wherein the pharmaceutical composition is administered to the subject by injection, optionally intravenous injection or subcutaneous injection.

45. The method of any one of claims 41 to 44, wherein the pharmaceutical composition is administered to the subject once every 2 days to about 6 months.

46. A method of preparing a hydrogen pamoate salt of trospium of Formula I as defined in claim 1, the method comprising reacting trospium or a salt thereof with alkali hydrogen pamoate to produce the salt of Formula I.

47. The method of claim 46, wherein the reacting is carried out at a molar ratio of trospium to pamoate of about 1:1.

48. The method of claim 46 or 47 wherein the method comprises reacting trospium chloride with the alkali hydrogen pamoate.

49. The method of any one of claims 46 to 48, wherein the alkali hydrogen pamoate is potassium hydrogen pamoate or sodium hydrogen pamoate.

50. The method of any one of claims 46 to 49, wherein the trospium or salt thereof is comprised in a first aqueous solution.

51. The method of any one of claims 46 to 50, wherein the alkali hydrogen pamoate is comprised in a second aqueous solution, optionally wherein the second aqueous solution comprises THF: water, optionally at a volume ratio of about 5: 1 to about 9:1, as a solvent.

52. The method of any one of claims 46 to 51, wherein the trospium or salt thereof is comprised in a first aqueous solution, and the alkali hydrogen pamoate is comprised in a second aqueous solution, and wherein the reacting comprises contacting the firstAttorney Docket No. 055920-813001WOaqueous solution with the second aqueous solution to obtain a trospium pamoate solution, optionally with stirring.

53. The method of claim 52, wherein the method further comprises filtering the trospium pamoate solution, optionally polish filtering.

54. The method of any one of claims 46 to 53, wherein the method further comprises providing the alkali hydrogen pamoate by reacting pamoic acid and alkali hydroxide at a molar ratio of pamoic acid to alkali hydroxide of about 1:1, optionally in a solvent of THF: water optionally at a volume ratio of about 5: 1 to about 9:1.

55. The method of any one of claims 46 to 53, wherein the method further comprises providing the alkali hydrogen pamoate by reacting pamoic acid and disodium pamoate at a molar ratio of pamoic acid to disodium pamoate of about 1:1, optionally in a solvent of THF: water, optionally at a volume ratio of about 1.5:1.

56. A method of preparing a crystalline form of the hydrogen pamoate salt of trospium as defined in claim 1, the method comprisingcrystallising a hydrogen pamoate salt of trospium of Formula I as defined in claim 1 in a solvent to obtain the crystalline form, wherein the solvent is selected from acetone: water, optionally at a volume ratio of about 1:1, acetonitrile: water, optionally at a volume ratio of about 1:1, water, THF: water, and ethanol: water.

57. The method of claim 56, wherein the solvent is acetone:water, optionally at a volume ratio of about 1:1, and the crystalline form is as defined in any one of claims 4 to 9, and wherein the method further comprises drying the crystalline form in vacuo, optionally wherein the drying is carried out overnight at about room temperature to about 60°C.

58. The method of claim 57, wherein the crystallising comprises providing a solution of the hydrogen pamoate salt of trospium in acetone: water, stirring the solution at about 50 °C to about 60 °C, for example at about 40 °C, for overnight, cooling the solution to room temperature.Attorney Docket No. 055920-813001WO59. The method of claim 56, wherein the solvent is acetonitrile:water, optionally at a volume ratio of about 1:1, and the crystalline form is as defined in any one of claims 15 to 18.

60. The method of claim 59, wherein the crystallising comprises providing a solution of the hydrogen pamoate salt of trospium in acetonitrile:water, stirring the solution at about 50 °C to about 60 °C, for example at about 40 °C, for overnight, cooling the solution to room temperature.

61. The method of claim 56, wherein the solvent is acetonitrile: water, optionally at a volume ratio of 1:1, wherein the method further comprises drying the crystalline form in vacuo at about 50 °C to about 70 °C, optionally about 60 °C, and wherein the crystalline form is as defined in any one of claims 10 to 14.

62. A method of preparing a crystalline form of the hydrogen pamoate salt of trospium as defined in any one of claims 4 to 9, the method comprising(i) seeding a solution of the salt in a first mixture of organic solvent and water with a first amount of a seed crystalline form as defined in any one of claims 3 to 34, optionally as defined in any one of claims 4 to 9, to obtain a first slurry, (ii) filtering the first slurry to obtain a first solid,(iii)suspending the first solid in a second mixture of organic solvent and water, and seeding with a second amount of the seed crystalline form as defined in any one of claims 4 to 9 to obtain a second slurry, wherein the second mixture comprises about 20% v / v or less than 20% v / v organic solvent, (iv)filtering the second slurry to obtain a second solid, and(v) drying the second solid in vacuo at about 30 °C to about 50 °C, optionally about 40 °C, to obtain the crystalline form of the salt of trospium and hydrogen pamoate as defined in any one of claims 4 to 9,optionally wherein the organic solvent is selected from THF, ethanol, acetonitrile, acetone and combinations thereof.

63. The method of claim 62, wherein the seed crystalline form is prepared according to the method of claim 57 or 58.

64. The method of claim 62 or 63, wherein step (i) is carried out at room temperature, optionally for overnight.Attorney Docket No. 055920-813001WO65. The method of any one of claims 62 to 64, further comprising after step (ii) and / or before step (iii) washing the first solid, optionally with 10% v / v THF: water and / or water.

66. The method of any one of claims 62 to 65, wherein step (iii) is carried out at room temperature for about 30 hours to about 50 hours, optionally about 40 hours.

67. The method of any one of claims 62 to 66, further comprising after step (iv) and prior to step (v) washing the second solid, optionally with 10% v / v THF: water and / or water.

68. The method of any one of claims 62 to 67, wherein step (v) is carried out for overnight.

69. A method of preparing a crystalline form of the hydrogen pamoate salt of trospium as defined in any one of claims 15 to 18, the method comprising(i) seeding a solution of the hydrogen pamoate salt of trospium as defined in claim 1 in acetonitrile:water with a seed crystalline form as defined in any one of claims 10 to 14 to obtain a slurry, the slurry comprising the crystalline form as defined in any one of claims 15 to 18, and optionally(ii) isolating the crystalline form from the slurry.

70. The method of claim 69, wherein the seed crystalline form is prepared according to the method of claim 62.

71. The method of claim 69 or 70, wherein step (i) is carried out at room temperature, optionally for overnight.

72. A method of preparing a crystalline form of the salt of trospium and hydrogen pamoate as defined in any one of claims 19 to 24, the method comprising(i) seeding a solution of the salt with a seed crystalline form as defined in any one of claims 4 to 9 in water to allow for formation of the crystalline form as defined in any one of claims 19 to 24, and optionally(ii) isolating the crystalline form as defined in any one of claims 19 to 24.

73. The method of claim 72, wherein the seed crystalline form is prepared according to the method of any one of claims 57 or 58.Attorney Docket No. 055920-813001WO74. The method of claim 72 or 73, further comprising drying the crystalline form as defined in any one of claims 19 to 24 in vacuo at about 50 °C to about 70 °C, optionally about 60 °C, and wherein the drying is carried out for about 3 days to about 5 days, optionally about 4 days.

75. A method of preparing a crystalline form of the hydrogen pamoate salt of trospium as defined in any one of claims 25 to 30, the method comprising(i) seeding a solution of the salt with a seed crystalline form as defined in any one of claims 4 to 9 in ethanol: water to allow for formation of the crystalline form as defined in any one of claims 25 to 30, and optionally(ii) isolating the crystalline form as defined in any one of claims 25 to 30.

76. The method of claim 75, wherein the seed crystalline form is prepared according to the method of claim 57 or 58.

77. The method of claim 75 or 76, wherein step (i) is carried out at room temperature, optionally for about one or two hours.

78. The method of any one of claims 75 to 77, further comprising drying the crystalline form as defined in any one of claims 25 to 30 in vacuo at about 40 °C to about 60 °C, optionally about 50 °C, and optionally wherein the drying is carried out for overnight.

79. A method of preparing a crystalline form of the salt of trospium and hydrogen pamoate as defined in any one of claims 31 to 34, the method comprising(i) seeding a solution of the hydrogen pamoate salt of trospium as defined in claim 1 in THF:water with a first amount of a seed crystalline form as defined in any one of claims 4 to 9 to obtain a first slurry,(ii) filtering the first slurry to obtain a first solid, and(iii)suspending the first solid in 10% v / v THF: water and seeding with a second amount of the seed crystalline form as defined in any one of claims 4 to 9 to obtain a second slurry, and(iv)filtering the second slurry to obtain a second solid, the second solid being the crystalline form as defined in any one of claims 31 to 34.

80. The method of claim 79, wherein the seed crystalline form is prepared according to the method of claim 57 or 58.Attorney Docket No. 055920-813001WO81. The method of any one of claims 56 to 80, wherein the method further comprises preparing the hydrogen pamoate salt of trospium, optionally according to a method as defined in any one of claims 46 to 55.

82. A crystalline form of the hydrogen pamoate salt of trospium as defined in claim 1, wherein the crystalline form is produced by a method of any one of claims 56 to 81.

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