New crystal form of xanomeline pamoate, and preparation method therefor and use thereof

Abstract

Provided in the present invention are a new crystal form of xanomeline pamoate represented by formula (I) and a preparation method therefor. The crystal form can be used for preparing a drug for preventing and / or treating diseases that are ameliorated by activating a muscarinic receptor.

Description

Novel crystal form of jambolin pamoate, its preparation method and uses

[0001] This application claims priority to the prior application filed by the applicant with the China National Intellectual Property Administration on December 9, 2024, with patent application number 202411802521.9 entitled "A new crystal form of pamoate and its preparation method and use"; the entire contents of the prior application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, specifically to a new crystal form of pramosiderin acetonide and its preparation method, as well as its application in the preparation of drugs for treating central nervous system disorders. Background Technology

[0003] In today's fast-paced society, people face various pressures from education, employment, work, and life. Once these pressures exceed a person's psychological limits, the brain's nervous system function can become disordered, leading to mental and physical symptoms such as insomnia, headaches, depression, obsessive-compulsive disorder, anxiety, palpitations, and stomach discomfort. When the body is affected by harmful internal or external factors that disrupt brain function, it can lead to neurological disorders, including mental illnesses and neurodegenerative diseases.

[0004] Xanomeline is an M1 and M4-preferred muscarinic receptor agonist used to treat neurological disorders such as schizophrenia and Alzheimer's disease. However, these patients often experience cognitive impairment, frequently exhibiting resistance to medication or forgetting to take it, affecting medication adherence and consequently, disease prognosis. Long-acting formulations of xanomeline reduce the frequency of dosing and prolong the duration of action, offering significant convenience to patients.

[0005] Zanomelin pamoate is a poorly soluble compound suitable for developing long-acting formulations, such as suspensions or lyophilized formulations, to prolong drug release time and achieve sustained drug action. CN114853750A discloses crystal forms A, B, and C of zanomelin pamoate. Based on practical needs, it is necessary to conduct in-depth research on the crystal forms and pharmaceutical properties of zanomelin pamoate to develop a new crystal form with clinical value. Summary of the Invention

[0006] The purpose of this invention is to provide a new crystal form of janomyl pamoate, its preparation method and uses, which is particularly suitable for preparing long-acting injectable formulations of janomyl pamoate.

[0007] The first objective of this invention is to provide the E and F crystal forms of genomeline pamoate.

[0008] A second objective of this invention is to provide methods for preparing the E and F crystal forms of tamsulosin pamoate.

[0009] A third object of the present invention is to provide a pharmaceutical composition comprising the E and / or F crystal forms of tamsulosin pamoate, and at least one pharmaceutically acceptable carrier.

[0010] A fourth object of the present invention is to provide the use of the E and F crystal forms of pramosiderin or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of diseases improved by activating muscarinic receptors.

[0011] A fifth object of the present invention is to provide a method for preventing and / or treating diseases improved by activating muscarinic receptors, comprising administering to a subject in need a therapeutically effective amount of pramocyanine pamoate E crystal form and / or F crystal form, or a pharmaceutical composition thereof.

[0012] The genomelephrine pamoate of the present invention has the structure shown in formula (I):

[0013] First, the present invention provides the E crystal form of pamoate of formula (I).

[0014] In one embodiment, the XRPD spectrum of the E crystal form, represented by the 2θ angle, has characteristic peaks at one or more of the following locations: approximately 6.6°±0.2°, 9.6°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 24.9°±0.2°, and 26.0°±0.2°.

[0015] In one embodiment, the XRPD spectrum of the E crystal form, represented by the 2θ angle, has no characteristic peaks at one or more locations at approximately 4.6°±0.2° and 5.6°±0.2°.

[0016] In one embodiment, the XRPD spectrum of the E crystal form, represented by a 2θ angle, has no characteristic peaks at one or more locations at approximately 5.6°±0.2° and 29.0°±0.2°.

[0017] In one embodiment, the XRPD spectrum of the E crystal form, represented by the 2θ angle, has characteristic peaks at one or more of the following locations: approximately 6.6°±0.2°, 8.3°±0.2°, 9.6°±0.2°, 13.0°±0.2°, 15.8°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 25.4°±0.2°, 26.0°±0.2°, 28.5°±0.2°, and 29.7±0.2°.

[0018] In one embodiment, the XRPD spectrum of the E crystal form, represented by the 2θ angle, has no characteristic peaks at one or more locations at approximately 4.6°±0.2°, 5.6°±0.2°, and 29.0°±0.2°.

[0019] In one embodiment, the E crystal form has an XRPD pattern that is basically as shown in Figure 2.

[0020] In one embodiment, the DSC chart of the E-type crystal has endothermic peaks at approximately 84°C and approximately 172°C. The temperatures have an error of ±3°C, preferably ±2°C, and more preferably ±1°C.

[0021] In one embodiment, the E crystal form has a DSC pattern essentially as shown in Figure 3.

[0022] The present invention also provides a method for preparing the E crystal form of janomyl pamoate. The method comprises: mixing the B crystal form of janomyl pamoate shown in formula (I) with methyl acetate, stirring and slurrying at a temperature below 50°C, and cooling to crystallize, thereby obtaining the E crystal form. Preferably, the stirring is carried out at 45±3°C (e.g., 45±2°C or 45±1°C), for example at 45°C.

[0023] Preferably, the ratio of the B crystal form to methyl acetate is 1g:5-20ml, for example 1g:8-15ml, or for example 1:10ml. The stirring is carried out for about 8-24 hours, for example 12-20 hours. The cooling crystallization can be carried out at room temperature or lower (e.g., 0-10°C).

[0024] The present invention also provides the F crystal form of the monomeline pamoate shown in formula (I).

[0025] In one embodiment, the XRPD plot of the F crystal form at a 2θ angle has characteristic peaks at one or more of the following locations: approximately 5.3°±0.2°, 6.7°±0.2°, 8.2°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 20.3°±0.2°, 20.7°±0.2°, and 23.9°±0.2°.

[0026] In one embodiment, the XRPD plot of the F crystal form at the 2θ angle has characteristic peaks at one or more of the following locations: approximately 5.3°±0.2°, 6.7°±0.2°, 8.2°±0.2°, 8.8°±0.2°, 11.4°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 16.0°±0.2°, 20.3°±0.2°, 20.7°±0.2°, 23.9°±0.2°, 24.4°±0.2°, 25.9°±0.2°, and 26.7°±0.2°.

[0027] In one embodiment, the F crystal form has an XRPD pattern essentially as shown in Figure 4.

[0028] In one embodiment, the DSC plot of the F crystal form has an endothermic peak in the range of approximately 140°C. The temperature has an error of ±3°C, preferably ±2°C, and more preferably ±1°C.

[0029] In one embodiment, the F crystal form has a DSC pattern essentially as shown in Figure 5.

[0030] The present invention also provides a method for preparing the F crystal form of janomyl pamoate. The method comprises: mixing the B crystal form of janomyl pamoate shown in formula (I) with isopropyl acetate, stirring and slurrying at 50-60°C, cooling and crystallizing to obtain the F crystal form.

[0031] In one embodiment, the ratio of the B crystal form to isopropyl acetate is 1g:5-20ml, for example 1g:8-15ml, or for example 1:10ml. The stirring is carried out for approximately 8-24 hours, for example 12-20 hours. The cooling crystallization can be carried out at room temperature or lower (e.g., 0-10°C).

[0032] The genomelin pamoate B crystal form described in this invention can be prepared according to methods known in the art, specifically, the preparation method described in CN114853750A.

[0033] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the B-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 16.285±0.2°, 24.032±0.2°, and 27.797±0.2°; preferably, the X-ray powder diffraction pattern of the B-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 16.285±0.2°, 24.032±0.2°, and 27.797±0.2°.

[0034] Preferably, the X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 16.285±0.2°, 18.868±0.2°, 24.032±0.2°, and 27.797±0.2°;

[0035] Preferably, the X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 18.868±0.2°, 24.032±0.2°, 27.797±0.2°, and 29.728±0.2°;

[0036] Preferably, the X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 17.862±0.2°, 18.868±0.2°, 19.538±0.2°, 21.095±0.2°, 24.032±0.2°, 27.797±0.2°, and 29.728±0.2°;

[0037] Preferably, the X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 13.685±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 17 0.862±0.2°, 18.868±0.2°, 19.538±0.2°, 20.463±0.2°, 21.095±0.2°, 24.032±0.2°, 24.743±0.2°, 27.542±0.2°, 27.797±0.2°, 29.374±0.2° and 29.728±0.2°.

[0038] According to an embodiment of the present invention, the method for preparing the B crystal form is as follows: mixing genomelin pamoate with a solvent, stirring, and then cooling to precipitate crystals; wherein the solvent is selected from ethanol, n-propanol, or a mixture thereof, preferably ethanol.

[0039] The present invention also provides a pharmaceutical composition comprising the E and / or F crystal forms of the jambolin pamoate, and optionally pharmaceutically acceptable excipients.

[0040] Optionally, the pharmaceutical composition may contain other active pharmaceutical ingredients, such as trox chloride.

[0041] The pharmaceutical composition can be prepared into various dosage forms, including but not limited to suspensions, lyophilized formulations, tablets, capsules, and granules. Preferably, the pharmaceutical composition is a suspension or a lyophilized formulation. The pharmaceutical formulation can be administered via different routes, including but not limited to injection and oral administration; preferably, it can be administered by injection, such as subcutaneous injection, intramuscular injection, intravenous injection, or intradermal injection.

[0042] Optionally, the content of phenomeline pamoate is 0.5 to 50 wt% based on the weight of the pharmaceutical composition. According to some embodiments of the present invention, the content of phenomeline pamoate is 1 to 45% based on the weight of the pharmaceutical composition, for example 3 to 42%, for example 5 to 40 wt%, for example 5, 10, 15, 20, 25, 30, 35 wt%, or any range defined by the above values.

[0043] Optionally, the pharmaceutically acceptable carrier includes a suspending agent selected from one or more of gums, celluloses, starches, carbomer, polyvinylpyrrolidone (PVP), dextran, or polyethylene glycol. For example, the suspending agent is selected from one or more of the following: sodium carboxymethyl cellulose (CMC-Na), calcium carboxymethyl cellulose (CMC-Ca), methyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl ethyl cellulose (HPEC), carboxymethyl acrylate, hydroxypropyl methyl cellulose phthalate (HPMCP); hydroxyethyl starch (HES); carbomer 980; gum arabic, xanthan gum; polyvinylpyrrolidone K12 (PVP-K12), polyvinylpyrrolidone K17 (PVP-K17), polyvinylpyrrolidone K30 (PVP-K30); dextran 40, dextran 70; polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000 or polyethylene glycol 8000. Preferably, the suspending agent is selected from one or more of CMC-Na, HPMC, PEG4000, PVP-K12, PVP-K17, xanthan gum, hydroxyethyl cellulose, and sodium alginate.

[0044] Optionally, the content of the suspending agent is 0.1 to 10 wt% based on the weight of the pharmaceutical composition. According to some embodiments of the present invention, the content of the suspending agent is 0.2 to 8 wt%, 0.3 to 7.5 wt%, 0.5 to 7 wt%, 0.8 to 6.5 wt%, 1 to 6 wt%, or any range defined above, based on the weight of the pharmaceutical composition.

[0045] Optionally, the pharmaceutically acceptable carrier may include a wetting agent. The wetting agent is selected from one or more of polysorbate (Tween), fatty acid sorbitan (Span), poloxamers, tylosaprol, phospholipids, vitamin E polyethylene glycol succinate (TPGS), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salts, higher fatty alcohol sulfates, sulfonates, higher fatty acid salts, and polyethylene glycol stearates. For example, the wetting agent is selected from one or more of Tween 20, Tween 40, Tween 80, poloxamer 188, lecithin, vitamin E polyethylene glycol 2000 succinate (TPGS), polyoxyethylene 40 hydrogenated castor oil (RH40), tylosaprol, poloxamer 188, sodium docusate, and sodium oleate.

[0046] Optionally, the wetting agent is selected from one or more of Tween 20, Tween 40, Tween 80, lecithin, TPGS, RH40, and tylosap.

[0047] Optionally, the content of the wetting agent is 0 to 6 wt% based on the weight of the pharmaceutical composition. According to some embodiments of the present invention, the content of the wetting agent is 0.01 to 5.5 wt%, 0.05 to 5 wt%, 0.08 to 4 wt%, 0.1 to 3 wt%, 0.2 to 2.5 wt%, 0.3 to 2 wt%, or any range defined above based on the weight of the pharmaceutical composition.

[0048] Optionally, the pharmaceutically acceptable carrier further comprises one or more of a pH adjuster, an osmotic pressure adjuster, and a solvent. The pH adjuster is selected from acids, bases, or buffer salts, such as hydrochloric acid, sulfuric acid, citric acid, tartaric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, meglumine, amino acids, phosphate buffers (disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc.), citrate buffers, tartaric acid buffers, malate buffers, and acetate buffers. The osmotic pressure adjuster is selected from one or more of sodium chloride, potassium chloride, and glycerol, and is used to adjust the osmotic pressure of the pharmaceutical composition to 250–1000 mOsm / kg, for example, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mOsm / kg; the solvent is water or vegetable oil, preferably water.

[0049] Optionally, the amount of the pH adjuster is used to adjust the pH of the pharmaceutical composition to about 4.0 to 8.5, for example about 4.5 to 8.0, 4.5 to 7.5, 4.0 to 7.0, 5.0 to 7.0 or any range defined by the above values.

[0050] Optionally, the pharmaceutically acceptable carrier includes a filler. The filler may be selected from one or more of mannitol, trehalose, sucrose, glycerol, xylitol, sorbitol, maltose, glucose, starch, sucralose, etc. The content of the filler is 0–10 wt% based on the weight of the pharmaceutical composition, preferably 1–9 wt%, 2–8 wt%, 3–6 wt%, or 4–5 wt%.

[0051] Optionally, the pharmaceutically acceptable carrier includes antibacterial agents, stabilizers, etc., wherein the antibacterial agent is selected from one or more of benzyl alcohol, chlorobutanol, etc., and the stabilizer is selected from one or more of sodium sulfite, sodium bisulfite, disodium EDTA, etc.

[0052] Optionally, the pharmaceutical composition includes a solvent, such as water, vegetable oil, etc.

[0053] Preferably, the pharmaceutical composition is an aqueous suspension.

[0054] The present invention also provides the use of the E and / or F crystal forms of the jambolin pamoate, or pharmaceutical compositions containing it, in the preparation of medicaments for the prevention and / or treatment of diseases improved by activating muscarinic receptors.

[0055] Accordingly, the present invention also provides E and / or F crystal forms of the tamsulpine pamoate, or pharmaceutical compositions containing thereof, for the prevention and / or treatment of diseases improved by activation of muscarinic receptors, the method comprising administering to a subject in need a therapeutically effective amount of the E and / or F crystal forms of the tamsulpine pamoate of the present invention, or pharmaceutical compositions containing thereof.

[0056] In this invention, the diseases that are improved by activating muscarinic receptors can be selected from schizophrenia, Alzheimer's disease, bipolar disorder, Parkinson's disease, Huntington's disease, depression, Lewy body dementia, movement disorders, drug addiction, pain, and neurodegenerative diseases such as tau protein diseases and conucleoprotein diseases.

[0057] According to these methods, the dosage form provides a therapeutically effective dose of phenomenal over at least one day. Preferably, the method does not require monitoring for post-injection delirium / sedation syndrome (PDSS).

[0058] In this invention, "optionally" or "optionally" means that the events or situations described below may or may not occur, and the corresponding implementations are all within the scope of this invention.

[0059] In this invention, "post-injection delirium / sedation syndrome" or "PDSS" should be understood as being defined as those symptoms or combinations of symptoms and conditions as defined in Detke, HC, et al., BMC Psychiatry 2010, 10:43, which is incorporated herein by reference; or as any person skilled in the art would understand the term. For example, delirium-related symptoms include disorientation, confusion, ataxia, and dysarthria. Sedation-related symptoms include, for example, somnolence, sedation, or other changes in level of consciousness.

[0060] The XRPD detection of the crystal form of the present invention uses Cu-Kα radiation.

[0061] The crystal form of the present invention can be defined according to the diffraction angle position of one or more locations in the diffraction peak data table corresponding to its embodiments (i.e., the crystal form of the present invention may optionally have a characteristic peak at one or more locations at 2θ listed in its diffraction peak data table), and the error range of the diffraction angle is 2θ ± 0.2°. The "one or more locations" with characteristic peaks mentioned in the present invention refer to locations 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30... of the listed characteristic peaks.

[0062] In this invention, the "pharmaceutical composition" contains a therapeutically effective amount of an active ingredient, for example, a therapeutically effective amount of the E and / or F crystal forms of nomereline pamoate. The term "therapeuticly effective amount" refers to the amount of an active compound or drug sought in a test subject to elicit a biological or medical response, including one or more of the following: (1) disease prevention: for example, prevention of disease, disorder or condition in individuals susceptible to disease, disorder or condition but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) disease inhibition: for example, inhibition of disease, disorder or condition in individuals experiencing or exhibiting the pathology or symptoms of the disease (i.e., prevention of further development of the pathology and / or symptoms); (3) disease relief: for example, relief of disease, disorder or condition in individuals experiencing or exhibiting the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms). Attached Figure Description

[0063] Figure 1: XPRD spectrum of compound B of formula (I);

[0064] Figure 2: XPRD spectrum of crystal form E of compound (I);

[0065] Figure 3: DSC spectrum of crystal form E of compound (I);

[0066] Figure 4: XPRD spectrum of crystal form F of compound (I);

[0067] Figure 5: DSC spectrum of crystal form F of compound (I);

[0068] Figure 6: XPRD spectrum of the amorphous form of compound (I);

[0069] Figure 7: XPRD spectrum of crystal form A of compound (I);

[0070] Figure 8: DSC spectrum of crystal form A of compound (I). Detailed Implementation

[0071] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. Unless otherwise specified, the materials used in the embodiments are commercially available or prepared by known or conventional methods. Unless otherwise specified, the experimental methods used are conventional methods.

[0072] Materials and Methods:

[0073] The janomyl pamoate in the examples has the structure shown in formula (I), wherein the ratio of janomyl free base to pamoate is 1:1. The janomyl pamoate or its A and B crystal forms used in the examples can be prepared according to methods known in the art, such as the method described by the applicant in CN114853750A, the entire contents of which are incorporated herein by reference.

[0074] XRPD (X-ray Powder Diffraction): Bruker D8 ADVANCE X-ray diffractometer; Optical tube: Cu, kα, Photodiode voltage: 40kV; Photodiode current: 40mA; Scan range: 3-45deg; Step size: 0.02deg; Step length: 0.12 seconds. Test method: Approximately 10-20mg of sample is used for XRPD detection.

[0075] DSC (Differential Scanning Calorimetry): METTLER TOLEDO DSC3+ differential scanning calorimeter; temperature range: 25–300℃; heating rate: 10℃ / min; nitrogen purge gas: 50ml / min. Test method: Place the sample (3–5mg) in the DSC aluminum pot for testing.

[0076] Unless otherwise specified, the reagents and methods used in the examples are all available to those skilled in the art through known or conventional means.

[0077] Example 1: Preparation of the E crystal form of nomereline pamoate

[0078] Preparation of B-type crystal:

[0079] Zanomeline (10 g, 35.5 mmol), pamoic acid (13.8 g, 35.5 mmol), dimethyl sulfoxide (30 ml), and ethanol (30 ml) were mixed, stirred, and heated until dissolved. Then, ethanol (440 ml) was added, and the solution was slowly cooled to 0-10 °C with stirring to induce crystallization for 6 hours. The mixture was filtered, the filter cake was washed with cold ethanol, and dried under vacuum at 40 °C to obtain zanomeline pamoic acid salt (22.5 g, yield 94.5%) in crystal form B. The XRPD spectrum is shown in Figure 1.

[0080] Preparation of E-type crystal form:

[0081] The prepared genomeline pamoate B crystal form (2.0 g) was mixed with methyl acetate (20 ml), heated to 45°C and stirred for about 12 hours, then cooled to room temperature. The mixture was filtered, the filter cake was washed with methyl acetate, and dried under vacuum at 40°C to obtain a pale yellow solid (1.5 g, 75%), which was in the E crystal form.

[0082] The melting point of the E crystal form is approximately 171.7℃. The XRPD pattern is shown in Figure 2, and the diffraction angle data are shown in Table 1. The DSC pattern is shown in Figure 3.

[0083] Table 1. XRPD characteristic diffraction peaks of crystal form E

[0084] Example 2: Preparation of the F crystal form of nomereline pamoate

[0085] The 2.0 g of jambrine pamoate B crystal form prepared in Example 1 was mixed with isopropyl acetate (20 ml), stirred and heated to 50 °C, and stirred for 12 hours. Then it was cooled to room temperature. The mixture was filtered, the filter cake was washed with isopropyl acetate, and dried under vacuum at 40 °C to obtain a pale yellow solid (1.6 g, yield 80%), which was in the F crystal form.

[0086] The melting point of the F crystal form is approximately 140.4℃. The XRPD pattern is shown in Figure 4, and the diffraction angle data are basically shown in Table 2. The DSC pattern is shown in Figure 5.

[0087] Table 2. XRPD characteristic diffraction peaks of crystal form F

[0088] Example 3: Preparation of Nomerin Pamoate A Crystal Form

[0089] The A crystal form of jambolin pamoate can be prepared according to the method described in CN114853750A or the method described below.

[0090] Zanomelin tartrate (200 g, 0.463 mol) was dissolved in methanol (1.2 L) and water (1.2 L) to obtain solution 1; disodium pamoate (208 g, 0.463 mol) was added to water (2 L), stirred and heated until completely dissolved to obtain solution 2. Solutions 1 and 2 were mixed and stirred until the reaction was complete. After cooling, crystals were precipitated, filtered, and the filter cake was washed with water and dried under vacuum at 50 °C to obtain a pale yellow powder (308 g, yield 75.5%), which was the amorphous form of zanomelin pamoate. The XRPD spectrum is shown in Figure 6.

[0091] The amorphous jammine pamoate prepared above (10.0 g) was mixed with ethyl acetate (200 ml) and stirred at 55–60 °C for 12 hours, then cooled to room temperature. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 40 °C to obtain a pale yellow solid (8.5 g, yield 85%), which was in crystal form A.

[0092] The melting point of crystal form A is approximately 166.7℃. The XRPD pattern is shown in Figure 7. The DSC pattern is shown in Figure 8. Both are consistent with the crystal form A pattern disclosed in CN114853750A.

[0093] Test Example 1: Study on the Physical Stability of Crystal Form

[0094] The E-type and F-type crystals prepared in Example 1 and Example 2, respectively, were laid flat and exposed in containers. Stability tests were conducted on the samples under high temperature (60°C), high humidity (RH 92.5%), and light irradiation (4500±500 Lux). Samples were taken at 0, 10, and 30 days to determine the crystal form and investigate the changes in the E-type and F-type crystals. The experimental results are shown in Table 3.

[0095] Table 3. Experimental results on the physical stability of crystal forms E and F.

[0096] The results showed that both the E and F crystal forms exhibited good physical stability.

[0097] Furthermore, according to the definition and range of hygroscopicity of drugs after equilibration at 25℃±1℃ and 80%±2%RH in the 2020 edition of the Chinese Pharmacopoeia, the E and F crystal forms of the phenomenal pamoate of the present invention exhibit low hygroscopicity.

[0098] Test Example 2: Study on the Chemical Stability of Crystal Forms

[0099] The E-type and F-type prepared in Example 1 were laid flat and exposed in containers. Stability tests were conducted on the samples under high temperature (60°C), high humidity (RH 92.5%) and light (4500±500 Lux) conditions. Samples were taken at 0, 10 and 30 days to determine the relevant substances and investigate the chemical stability of the E-type and F-type. The experimental results are shown in Table 4.

[0100] Table 4. Experimental results on the chemical stability of crystal forms

[0101] The results showed that both the E and F crystal forms exhibited good chemical stability.

[0102] Test Example 3 Crystal Transformation Study

[0103] The E-type crystal prepared in Example 1 and the F-type crystal prepared in Example 2 were respectively mixed with the solvents shown in Table 3, stirred at room temperature in the dark for 3 days, and the mixtures were centrifuged, dried in solid form, and XRPD was measured to study the crystal form changes. The results are shown in Table 5.

[0104] Table 5. Crystallization Research

[0105] The results showed that both the E and F crystal forms had good stability, with the E crystal form exhibiting better stability.

[0106] Test Example 4: Study on the solubility of crystal forms

[0107] 25 mg of zanomeline free base, zanomeline pamoate E crystal form from Example 1, zanomeline F crystal form from Example 2, and zanomeline A crystal form from Example 3 were added to acetate buffer (pH 4.0), phosphate buffer (pH 5.0), and phosphate buffer (pH 7.0), respectively. The mixtures were stirred thoroughly for 24 h, centrifuged at 12000 rpm for 3 min, and the supernatant was collected for HPLC analysis to determine the zanomeline content. The results are shown in Table 6.

[0108] Table 6 Solubility of different crystal forms

[0109] The results showed that the solubility of zenomeline pamoate at different pH values ​​was significantly lower than that of the free base. Specifically, the solubility of zenomeline pamoate crystal form F was significantly higher than that of crystal forms A and E, with crystal form E exhibiting the lowest solubility. Compared to crystal forms A and F, the lower solubility of crystal form E results in a slower drug release rate, thus prolonging the drug's duration of action and achieving a long-acting sustained-release effect. Therefore, crystal form E is the preferred crystal form for preparing long-acting sustained-release injectable formulations of zenomeline pamoate.

[0110] Physical stability study of the formulation in Test Example 5

[0111] Injectable suspensions were prepared using the E crystal form of Example 1, the F crystal form of Example 2, and the A crystal form of Example 3, respectively, and the physical stability of the formulations was investigated.

[0112] Preparation method of suspension: 1) Dissolve 1.0wt% PVP K12 (suspending agent), 0.5wt% Tween 80 (wetting agent) and 25Mmol phosphate in an appropriate amount of water for injection to obtain an excipient solution; 2) Add monamide pamoate to the excipient solution in step 1, disperse evenly, and then process to a suitable particle size using a high-pressure homogenizer; 3) Adjust the pH of the suspension to 4-6 with 1N hydrochloric acid or sodium hydroxide solution; 4) Add water for injection to 100wt% to obtain the final product.

[0113] Stability testing method: The suspension sample was placed at 40℃ (dry) and samples were taken at 0 days, 1 month, and 3 months. The sample was shaken 80-120 times within 30 seconds (one round trip is counted as one). The particle size D50 of the omeprazole pamoate (API) in the suspension was measured using a particle size analyzer (Malvin 3000 laser particle size analyzer). Simultaneously, any change in crystal form was determined. The results are shown in Table 7.

[0114] Table 7. D50 of nomoryl pamoate in suspensions

[0115] The results showed that the suspension prepared with crystal form E maintained a stable particle size of API, indicating good formulation stability. In the suspension prepared with crystal form A, the API particle size increased slightly. In the suspension prepared with crystal form F, the API particles aggregated, and the particle size increased significantly over time, resulting in poor stability. Therefore, crystal form E is the preferred crystal form for preparing pramosiderin injection suspension. Crystal forms A and E did not undergo crystal form changes in aqueous suspensions, while crystal form F did.

[0116] Chemical stability study of the formulation in Test Example 6

[0117] Injectable suspensions were prepared using the E crystal form of Example 1 and the A crystal form of Example 3, respectively, and the chemical stability of the formulations was investigated.

[0118] Preparation method of suspension: 1) Dissolve 1.0wt% PVP K12 (suspending agent), 0.5wt% Tween 80 (wetting agent) and 25Mmol phosphate in an appropriate amount of water for injection to obtain an excipient solution; 2) Add monamide pamoate to the excipient solution in step 1, disperse evenly, and then process to a suitable particle size using a high-pressure homogenizer; 3) Adjust the pH of the suspension to 4-6 with 1N hydrochloric acid or sodium hydroxide solution; 4) Add water for injection to 100wt% to obtain the final product.

[0119] Stability testing method: The suspension sample was placed at 40℃ (dry) and samples were taken at 0 days and 1 month to detect related substances in the formulation accounting for nomerin pamoate (API). The results are shown in Table 8.

[0120] Table 8 Chemical stability of suspensions

[0121] The results showed that the suspensions prepared by the A and E crystal forms had good stability, with the E crystal form exhibiting better chemical stability in the suspension.

[0122] Test Example 7: Pharmacokinetic Properties Study

[0123] Experimental materials: Male SD rats (weighing 200-250g, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into two groups of three rats each. Rats had free access to water during the experiment.

[0124] Experimental Methods: Group 1 SD rats were administered a single intramuscular injection of the A crystal suspension at a dose of 100 mg / kg (based on the free base of nomereline). Group 2 SD rats were administered a single intramuscular injection of the E crystal suspension at a dose of 100 mg / kg (based on the free base of nomereline). Blood samples were collected from the retro-orbital venous plexus of all animals without anesthesia. The sampling points for each group were designed as follows: blood samples were collected at 0 h before administration and at 0.5 h, 1 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 192 h, and 240 h after administration into K2EDTA anticoagulant tubes and temporarily stored on ice until centrifugation.

[0125] Using WinNonlin TM Using pharmacokinetic software (Version 8.3, Certara, USA), a non-compartmental model, the logarithmic linear trapezoidal rule was employed to process plasma drug concentration data. The experimental results are shown in Table 9.

[0126] Table 9. Pharmacokinetic parameters of nomilin in rat plasma

[0127] The experimental results show that, compared with the A-type crystal suspension, after rats were given the E-type crystal suspension of this invention, T... 1 / 2 (Half-life) significantly increased, C max The peak concentration is significantly reduced, resulting in a more sustained-release therapeutic effect.

[0128] In summary, through polymorph screening, the inventors obtained two new crystal forms, E and F, of janomyl pamoate, which exhibit different melting points, solubilities, and stability—key factors affecting drug-likeness. Janomyl pamoate form E has a high melting point, low hygroscopicity, low solubility, and excellent stability in formulations. It is also easy to prepare and is highly suitable for the development of long-acting injectable formulations of janomyl.

[0129] Based on the above disclosure, those skilled in the art can make changes to the technical solution of the present invention. Without departing from the spirit of the present invention, all such changes fall within the protection scope of the present invention.

Claims

1. The E crystal form of jambrine pamoate shown in Formula (I) has a characteristic peak in one or more of the XRPD spectrum at approximately 6.6°±0.2°, 9.6°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 24.9°±0.2°, and 26.0°±0.2°, and no characteristic peak at approximately 5.6°±0.2° and 29.0°±0.2°.

2. The E-type as described in claim 1, wherein the XRPD pattern represented by the 2θ angle is at approximately 6.6°±0.2°, 8.3°±0.2°, 9.6°±0.2°, 13.0°±0.2°, 15.8°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 2 Characteristic peaks are present at one or more of the following values: 0.2°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 25.4°±0.2°, 26.0°±0.2°, 28.5°±0.2°, and 29.7±0.2°. No characteristic peaks are present at one or more of the following values: 4.6°±0.2°, 5.6°±0.2°, and 29.0°±0.2°.

3. The E-type as described in claim 1, which has an XRPD pattern as shown in Figure 2.

4. The E crystal form as described in claim 1, wherein its DSC pattern has endothermic peaks at about 84°C and about 172°C; and / or, wherein it has a DSC pattern substantially as shown in Figure 3.

5. The F-crystal form of jambrine pamoate shown in formula (I) has a characteristic peak in one or more of the following XRPD spectra at approximately 5.3°±0.2°, 6.7°±0.2°, 8.2°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 20.3°±0.2°, 20.7°±0.2°, and 23.9°±0.2°: 20.3°±0.2°, 20.7°±0.2°, and 23.9°±0.2°: 20.7°±0.2°. Preferably, characteristic peaks are present at one or more of the following locations: approximately 5.3°±0.2°, 6.7°±0.2°, 8.2°±0.2°, 8.8°±0.2°, 11.4°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 16.0°±0.2°, 20.3°±0.2°, 20.7°±0.2°, 23.9°±0.2°, 24.4°±0.2°, 25.9°±0.2°, and 26.7°±0.2°. Preferably, it has an XRPD pattern as shown in Figure 4.

6. The F-type as described in claim 5, wherein its DSC pattern has an endothermic peak at approximately 140°C; Preferably, it has a DSC spectrum as shown in Figure 5.

7. A method for preparing the E-type crystal according to any one of claims 1-4, comprising: The B crystal form of genomeline pamoate shown in formula (I) is mixed with methyl acetate, stirred and slurried at a temperature below 50°C, and then cooled to crystallize, thus obtaining the E crystal form.

8. A method for preparing the F-type crystal as described in claim 5 or 6, comprising: Mix the B crystal form of genomeline pamoate shown in formula (I) with isopropyl acetate, stir and beat at 50-60°C, cool and crystallize to obtain the F crystal form.

9. A pharmaceutical composition comprising the E crystal form of tamsulosin pamoate as claimed in any one of claims 1 to 4 or the F crystal form of tamsulosin pamoate as claimed in claim 5 or 6.

10. Use of the E crystal form of jambolin pamoate according to any one of claims 1 to 4, the F crystal form of jambolin pamoate according to claim 5 or 6, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for the prevention and / or treatment of diseases improved by activating muscarinic receptors.

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