Novel crystal forms of Bramesene and hydrochloride thereof and preparation method of novel crystal forms

Abstract

The invention provides a novel crystal form APTI-I of Brameson, a novel crystal form APTI-II of Brameson hydrochloride and a preparation method of the novel crystal form APTI-I and the novel crystal form APTI-II. The novel crystal form APTI-I is radiated by Cu-K alpha, and an XRPD (X-Ray Powder Diffraction) spectrum of the novel crystal form APTI-I expressed by a 2 theta angle has characteristic peaks at 7.4 degrees + / -0.2 degrees, 11.0 degrees + / -0.2 degrees, 11.6 degrees + / -0.2 degrees, 12.1 degrees + / -0.2 degrees, 20.7 degrees + / -0.2 degrees and 22.8 degrees + / -0.2 degrees. The novel crystal form APTI-II is radiated by Cu-K alpha, and an XRPD (X-ray powder diffraction) spectrum of the novel crystal form APTI-II, which is expressed by a 2 theta angle, has characteristic peaks at 10.9 degrees + / -0.2 degrees, 11.5 degrees + / -0.2 degrees, 13.7 degrees + / -0.2 degrees, 17.1 degrees + / -0.2 degrees, 19.8 degrees + / -0.2 degrees and 21.6 degrees + / -0.2 degrees. The novel crystal form has high preparation yield and good impurity removal effect, and provides more options for pharmaceutical preparations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal chemistry, and more specifically, relates to new crystal forms of Bramison and their hydrochloride salts, as well as methods for their preparation. Background Technology

[0002] Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death in adults over 65. With an aging population and a growing elderly population, the number of patients is increasing annually. Patients urgently need new treatments to improve their condition and enhance their survival and quality of life.

[0003] Blarcamesine is an orally administered small-molecule activator of the Sigma-1 receptor (SIGMAR1). Data suggests it is crucial for restoring neuronal homeostasis and promoting neuroplasticity. Existing clinical data also indicate that blarcamesine significantly improves symptoms in Alzheimer's disease patients.

[0004] The chemical name of Bramison is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine, and its structural formula is shown in formula (I) below. The structural formula of its hydrochloride salt is shown in formula (II) below:

[0005]

[0006] As is well known, different spatial arrangements of drug molecules will form different crystal forms, and different crystal forms of drug molecules usually bring about significant differences in physicochemical properties. In chemical production, different crystal forms will also lead to different impurity removal effects due to their different precipitation methods.

[0007] Currently, the following existing technologies have been used to study the Brammerson crystal form:

[0008] The prior art WO2017013498A2 discloses three crystal forms of Brahmerson, but all of them are prepared by supercritical fluid method. This preparation method has high requirements for conditions and is not easy to scale up for production.

[0009] Prior art WO2019200345A1 discloses eight crystal forms of Bramason hydrochloride, including amorphous and hydrated crystal forms I to VIII. Amorphous form I has already been disclosed in prior art WO2018231216 A1 and is the crystal form used in pharmaceutical formulations. The disclosed data also indicates that Bramason hydrochloride crystal form I is currently the optimal crystal form. Furthermore, this prior art also discloses Bramason free base crystal form I. While the free base has relatively poor water solubility compared to the hydrochloride form, it still has potential development value in terms of pharmaceutical absorption.

[0010] The prior art WO2021158586A1 discloses the crystal form of Bramison hydrochloride, Form B3, which is a n-pentanol solvate. The solvate contains a high amount of n-pentanol, and its potential for pharmaceutical use has not yet been shown.

[0011] Therefore, it is necessary to develop new crystal forms of Bramisen or its salts that are superior to facilitate large-scale industrial production and improve their existing physicochemical properties, making them more suitable for the preparation of pharmaceutical formulations. Summary of the Invention

[0012] One aspect of the present invention is to provide a new Brahmsson crystal form, APTI-I, which, when irradiated with Cu-Kα, exhibits characteristic peaks in its XRPD spectrum, expressed in 2θ angles, at 7.4°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.1°±0.2°, 20.7°±0.2°, and 22.8°±0.2°.

[0013] In another preferred embodiment, the XRPD spectrum of the new Bramison crystal form APTI-I also exhibits characteristic peaks at one or more of the following 2θ angles:

[0014] 10.2°±0.2°, 15.1°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 19.6°±0.2°, 21.4°±0.2°, 22.2°±0.2°, 24.6°±0.2°, 26.6°±0.2°, 27.2°±0.2°, 28.3°±0.2°, 31.8°±0.2°, 33.6°±0.2°, 37.2°±0.2°.

[0015] In another preferred embodiment, the APTI-I differential scanning calorimetry spectrum of the new Bramison crystal form exhibits endothermic peaks at 84.5±5℃ and 91.2±5℃.

[0016] This invention also provides a method for preparing the above-mentioned new Bramison crystal form APTI-I, comprising the following steps:

[0017] The free base of Bramison is added to an organic solvent and stirred until the solution is clear. The solvent evaporates to less than 1 / 3 of its original volume, crystals precipitate, and are filtered to obtain a new crystal form of Bramison, APTI-I. The solvent is selected from methanol, ethanol, dichloromethane, or a combination thereof.

[0018] In another preferred embodiment, the solvent is selected from methanol.

[0019] In another preferred embodiment, the solvent is evaporated to a volume less than 1 / 4, 1 / 5, 1 / 10, 1 / 15, 1 / 20, or 1 / 30 of its original volume to precipitate crystals. In yet another preferred embodiment, the solvent is evaporated to dryness to precipitate crystals.

[0020] In another preferred embodiment, the amount of solvent used is 5 mL / 1g to 50 mL / 1g, more preferably 10 mL / 1g to 30 mL / 1g, as its volume-to-weight ratio with Bramison free base.

[0021] In another preferred embodiment, the solvent evaporation temperature is 20–50°C, more preferably 25–35°C.

[0022] In another preferred embodiment, solvent evaporation is carried out at atmospheric pressure or under vacuum, wherein the vacuum level is 0 to 0.1 MPa, more preferably 0.01 to 0.08 MPa.

[0023] The present invention also provides a new crystalline form of Bramison hydrochloride, APTI-II, which, when irradiated with Cu-Kα, exhibits characteristic peaks in its XRPD spectrum expressed at 2θ angles at 10.9°±0.2°, 11.5°±0.2°, 13.7°±0.2°, 17.1°±0.2°, 19.8°±0.2°, and 21.6°±0.2°.

[0024] In another preferred embodiment, the XRPD spectrum of the novel crystalline form APTI-II of the allassyl group dihydrochloride also exhibits characteristic peaks at one or more of the following 2θ angles:

[0025] 10.5°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 25.1°±0.2°, 25.5°±0.2°, 26.2°±0.2°, 26.5°±0.2°, 28.0°±0.2°, 30.5°±0.2°.

[0026] In another preferred embodiment, the differential scanning calorimetry (DSC) spectrum of the novel crystalline form APTI-II of the alastan dihydrochloride exhibits endothermic peaks at 75.4±5℃ and 227.9±5℃ (peak).

[0027] In another preferred embodiment, the thermogravimetric analysis (TGA) spectrum of the new crystalline form APTI-II of the alastan dihydrochloride showed a weight loss of approximately 9.5% at temperatures ranging from approximately 40°C to 110°C.

[0028] The present invention also provides a method for preparing a new crystalline form of Bramison hydrochloride, APTI-II, comprising: adding a free base of Bramison to an organic solvent, stirring until the solution is clear, adding a concentrated hydrochloric acid organic solvent diluent to the solution, stirring at 20°C to 50°C for 0.5 h to 36 h, filtering, and vacuum drying the resulting solid to obtain the new crystalline form of Bramison hydrochloride, APTI-II, wherein the molar ratio of the free base of Bramison to the hydrogen chloride molecules in the concentrated hydrochloric acid organic solvent diluent is 1:1.0 to 1.2.

[0029] In another preferred embodiment, the organic solvent used to dissolve the free Bramison base is the same as the organic solvent used to dilute the concentrated hydrochloric acid, and the organic solvent is selected from toluene, acetonitrile, dibutyl ketone, methyl ethyl ketone, ethyl acetate, or combinations thereof. In another more preferred embodiment, the organic solvent is selected from toluene.

[0030] In another preferred embodiment, the amount of solvent used to dissolve the free Bramison base is 5 mL / 1g to 50 mL / 1g, more preferably 12 mL / 1g to 30 mL / 1g, in a volume-to-weight ratio to the free Bramison base.

[0031] In another preferred embodiment, the molar ratio of the Bramison free base to the hydrogen chloride molecules in the organic solvent dilution of concentrated hydrochloric acid is 1:1.05 to 1.15.

[0032] In another preferred embodiment, the concentrated hydrochloric acid refers to an aqueous solution of hydrochloric acid with a mass concentration of 30-36%.

[0033] In another preferred embodiment, the dilution factor of concentrated hydrochloric acid in the organic solvent dilution solution is 5 to 15 times, more preferably 8 to 12 times.

[0034] In another preferred embodiment, the stirring temperature is 25℃~35℃ and the stirring time is 4h~8h.

[0035] In another preferred embodiment, the vacuum drying temperature is 20°C to 45°C, more preferably 20°C to 30°C.

[0036] The present invention also provides the use of the new crystalline form of Bramesen APTI-I and the new crystalline form of Bramesen hydrochloride APTI-II in the preparation of drugs containing Bramesen or in the purification of Bramesen or its salts. Attached Figure Description

[0037] Figure 1 XRPD pattern of the new Bramison crystal form APTI-I;

[0038] Figure 2 DSC spectrum of the new Bramison crystal form APTI-I;

[0039] Figure 3XRPD pattern of APTI-II, a new crystal form of Bramison hydrochloride;

[0040] Figure 4 DSC spectrum of APTI-II, a new crystal form of Bramison hydrochloride;

[0041] Figure 5 TGA spectrum of APTI-II, a new crystal form of Bramison hydrochloride;

[0042] Figure 6 The images shown in the middle, from bottom to top, are XRPD patterns of the new APTI-II crystal form of Bramison hydrochloride before and after grinding.

[0043] Figure 7 From bottom to top, the images are overlays of XRPD spectra before and after the hygroscopic stability test of the new crystal form of Bramison hydrochloride, APTI-II.

[0044] Figure 8 From bottom to top, the XRPD patterns of the new crystal form APTI-II of Bramison hydrochloride are superimposed images of the XRPD patterns of this crystal form after being packaged in PE bags and aluminum foil bags and placed at 25℃ / 60%RH and 40℃ / 70%RH for one week, respectively.

[0045] Figure 9 XRPD image of Bramison hydrochloride crystal form I obtained in Comparative Example 1;

[0046] Figure 10 The liquid chromatogram of the starting material, Bramison free base;

[0047] Figure 11 The liquid chromatogram of crystal form I in Comparative Example 1;

[0048] Figure 12 The liquid chromatogram is of the APTI-II crystal form of Bramison hydrochloride obtained in Example 3. Detailed Implementation

[0049] Through extensive and in-depth research, the inventors of this application have obtained two new crystalline forms of Brahmerson hydrochloride: APTI-I and APTI-II. APTI-II, in particular, exhibits advantages such as high stability, low hygroscopicity, high purity, and high solubility. It also demonstrates excellent impurity removal, a simple production method, and stable quality, making it suitable for large-scale industrial production. This invention is based on these findings.

[0050] In the description of this invention, "room temperature" refers to 5–40°C, more preferably 15–28°C.

[0051] The new Bramison crystal form APTI-I

[0052] The new Brahmsson crystal form APTI-I provided by this invention uses Cu-Kα radiation, and its XRPD spectrum, expressed in 2θ angles, has characteristic peaks at 7.4°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.1°±0.2°, 20.7°±0.2°, and 22.8°±0.2°.

[0053] Furthermore, the new Brahmsson crystal form APTI-I provided by this invention uses Cu-Kα radiation, and its XRPD spectrum, expressed in 2θ angles, is available at 7.4°±0.2°, 10.2°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.1°±0.2°, 15.1°±0.2°, 16.4°±0.2°, and 17.4°±0.2°. Characteristic peaks are observed at 19.6°±0.2°, 20.7°±0.2°, 21.4°±0.2°, 22.2°±0.2°, 22.8°±0.2°, 24.6°±0.2°, 26.6°±0.2°, 27.2°±0.2°, 28.3°±0.2°, 31.8°±0.2°, 33.6°±0.2°, and 37.2°±0.2°.

[0054] Furthermore, the new Brahmsson crystal form APTI-I provided by this invention, using Cu-Kα radiation, exhibits the characteristic peaks shown in Table 1 below in its XRPD spectrum expressed at a 2θ angle:

[0055] Table 1

[0056] No. <![CDATA[2θ( o )]]> relative strength 1 7.4 35.9％ 2 10.2 22.1％ 3 11.0 46.5％ 4 11.6 78.3％ 5 12.1 28.4％ 6 15.1 6.0％ 7 15.6 1.0％ 8 16.4 4.2％ 9 17.4 9.4％ 10 18.6 1.7％ 11 19.0 1.6％ 12 19.6 2.0％ 13 20.2 1.4％ 14 20.7 100％ 15 21.4 7.7％ 16 22.2 12.6％ 17 22.8 77.2％ 18 24.6 2.1％ 19 26.6 6.1％ 20 27.2 2.7％ 21 28.3 5.7％ 22 31.8 2.0％ 23 33.6 3.4％ 24 37.2 2.1％

[0057] Furthermore, the XRPD pattern of the new Bramison crystal form APTI-I provided by this invention is consistent with... Figure 1 Maintain consistency.

[0058] Furthermore, the differential scanning calorimetry (DSC) spectrum of the new Bramison crystal form APTI-I provided by the present invention shows endothermic peaks at 84.5±5℃ and 91.2±5℃.

[0059] Furthermore, the DSC spectrum of the new Bramison crystal form APTI-I provided by this invention is consistent with... Figure 2 Maintain consistency.

[0060] New crystal form of Bramison hydrochloride, APTI-II

[0061] The new crystalline form of Bramison hydrochloride, APTI-II, provided by this invention, exhibits characteristic peaks at 10.9°±0.2°, 11.5°±0.2°, 13.7°±0.2°, 17.1°±0.2°, 19.8°±0.2°, and 21.6°±0.2° when XRPD spectrum is expressed in 2θ angles.

[0062] Furthermore, the novel Bramison hydrochloride crystal form APTI-II provided by this invention, using Cu-Kα radiation, exhibits XRPD spectra expressed at 2θ angles at 10.5°±0.2°, 10.9°±0.2°, 11.5°±0.2°, 12.5°±0.2°, 13.7°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.0°±0.2°, and 17.1°±0.2°. Characteristic peaks are found at 2°, 18.4°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 25.1°±0.2°, 25.5°±0.2°, 26.2°±0.2°, 26.5°±0.2°, 28.0°±0.2°, and 30.5°±0.2°.

[0063] Furthermore, the new Brahmsson crystal form APTI-I provided by this invention, using Cu-Kα radiation, exhibits the characteristic peaks shown in Table 2 below in its XRPD spectrum expressed at a 2θ angle:

[0064] Table 2

[0065]

[0066]

[0067] Furthermore, the XRPD pattern of the new crystalline form APTI-II of Bramison hydrochloride provided by this invention is consistent with... Figure 3 Maintain consistency.

[0068] Furthermore, the differential scanning calorimetry (DSC) spectrum of the new crystalline form APTI-II of Bramison hydrochloride provided by the present invention shows endothermic peaks at 75.4±5℃ and 227.9±5℃ (peak);

[0069] Furthermore, the differential scanning calorimetry (DSC) spectrum of the new crystalline form APTI-II of Bramison hydrochloride provided by this invention is consistent with... Figure 4 Maintain consistency.

[0070] Furthermore, the thermogravimetric analysis (TGA) spectrum of the new crystalline form APTI-II of Bramison hydrochloride provided by this invention shows a weight loss of approximately 9.5% at temperatures ranging from approximately 40°C to 110°C.

[0071] Furthermore, the thermogravimetric analysis (TGA) spectrum of the new crystalline form APTI-II of Bramison hydrochloride provided by this invention is consistent with... Figure 5 Maintain consistency.

[0072] The effective effects of this invention are as follows:

[0073] The bramson hydrochloride crystal form APTI-II prepared by this invention has the advantages of simple preparation method, higher yield and better impurity removal effect than the original crystal form I, and it also shows good grinding stability and packaging stability, making it suitable for long-term storage.

[0074] The new crystalline form of Bramesen APTI-I provided by this invention is a new crystalline form of free base of Bramesen. The preparation method is simple and the yield is high, providing a new option for the pharmaceutical crystalline form of Bramesen.

[0075] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0076] The following general methods of implementation are as follows:

[0077] 1. XRPD spectral determination method

[0078] X-ray powder diffractometer: BRUKER AXSD2 PHASER X-ray powder diffractometer; Radiation source: Intensity ratio α1 / α2 is 0.5; Generator kV: 30.0 kV; Generator mA: 10.0 mA; Scan range: 3.0°~40.0°.

[0079] 2. DSC Measurement Method

[0080] The METTLEER DSC1 differential scanning calorimeter has a temperature rise program of 20°C per minute, ranging from 30°C to 360°C.

[0081] 3. TGA determination method

[0082] Instrument model: METTLEER TGA / DSC1 thermogravimetric analyzer. Temperature program: 30℃~400℃, 10℃ increase per minute.

[0083] The bramysen free bases in the following examples were prepared according to the preparation method disclosed in Example WO1997 / 30983 of the prior art, and their HPLC chromatograms are shown in [image missing]. Figure 10 The HPLC purity is 99.4%.

[0084] Example 1: Preparation of a new Bramison crystal form, APTI-I

[0085] Add 50 mg of Bramison free base to 1 mL of methanol, stir until the solution is clear, filter into a 5 mL centrifuge tube, and allow to evaporate at room temperature for 1 day until the solution is completely evaporated. Collect the solid, dry it under vacuum at 50 °C to obtain 45 mg of solid. Detect the solid using XRPD; its XRPD chromatogram is shown below. Figure 1 This crystal form is a novel crystal form of the Bramison free base, named crystal form APTI-I. The DSC results for this crystal form are shown below. Figure 2 .

[0086] Example 2: Preparation of a new Bramison crystal form, APTI-I

[0087] Weigh 5g of Bramison free base, add 100mL of MeOH, stir at room temperature until the solution is clear, filter into a 250mL single-necked flask, concentrate under reduced pressure at 25℃ for 2-4h, a large amount of solid precipitates and adheres to the wall, separate and filter out the remaining about 5mL of solution, collect the solid, dry under vacuum at 50℃ to obtain 4.85g of solid, which is identified by XRPD as crystalline form APTI-I.

[0088] Example 3: Preparation of a new crystal form of Bramison hydrochloride, APTI-II

[0089] 5 g (approximately 17.66 mmol) of Bramison free base was added to 100 mL of toluene. The mixture was stirred at room temperature until clear, then filtered into a 250 mL three-necked flask. 36% hydrochloric acid, diluted 10-fold with toluene, was slowly added dropwise to the three-necked flask (approximately 16 mL, containing 1.1 eq HCl) with stirring at 20–30 °C. After the addition was complete, stirring was continued at 20–30 °C for 4 h, resulting in the precipitation of a large amount of solid. This was filtered to obtain a white solid. The obtained solid was dried under vacuum at 25–35 °C for 4 h to yield 5.9 g of solid, with a molar yield of 95% (calculated based on a water content of approximately 9.5%). XRPD and DSC analyses were performed on the solid; the XRPD spectrum is shown below. Figure 3 As shown, the DSC spectrum is as follows Figure 4 As shown. This solid was named crystal form APTI-II. TGA analysis was performed on this crystal form, and the results are shown in (see...). Figure 5 The results showed a step weight loss of approximately 9.5% at temperatures between approximately 40 and 110°C. HPLC analysis of this crystal form indicated a product purity of 99.91% (see...). Figure 12 ).

[0090] Example 4: Preparation of a new crystal form of Bramison hydrochloride, APTI-II

[0091] 5 g (approximately 17.66 mmol) of Bramison free base was added to 50 mL of methyl ethyl ketone. The mixture was stirred at room temperature until the solution became clear, then filtered into a 100 mL three-necked flask. 36% hydrochloric acid was diluted 10-fold with methyl ethyl ketone solution and slowly added dropwise to the three-necked flask with stirring at 20–30 °C (the amount of hydrogen chloride added was 1.1 eq, approximately 16 mL of diluent). After the addition was complete, stirring was continued at 20–30 °C for 4 h, resulting in the precipitation of a large amount of solid. This was filtered to obtain a white solid. The obtained white solid was vacuum dried at 25–35 °C for 4 h to obtain 5.6 g of solid, with a molar yield of approximately 90.2% (calculated based on a water content of approximately 9.5%). XRPD analysis of the solid was performed, and its XRPD spectrum was similar to... Figure 3 Consistent with the results, it was confirmed to be crystal form APTI-II.

[0092] Example 5: Polishing stability of Bramison hydrochloride crystal form APTI-II

[0093] Weigh 200 mg of Brammerson hydrochloride (APTI-II) solid into an agate mill. After manual dry grinding for 30 min at room temperature, perform XRPR analysis. The results are shown below. Figure 6 (The image shows a superimposed XRPD pattern of the new APTI-II form of Bramison hydrochloride before and after grinding, from bottom to top). From Figure 6 A comparison of the two XRPD spectra shows that the crystal form and purity of the solid remained unchanged before and after grinding.

[0094] Example 6: Evaluation of the hygroscopicity of Bramison hydrochloride crystal form APTI-II

[0095] Accurately weigh 1643.0 mg of Bramison hydrochloride crystalline form APTI-II solid into a 100 mm glass dish and spread it evenly. After placing the product in an open-top chamber at 25℃ / 80%RH for 24 hours, the tare weight was 1723.1 mg, a weight gain of 80.1 mg, or 4.8%, indicating that this crystalline form is hygroscopic. XRPD analysis was performed on the product; the results are shown below. Figure 7 (The images shown, from bottom to top, are overlays of the XRPD spectra of the new Brinellon hydrochloride crystal form APTI-II before and after 24 hours of open storage in a 25°C / 80%RH constant temperature and humidity chamber) and Table 3. Figure 7 A comparison of the two XRPD spectra shows that the crystal form and purity of the solid did not change before and after being placed in an open temperature and humidity chamber at 25℃ / 80%RH for 24 hours.

[0096] Example 7: Stability assessment of Bramison hydrochloride crystal form APTI-II packaging

[0097] The Bramisen hydrochloride crystal form APTI-II was packaged in PE bags and aluminum foil bags and placed at 25℃ / 60%RH and 40℃ / 70%RH for one week, respectively. Samples were taken for XRPD and purity testing, and the results are shown in [reference missing]. Figure 8 (The XRPD patterns of the new crystalline form APTI-II of Bramison hydrochloride, as well as the overlays of the XRPD patterns of APTI-II after being packaged in PE bags and aluminum foil bags and placed at 25℃ / 60%RH and 40℃ / 70%RH for one week, respectively, are shown from bottom to top) and Table 3. Figure 8 The XRPD spectrum comparison shows that after packaging in PE bags and aluminum foil bags and placing them at 25℃ / 60%RH and 40℃ / 70%RH for one week respectively, the crystal form and purity of the solid remained unchanged.

[0098] The above assessments are summarized in Table 3.

[0099] Table 3

[0100] Stability assessment conditions time Crystal form purity Grinding stability 30 minutes constant constant 25℃ / 80%RH open 24 hours constant constant Packaging at 25℃ / 60%RH 7 days constant constant Packaging at 40℃ / 75%RH 7 days constant constant

[0101] Comparative Example 1: Preparation of Bramison hydrochloride crystal form I according to prior art WO2018231216 A1

[0102] 5g of free Bramisene base (its HPLC chromatogram is shown below) was added. Figure 10 Add the solution to 50 mL of isopropanol, stir at room temperature until dissolved, and filter into a 100 mL three-necked flask. Slowly add 1.1 eq of concentrated HCl (36% w / w) dropwise to the three-necked flask under stirring at 20–30 °C. After the addition is complete in about 5 minutes, continue stirring at 20–30 °C for 4 hours. A large amount of solid precipitates, which is filtered to obtain a white solid. Dry under vacuum at 55 °C for 4 hours to obtain 4.28 g of solid, yield 76%, HPLC purity 99.59% (its HPLC chromatogram is shown in [reference needed]). Figure 11 XRPD detection was performed, and its XRPD pattern is shown below. Figure 9 As shown, the solid was confirmed to be crystal form I as disclosed in prior art WO2018231216 A1. A comparison of the impurity removal effect with Example 3 is shown in Table 4 (the HPLC chromatogram of Example 3 is shown in...). Figure 12 As can be clearly seen from the comparison in Table 4, the preparation of crystal form APTI-II has a significant effect on improving the removal of RRT1.11 impurities.

[0103] Table 4

[0104]

[0105] The bromide hydrochloride crystal form APTI-II obtained by this invention is a novel crystal form different from existing disclosed crystal forms. Compared with the original crystal form I, this crystal form has a higher preparation yield and better impurity removal effect, providing a new option for producing higher quality products and reducing costs. Furthermore, the novel bromide free base crystal form APTI-I offers more possibilities for pharmaceutical formulations.

Claims

1. A novel Brahmerson crystal form, APTI-I, characterized in that, Using Cu-Kα radiation, the XRPD spectrum, expressed in 2θ angles, has characteristic peaks at 7.4°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.1°±0.2°, 20.7°±0.2°, and 22.8°±0.2°.

2. The new Brahmsson crystal form APTI-I according to claim 1, characterized in that, The new Bramison crystal form APTI-I also has one or more features selected from the following: (i) Its XRPD spectrum also has characteristic peaks at one or more of the following 2θ angles: 10.2°±0.2°、15.1°±0.2°、16.4°±0.2°、17.4°±0.2°、19.6°±0.2°、21.4°±0.2°、22.2°±0.2°、24.6°±0.2°、26.6°±0.2°、27.2°±0.2°、28.3°±0.2°、31.8°±0.2°、33.6°±0.2°、37.2°±0.2°。 (ii) The differential scanning calorimetry spectrum shows endothermic peaks at 84.5±5℃ and 91.2±5℃.

3. The method for preparing the new Bramison crystal form APTI-I according to claim 1 or 2, characterized in that, The preparation method includes the following steps: The free base of Bramisen was added to an organic solvent and stirred until the solution became clear. The solvent evaporated to less than 1 / 3 of its original volume, causing crystals to precipitate. After filtration, the new crystalline form of Bramisen, APTI-I, was obtained. The solvent is selected from methanol, ethanol, dichloromethane, or combinations thereof, preferably methanol.

4. The method for preparing the new Bramison crystal form APTI-I according to claim 3, characterized in that, The amount of solvent used is such that its volume-to-weight ratio with the free Bramison base is 5 mL to 50 mL / g, more preferably 10 mL to 30 mL / g, and / or The solvent evaporates at a temperature of 20–50°C, more preferably 25–35°C, and / or Solvent evaporation is carried out under normal pressure or vacuum conditions, wherein the vacuum degree is 0 to 0.1 MPa, more preferably 0.01 to 0.08 MPa.

5. A novel crystalline form of Bramison hydrochloride, APTI-II, characterized in that, Using Cu-Kα radiation, the XRPD spectrum, expressed in 2θ angles, has characteristic peaks at 10.9°±0.2°, 11.5°±0.2°, 13.7°±0.2°, 17.1°±0.2°, 19.8°±0.2°, and 21.6°±0.2°.

6. The novel crystalline form APTI-II of ellastan dihydrochloride according to claim 5, characterized in that, The APTI-II crystal form also has one or more features selected from the following: (i) Its XRPD spectrum also has characteristic peaks at one or more of the following 2θ angles: 10.5°±0.2°、12.5°±0.2°、14.0°±0.2°、14.9°±0.2°、15.1°±0.2°、16.0°±0.2°、18.4°±0.2°、19.1°±0.2°、22.0°±0.2°、23.2°±0.2°、23.6°±0.2°、24.0°±0.2°、25.1°±0.2°、25.5°±0.2°、26.2°±0.2°、26.5°±0.2°、28.0°±0.2°、30.5°±0.2°， (ii) The differential scanning calorimetry spectrum shows endothermic peaks at 75.4±5℃ and 227.9±5℃. (iii) Its thermogravimetric analysis spectrum shows a weight loss of about 9.5% at temperatures ranging from about 40℃ to 110℃.

7. The method for preparing the new crystalline form APTI-II of Bramison hydrochloride according to any one of claims 5-6, characterized in that, The preparation method includes: adding Bramison free base to an organic solvent, stirring until the solution is clear, adding concentrated hydrochloric acid to the organic solvent dilution solution, stirring at 20℃~50℃ for 0.5h~36h, filtering, and vacuum drying the resulting solid to obtain the new crystal form of Bramison hydrochloride, APTI-II. The molar ratio of the Bramison free base to the hydrogen chloride molecules in the organic solvent dilution of concentrated hydrochloric acid is 1:1.0 to 1.

2.

8. The preparation method according to claim 7, characterized in that, The organic solvent used to dissolve the free Bramison base is the same as the organic solvent used to dilute concentrated hydrochloric acid, said organic solvent being selected from toluene, acetonitrile, dibutyl ketone, methyl ethyl ketone, ethyl acetate or combinations thereof, more preferably toluene, and / or The amount of solvent used to dissolve the free base of Bramison is 5 mL to 50 mL / g, more preferably 12 mL to 30 mL / g, in a volume-to-weight ratio to the free base of Bramison.

9. The preparation method according to claim 7, characterized in that, The molar ratio of hydrogen chloride molecules in the organic solvent dilution of the Bramison free base and concentrated hydrochloric acid is 1:1.05–1.15, and / or The stirring temperature is 25℃~35℃, the stirring time is 4h~8h, and / or The vacuum drying temperature is 20℃~45℃, more preferably 20℃~30℃.

10. Use of the new crystalline form of Bramesen APTI-I or the new crystalline form of Bramesen hydrochloride APTI-II in the preparation of a drug containing Bramesen or in the purification of Bramesen or its salts.

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