Crystal form of pilocarpine phenylacetic acid derivative as well as preparation method and application thereof

Abstract

The pilocarpine p-methyl phenylacetate crystal form A disclosed for the first time is good in solid stability, free of crystal transformation and convenient to store for a long time. And the preparation process is simple, good in reproducibility, stable and controllable, and beneficial to industrial large-scale production.

Description

[0001] This application claims priority to the prior application filed on July 28, 2023, with patent application number 202310940520.X, and invention name "A crystalline form of pilocarpine phenylacetic acid derivative, preparation method and use thereof". The full text of this application is incorporated into this application by reference. Technical Field

[0002] The invention relates to the technical field of drug crystal forms, and in particular to a crystal form of pilocarpine p-methylphenyl acetate, a preparation method and use thereof. Background Art

[0003] Pilocarpine is a cholinergic muscarinic agonist used to treat primary glaucoma, both open-angle and closed-angle glaucoma, that activates muscarinic receptors located on smooth muscles such as the iris sphincter and ciliary muscle. It contracts the iris sphincter, constricting the pupil to improve near and intermediate vision while maintaining some pupillary response to light. It also constricts the ciliary muscle and may shift the eye to a more myopic state, acting as a topical medication for presbyopia.

[0004] The salt forms of pilocarpine disclosed in the prior art are mainly pilocarpine hydrochloride or pilocarpine nitrate, and there is no in-depth research report on other salt forms of pilocarpine. Therefore, the research on pilocarpine in different salt forms has important medicinal value. Summary of the invention

[0005] The present invention provides a pilocarpine p-methylphenyl acetate crystal form A (hereinafter referred to as "crystal form A") which uses Cu-Kα radiation and in an X-ray powder diffraction pattern represented by 2θ values ​​±0.2°, has characteristic peaks selected from any three peaks of 9.94, 13.71, 19.59 and 22.27 or at 9.94, 13.71, 19.59 and 22.27.

[0006] In some specific embodiments, the X-ray powder diffraction pattern of Form A using Cu-Kα radiation, represented by 2θ values ​​±0.2°, also includes peaks at one or more of the following positions: 8.95, 17.72, 20.71, 26.68, 29.06.

[0007] In some specific embodiments, the X-ray powder diffraction pattern of Form A using Cu-Kα radiation, represented by 2θ values ​​±0.2°, further includes peaks at one or more of the following positions: 6.16, 12.00, 14.55, 16.02, 24.01, 26.19, 30.43.

[0008] In some specific embodiments, the X-ray powder diffraction data of Form A are shown in the following table, more specifically Figure 1 As shown;

[0009]

[0010]

[0011] In some specific embodiments, the differential scanning calorimetry diagram of Form A shows a melting endothermic peak at 51.6±5°C.

[0012] In some specific embodiments, the thermogravimetric analysis of Form A begins to decompose at 165°C±5°C.

[0013] The present invention also provides a method for preparing pilocarpine p-methylphenyl acetate crystal form A, which is specifically:

[0014] The pilocarpine p-methylphenyl acetate is dissolved in a good solvent, a poor solvent is added thereto, and the temperature is lowered, crystallization is performed and filtration is performed to obtain Form A;

[0015] Alternatively, pilocarpine p-methylphenylacetic acid is dissolved in a poor solvent, heated to dissolve, cooled to crystallize and filtered to obtain Form A;

[0016] The good solvent is at least one of ethyl acetate and acetone, and the poor solvent is isopropyl ether.

[0017] The present invention discloses use of pilocarpine p-methylphenyl acetate crystal form A in preparing a drug for treating and / or preventing eye diseases or disorders and related diseases or conditions; or use of pilocarpine p-methylphenyl acetate crystal form A in preparing a drug for miosis.

[0018] Preferably, the ocular disease or disorder is selected from glaucoma, cataract, intraocular lens, aphakia, astigmatism, blepharospasm, conjunctivitis, corneal disease, corneal edema, corneal ulcer, dry eye, eyelid disease, tear apparatus disease, tear duct obstruction, pupillary disorder, refractive disorder and strabismus, myopia, hyperopia, presbyopia, pupillary disorder;

[0019] Preferably, the eye disease is selected from glaucoma or presbyopia.

[0020] The invention discloses a pharmaceutical composition, comprising pilocarpine p-methylphenyl acetate crystal form A and pharmaceutically acceptable excipients thereof.

[0021] Definition and Description

[0022] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding product or activity.

[0023] It should be noted that in the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be errors in the position of the peak. The measurement error of the 2θ value can be ±0.2°, so this error should be taken into account when determining each crystal form, and the error is also within the scope of this application.

[0024] The phenomenon that the lattice planes or crystal edges of some grains in the crystal predominantly diffract certain directions and plane arrays is called preferred orientation. In the powder method, the calculation of the relative intensity of the lines requires that the crystals in the powder sample are completely irregularly oriented. If the number of oriented crystals in the sample increases, the intensity will inevitably increase. This makes the diffraction intensity and orientation degree have a certain diffraction relationship. ("X-ray Structure Analysis", edited by Qi Jingyu, Tongji University Press, 1st edition, April 2003).

[0025] Preferred orientation will affect the test results of the powder diffraction method for determining the crystal structure. There are differences in the XPRD test results of different batches of crystal forms, but this does not prevent technicians in this field from making judgments on whether they are the same crystal form.

[0026] It should be noted that for the same crystal form, the position of the endothermic peak of DSC may vary due to factors such as the measuring instrument and the conditions of the measuring method. For any specific crystal form, there may be an error in the position of the endothermic peak, which may be ±5°C or ±3°C. Therefore, this error should be taken into account when determining each crystal form, and the error is also within the scope of this application.

[0027] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredient and are conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0028] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0029] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0030] Typical routes of administration of the crystalline forms described herein or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0031] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0032] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0033] The term "treatment" means administering the pilocarpine p-methylphenylacetate crystal form A compound or preparation of the present application to improve or eliminate the disease and one or more symptoms associated with the disease, and includes:

[0034] (1) To inhibit a disease or disease state, that is, to curb its development;

[0035] (2) Relief of a disease or disease state, i.e., regression of the disease or disease state.

[0036] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0037] The pilocarpine p-methylphenyl acetate crystal form A disclosed for the first time in the present invention has good solid stability, no crystal transformation, and is convenient for long-term storage. The preparation process is simple, reproducible, stable and controllable, and is conducive to industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the XRPD pattern of Form A of the present invention;

[0039] Figure 2 This is the TGA diagram of the crystal form A of the present invention;

[0040] Figure 3 This is the DSC diagram of the crystal form A of the present invention;

[0041] Figure 4 This is the XRPD pattern of Form A of Example 7 of the present invention at 0h;

[0042] Figure 5 This is the XRPD pattern of Form A of Example 7 of the present invention after exposure to light for 12 days;

[0043] Figure 6 This is the XRPD pattern of Form A of Example 7 of the present invention after 40°C-12d; DETAILED DESCRIPTION

[0044] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0045] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0046] Explanation of English abbreviations of proper nouns:

[0047] EtOH: ethanol;

[0048] Example 1

[0049] Example 1 - Preparation of pilocarpine p-methylphenyl acetate

[0050] At room temperature, pilocarpine (5.00 g, 24 mmol) was dissolved in EtOH (15 mL), 4-methylphenylacetic acid (3.61 g, 24 mmol) was added, and stirred at room temperature for 1 hour. HPLC showed that the reaction was complete, the solvent was dried, and the residue was stored at -20°C overnight to obtain a white solid. The obtained solid was slurried with 16 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to obtain a white solid, namely the compound pilocarpine p-methylphenylacetate (8.40 g, yield 97.6%).

[0051] Example 2-Preparation of Form A

[0052] Detection instruments and methods

[0053] 1. X-ray powder diffraction (XRPD)

[0054] The solid sample obtained in the experiment of this embodiment was analyzed by X-ray powder diffractometer D8 Advance X-ray Diffractometer, the 2θ scanning angle was from 3° to 40°, the scanning step was 0.02°, and the tube voltage and current were 40KV and 40mA respectively when the sample was tested.

[0055] 2. Thermogravimetric analysis (TGA)

[0056] The thermogravimetric analyzer was PerkinElmer TGA4000, and the samples were heated to the final temperature at a rate of 10°C / min.

[0057] 3. Differential Scanning Calorimetry (DSC)

[0058] The differential scanning calorimeter was NETZSCH DSC3500, sample holder / thermocouple: DSC 3500t-sensor / E;

[0059] Heating at a rate of 10°C / min to the final temperature. Atmosphere: N2, 40.0 mL / min / N2, 60.0 mL / min.

[0060] Dissolve 2.0 g of pilocarpine p-methylphenyl acetate in 1 mL of ethyl acetate, add 10 mL of isopropyl ether, cool to 0°C, stir for 1 hour, precipitate solid, filter, collect the filter cake, and dry under reduced pressure to obtain Form A.

[0061] The powder X-ray diffraction pattern of Form A is as follows: Figure 1 The specific data are shown in the following Table 1.

[0062] Table 1: X-ray powder diffraction data of Form A

[0063] NO. Angle d value Intensity Intensity% 1 6.163 14.329 89.0 18.3 2 8.953 9.870 225.0 46.4 3 9.943 8.889 486.0 100.0 4 11.998 7.371 138.0 28.4 5 13.707 6.455 378.0 77.8 6 14.551 6.082 185.0 38.1 7 16.019 5.528 65.4 13.5 8 17.717 5.002 294.0 60.5 9 19.589 4.528 313.0 64.4 10 20.710 4.285 291.0 60.0 11 22.272 3.988 482.0 99.3 12 24.006 3.704 99.8 20.6 13 26.189 3.400 103.0 21.2 14 26.681 3.338 122.0 25.2 15 29.060 3.070 140.0 28.8 16 30.427 2.935 87.1 17.9

[0064] Among the above diffraction peaks, the main characteristic peaks of form A are located at 9.94, 13.71, 19.59 and 22.27, and also include one or more diffraction peaks of 8.95, 17.72, 20.71, 26.68, and 29.06, and further include one or more diffraction peaks of 6.16, 12.00, 14.55, 16.02, 24.01, 26.19, and 30.43.

[0065] TGA spectrum see Figure 2 As shown: Form A begins to decompose when the temperature rises to 165°C.

[0066] DSC spectrum see Figure 3 As shown: Form A has a melting endothermic peak at 51.6 degrees Celsius.

[0067] Example 3 - Preparation of Form A

[0068] Dissolve 2.0 g of pilocarpine p-methylphenyl acetate in 1 mL of acetone, add 10 mL of isopropyl ether, cool to 0°C, stir for 1 hour, stir the solid, filter, collect the filter cake, and dry under reduced pressure to obtain Form A.

[0069] Example 4 - Preparation of Form A

[0070] 2.0 g of pilocarpine p-methylphenyl acetate was dissolved in 10 mL of isopropyl ether, heated to 60° C. to dissolve, then cooled to 0° C. to precipitate a solid, filtered, the filter cake was collected, and dried under reduced pressure to obtain Form A.

[0071] Example 5 - Determination of melting point of Form A

[0072] The crystal form A was heated until it melted, and the melting point of the crystal form A was measured to be approximately 52.5±2°C.

[0073] Example 6-Solubility determination of Form A

[0074] The rough solubility of Form A in different solvent systems was tested at room temperature, and the results are shown in Table 2 below:

[0075] Table 2: Solubility of Form A in different solvents

[0076] Solvents Solubility water Soluble Methanol Soluble Ethanol Soluble Ethanol Soluble

[0077] Classification based on conventional solubility:

[0078] Soluble means that the solubility in the specified solvent is greater than or equal to 10g / 100mL;

[0079] Soluble means that the solubility in the specified solvent is greater than or equal to 1.0g / 100mL and less than 10g / 100mL;

[0080] Slightly soluble means that the solubility in the specified solvent is greater than or equal to 0.01 g / 100 mL and less than 1.0 g / 100 mL;

[0081] Insoluble means that the solubility in a specified solvent is less than 0.01 g / 100 mL.

[0082] It can be seen from Table 2 above that Form A has good solubility in water, methanol and ethanol, indicating that Form A has good drug development prospects.

[0083] Example 7-Determination of stability of Form A

[0084] According to the EP Pharmacopoeia, the key substances of pilocarpine are: impurity A iso-pilocarpine (ZA), impurity B pilocarpic acid (ZB), impurity C iso-pilocarpic acid (ZC), and the samples prepared according to the method of Example 3 were sampled at 0 hours (0h), placed under light conditions for 12 days (light-12d), and placed under 40 degrees Celsius for 12 days (40℃-12d). The samples were tested by high-performance liquid chromatography to observe the trend of changes in stability under the experimental conditions of the influencing factors. The relevant substances were determined by high-performance liquid chromatography (General Rules 0512 of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia), and the experimental results are shown in Table 3 below. At the same time, XRPD determination was carried out at 0h, light-12d, and 40℃-12d to investigate the stability of Form A.

[0085] This test was analyzed using an X-ray powder diffractometer SmartLab SE, and the XRPD test conditions were:

[0086]

[0087] Table 3. Stability study data of Form A

[0088]

[0089] Depend on Figures 4 to 6 It can be seen that the XRPD patterns of Form A at 0 hours, when placed under light conditions for 12 days, and when placed under 40 degrees Celsius for 12 days are consistent, and the crystal form does not change. It can be seen from Table 3 above that Form A has good thermal stability.

Claims

1. A crystalline form A of pilocarpine p-toluene acetate, characterized in that: The X-ray powder diffraction pattern thereof using Cu-Kα radiation and represented by 2θ value ±0.2° has characteristic peaks selected from any three peaks of 9.94, 13.71, 19.59 and 22.27 or at 9.94, 13.71, 19.59 and 22.

27.

2. The pilocarpine p-methylphenyl acetate crystal form A according to claim 1, characterized in that: The X-ray powder diffraction pattern thereof using Cu-Kα radiation and represented by a 2θ value of ±0.2° further includes peaks at one or more of the following positions: 8.95, 17.72, 20.71, 26.68, and 29.

06.

3. The pilocarpine p-methylphenyl acetate crystal form A according to claim 2, characterized in that: The X-ray powder diffraction pattern using Cu-Kα radiation and represented by 2θ value ±0.2° further includes one or more peaks at the following positions: 6.16, 12.00, 14.55, 16.02, 24.01, 26.19, 30.

43.

4. The pilocarpine p-methylphenyl acetate crystal form A according to claim 1, characterized in that: Its differential scanning calorimetry graph shows a melting endothermic peak at 51.6±5°C; And / or its thermogravimetric analysis chart begins to decompose at 165°C±5°C.

5. A method for preparing the pilocarpine p-toluene acetate crystal form A according to any one of claims 1 to 4, characterized in that: The pilocarpine p-methylphenyl acetate is dissolved in ethyl acetate and / or acetone, isopropyl ether is added thereto, and the mixture is cooled, crystallized and filtered to obtain Form A; Alternatively, pilocarpine p-methylphenyl acetate is added to isopropyl ether, heated to dissolve, cooled, crystallized and filtered to obtain Form A.

6. Use of the pilocarpine p-methylphenylacetate crystal form A according to any one of claims 1 to 4 in the preparation of a medicament for treating and / or preventing eye diseases or disorders and related diseases or conditions; or use of the medicament for preparing a miotic pupil.

7. The use according to claim 6, characterized in that The ocular disease or disorder is selected from glaucoma, cataract, intraocular lens, aphakia, astigmatism, blepharospasm, conjunctivitis, corneal disease, corneal edema, corneal ulcer, dry eye, eyelid disease, tear apparatus disease, tear duct obstruction, pupillary disorder, refractive disorder and strabismus, myopia, hyperopia, presbyopia, pupillary disorder; Preferably, the eye disease is selected from glaucoma or presbyopia.

8. A pharmaceutical composition, characterized in that The invention comprises the pilocarpine p-methylphenyl acetate crystal form A as described in any one of claims 1 to 4 and pharmaceutically acceptable excipients thereof.

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