A deuterated tetrabenazine l-malate co-crystal and a method of making the same

Abstract

The application belongs to the technical field of pharmaceutical crystal forms, and specifically provides a deuterated trihexyphenidyl L-malic acid co-crystal and a preparation method thereof. The L-malic acid co-crystal of the deuterated trihexyphenidyl co-crystal is suitable for purification of deuterated trihexyphenidyl, has high stability, is obviously superior to deuterated trihexyphenidyl in solubility, and is simple in crystallization process preparation, good in repeatability, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical cocrystallization technology, specifically relating to a deuterated butylbenazine L-malic acid cocrystallization and its preparation method. Background Technology

[0002] Deuterated tetrabenazine (d6-Tetrabenazine) is a deuterated analogue of tetrabenazine, marketed in the United States under the trade name [not specified]. Sold for the treatment of chorea associated with Huntington's disease and tardive dyskinesia in adults, with the following specific structure:

[0003]

[0004] Patent CN111728971A discloses two crystal forms of deuterated butylbenazine, anhydrous crystal form I and crystal form II, as well as pharmaceutically acceptable salts and pharmaceutical compositions thereof. Patent US10632107B discloses luteolin cocrystals and quercetin cocrystals of deuterated butylbenazine.

[0005] Some compounds exhibit polymorphism. The same substance can produce various polymorphs with different crystal structures and physical properties, showing differences in PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubility. Polymorphs are different solids with the same molecular structure, but possess different physical properties compared to other polymorphs with the same structure.

[0006] The discovery of polymorphs, solvates, or cocrystals of drug compounds offers opportunities to improve the stability of active pharmaceutical ingredients, the performance of formulations in terms of bioavailability, or in vivo release characteristics, and these opportunities are unpredictable.

[0007] The existing polymorphs and cocrystals of deuterated butylbenazine disclosed in the prior art still have some physical properties that need to be improved. Therefore, there is still a need to provide new polymorphs or cocrystals of deuterated butylbenazine that can be used in drug formulations. Summary of the Invention

[0008] This invention provides a deuterated benzoxazine L-malic acid cocrystal, its preparation method, and a pharmaceutical composition containing the cocrystal.

[0009] This invention provides a deuterated benzoxazine L-malic acid eutectic.

[0010] In some embodiments, the deuterated benzoxazine L-malic acid eutectic is wherein the molar ratio of deuterated benzoxazine to L-malic acid is 1:1.

[0011] In some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic has characteristic peaks at diffraction angles 2θ: 14.1±0.2°, 15.8±0.2°, 17.8±0.2°, 21.2±0.2°, 24.6±0.2°.

[0012] In some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic has characteristic peaks at diffraction angles 2θ: 10.7±0.2°, 14.1±0.2°, 15.8±0.2°, 17.8±0.2°, 18.9±0.2°, 20.0±0.2°, 21.2±0.2°, 21.6±0.2°, 23.5±0.2°, 24.6±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic has characteristic peaks at diffraction angles 2θ: 6.8±0.2°, 10.7±0.2°, 14.1±0.2°, 14.6±0.2°, 15.8±0.2°, 17.3±0.2°, 17.8±0.2°, 18.9±0.2°, 20.0±0.2°, 21.2±0.2°, 21.6±0.2°, 22.4±0.2°, 22.8±0.2°, 23.5±0.2°, 24.2±0.2°, 24.6±0.2°, 25.1±0.2°, 25.8±0.2°, 29.0±0.2°, and 29.3±0.2°.

[0014] In some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid cocrystal is as follows at diffraction angles 2θ: 6.8±0.2°, 7.5±0.2°, 10.7±0.2°, 11.2±0.2°, 12.2±0.2°, 14.1±0.2°, 14.6±0.2°, 15.8±0.2°, 16.5±0.2°, 17.3±0.2°, 17.8±0.2°, 18.9±0.2°. 20.0±0.2°, 21.2±0.2°, 21.6±0.2°, 22.4±0.2°, 22.8±0.2°, 23.5±0.2°, 24.2±0.2°, 24.6±0.2°, 25.1±0.2°, 25.8±0.2°, 27.0±0.2°, 27.6±0.2°, 29.0±0.2°, 29.3±0.2°, 30.4±0.2°, 31.2±0.2°

[0015] Characteristic peaks are present at 33.3±0.2° and 36.7±0.2°.

[0016] Furthermore, in some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic has the relevant diffraction data shown in Table 1.

[0017] Table 1. Characteristic XRPD diffraction peaks of deuterated benzoxazine L-malic acid eutectic

[0018]

[0019]

[0020] In some embodiments, the X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic is as follows: Figure 1 As shown.

[0021] In some embodiments, the differential scanning calorimetry (DSC) curve of the deuterated benzoxazine L-malic acid eutectic has an endothermic peak with an onset temperature of 211.6 ± 3 °C.

[0022] In some embodiments, the differential scanning calorimetry (DSC) curve of the deuterated benzoxazine L-malic acid eutectic is as follows: Figure 2 As shown.

[0023] In some embodiments, the deuterated benzoxazine L-malic acid eutectic is anhydrous.

[0024] In some embodiments, the thermogravimetric analysis curves of the deuterated benzophenone L-malic acid eutectic show almost no weight loss.

[0025] In some embodiments, the thermogravimetric analysis (TGA) curves of the deuterated benzoxazine L-malic acid eutectic are essentially as follows: Figure 3 As shown.

[0026] On the other hand, the present invention also provides a method for preparing a deuterated benzoxazine L-malic acid eutectic, the method comprising: dissolving L-malic acid and deuterated benzoxazine in a good solvent, cooling to crystallize after complete dissolution, stirring and filtering, and drying.

[0027] In some embodiments, the molar ratio of L-malic acid to deuterated benzodiazepine in the preparation method is 0.5 to 2:1.

[0028] Furthermore, in some embodiments, the molar ratio of L-malic acid to deuterated benzodiazepine in the preparation method is 1 to 1.2:1.

[0029] In some embodiments, the dissolution temperature of L-malic acid and deuterated benzoxazine in the preparation method is 20–90°C.

[0030] In some embodiments, the stirring conditions in the preparation method are stirring at room temperature for 1 to 3 hours.

[0031] In some embodiments, the good solvent in the preparation method is selected from one or more of methanol, ethanol, acetone, acetonitrile, and tetrahydrofuran.

[0032] Furthermore, in some embodiments, the good solvent in the preparation method is any one of methanol, ethanol, or tetrahydrofuran.

[0033] On the other hand, the present invention also provides a pharmaceutical composition comprising a deuterated benzoxazine L-malic acid cocrystal and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0034] On the other hand, the present invention provides the use of deuterated benzoxazine L-malate cocrystal or pharmaceutical combinations thereof in the preparation of medicaments for treating chorea associated with Huntington's disease and diseases related to tardive dyskinesia in adults.

[0035] The deuterated benzophenazine L-malic acid eutectic described in this invention exists in a substantially pure crystalline form.

[0036] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0037] "Substantially free of" means that one or more other crystal forms account for less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0038] In an X-ray powder diffraction pattern, "relative intensity" (or "relative peak height") refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in the X-ray powder diffraction pattern (XRPD) is 100%.

[0039] The present invention has the following beneficial effects:

[0040] The deuterated butylbenazine L-malic acid eutectic provided by this invention has good purification effect, low impurities, high deuteration rate, high melting point, high stability, good scalability, and is suitable for long-term storage without any protective measures and for large-scale preparation of high-purity deuterated butylbenazine. Attached Figure Description

[0041] Figure 1 Example 1-1 XRPD pattern of deuterated benzoxazine L-malic acid eutectic;

[0042] Figure 2 Example 1-1 DSC curves of deuterated benzoxazine L-malic acid eutectic;

[0043] Figure 3 Example 1-1 TGA curves of deuterated benzoxazine L-malic acid eutectic. Detailed Implementation

[0044] The present application will be further described in detail below with reference to the embodiments. The embodiments of the present application are only used to illustrate the technical solutions of the present application and are not intended to limit the substance and scope of the present application.

[0045] The terms used in this application are explained as follows:

[0046] The term XRD refers to X-ray powder diffraction. In this invention, the powder X-ray diffraction testing instrument is a Bruker D2 Phaser. 2nd Powder diffractometer; Test conditions: CuKα radiation, 30kV, 10mA, 3-40°.

[0047] The term DSC refers to Differential Scanning Calorimeter. In this invention, the differential scanning calorimeter involved is the American TADSC25; test conditions: 20-300℃, 10℃ / min; N2 (60mL / min).

[0048] The term TGA refers to thermogravimetric analyzer. In this invention, the thermogravimetric analyzer involved is: TA TGA55 (USA); test conditions: room temperature - 300℃, 10℃ / min; N2 (50mL / min).

[0049] In the context of this invention, the diffraction angle 2θ (also known as 2-theta or diffraction peak) values ​​in X-ray powder diffraction patterns are all expressed in degrees (°).

[0050] When referring to spectra and / or data in figures, the term "diffraction peak" refers to a feature that a person skilled in the art would not attribute to background noise.

[0051] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be ±0.2 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0052] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0053] The thermogravimetric analysis (TGA) curves of the crystals are subject to experimental error. The endothermic curves or weight loss rates may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 0.4%, 0.3%, 0.2%, or 0.1%. Therefore, the thermogravimetric analysis curves or their weight loss rates cannot be considered absolute.

[0054] The crude deuterated butylbenazine used in the examples had a high-performance liquid chromatography purity of 90.1% and a deuteration rate of 94.0%. This crude deuterated butylbenazine can be prepared according to existing methods or obtained by purchase.

[0055] Example 1: Preparation of deuterated butyrate L-malic acid eutectic

[0056] Example 1-1

[0057] 100g of deuterated benzoxazine and 50.67g of L-malic acid were weighed and dissolved in 500mL of anhydrous ethanol at 50℃. After stirring until completely dissolved, a large amount of solid precipitated out. The mixture was stirred at 15℃ for 1h, filtered, and dried to obtain 132.7g of deuterated benzoxazine-L-malic acid eutectic product with a molar yield of 93.3%, a purity of 99.90%, and a deuteration rate of 99.5%. Figure 1 Its XRPD map, Figure 2 Its DSC spectrum, Figure 3 Its TGA spectrum.

[0058] Examples 1-2

[0059] 100g of deuterated benzoxazine and 50.67g of L-malic acid were weighed and dissolved in 450mL of methanol at 45℃. After stirring until completely dissolved, a large amount of solid precipitated out. The mixture was stirred at 15℃ for 1h, filtered, and dried to obtain 121.7g of deuterated benzoxazine-L-malic acid eutectic product with a molar yield of 85.6%, a purity of 99.93%, and a deuteration rate of 99.5%.

[0060] Examples 1-3

[0061] 100g of deuterated benzoxazine and 50.67g of L-malic acid were weighed and dissolved in 1000mL of acetone at 45℃. After stirring until completely dissolved, a large amount of solid precipitated out. The mixture was stirred at 15℃ for 1 hour, filtered, and dried to obtain 102.7g of deuterated benzoxazine-L-malic acid eutectic product with a molar yield of 72.2%, a purity of 98.02%, and a deuteration rate of 98.5%.

[0062] Example 2: Preparation of deuterated butylbenazine crystal form I according to the method in patent CN111728971A

[0063] 100 g of deuterated butylbenazine was dissolved in 300 mL of anhydrous ethanol at room temperature, and heated until completely dissolved. The solution was stirred at a rate of 20 °C / h and cooled to room temperature. The mixture was then stirred at 0 °C for 1 h, filtered, and dried to obtain 85.9 g of butylbenazine product, with a molar yield of 85.9%, a purity of 98.01%, and a deuteration rate of 98.9%.

[0064] X-ray powder diffraction confirmed it to be crystal form I.

[0065] Example 3: Preparation of deuterated butylbenazine crystal form II according to the method in patent CN111728971A

[0066] 10 g of deuterated butylbenazine was dissolved in 50 mL of methanol at room temperature and heated until dissolved. The solution was then slowly evaporated at ambient temperature and under moderate conditions to obtain 9.9 g of butylbenazine product. The molar yield was 99.0%, the purity was 90.01%, and the deuteration rate was 94.0%.

[0067] X-ray powder diffraction confirmed it to be crystal type II.

[0068] Example 4: Preparation of deuterated butylbenazine luteolin eutectic (patent US10632107B2)

[0069] 30 g of deuterated butylbenazine was dissolved in 300 mL of isopropanol at room temperature, and the solution was heated to 50 °C and stirred until dissolved. 150 mL of water and 37.2 g of luteolin were added to the dissolved solution, and the suspension was stirred at 50 °C for 4 h, then cooled to room temperature. The solution was filtered, and the wet filter cake was washed with 200 mL of 50% (v / v) isopropanol-water solution. The solution was dried under reduced pressure at room temperature for 16 h to obtain 50.5 g of butylbenazine-luteolin cocrystal product, with a molar yield of 88.5%, purity of 97.08%, and deuteration rate of 98.0%.

[0070] X-ray powder diffraction confirmed it to be eutectic APO-II.

[0071] Example 5: Preparation of deuterated butylbenazine-quercetin cocrystal (patent US10632107B2)

[0072] 30 g of deuterated butylbenazine was dissolved in 600 mL of isobutanol at room temperature, and the solution was heated to 50 °C and stirred until dissolved. 31.2 g of quercetin was added to the dissolved solution, and the suspension was stirred at 50 °C for 3 h, then cooled to room temperature. The solution was filtered, and the wet filter cake was washed with 150 mL of isobutanol. The solution was dried under reduced pressure at room temperature for 16 h to obtain 52.8 g of butylbenazine-quercetin cocrystal product, with a molar yield of 86.6%, purity of 97.77%, and deuteration rate of 98.8%.

[0073] X-ray powder diffraction confirmed it to be eutectic APO-I.

[0074] Example 6: Purification effect of various crystal forms / cocrystals of deuterated butylbenazine

[0075] The crystallization status, crystal purity, deuteration rate, and yield in Examples 1-5 above were detected and calculated, and the results are shown in Table 1.

[0076] Table 1. Purity (HPLC) results of various crystal forms / eutectic of deuterated butylbenazine

[0077] Example Purity of main compound Deuteration rate molar yield Example 1-1 99.90％ 99.5％ 98.3％ Examples 1-2 99.90％ 99.5％ 85.6％ Examples 1-3 98.02％ 98.5％ 72.2％ Example 2 98.01％ 98.9％ 85.9％ Example 3 90.01％ 94.0％ 99.0％ Example 4 97.08％ 98.0％ 88.5％ Example 5 97.77％ 98.8％ 86.6％

[0078] Example 7: Comparison of melting point and solubility of various crystal forms / eutectic crystals in Examples 1-5

[0079] Different compound forms may have different physicochemical properties. It is well known that active pharmaceutical ingredients (APIs) have high melting points, which are often beneficial in API preparation and formulation processes. Therefore, to verify the melting point of the crystals prepared in this invention, the melting points of the crystals in the embodiments and comparative examples of this invention were tested. Detailed results are shown in Table 2 below:

[0080] Table 2 Melting point results of various crystal forms / eutectic of deuterated benzoxazine

[0081] Example Crystal form / eutectic Melting point Equilibrium solubility in water (at 37°C) Example 1-1 L-malic acid eutectic 211.6℃ 50mg / mL Example 2 Crystal form I 126.5℃ 0.5 mg / mL Example 3 Crystal form II 125.9℃ 0.2 mg / mL Example 4 Crystal form APO-II 136.1℃ 3mg / mL Example 5 Crystal form APO-I 141.0℃ 5mg / mL

[0082] Table 2 shows that the deuterated benzoxazine L-malic acid cocrystal of the present invention has a higher melting point than deuterated benzoxazine crystal forms I, II, APO-II, and APO-I. Surprisingly, the L-malic acid cocrystal, while having a high melting point, also exhibits higher solubility, which is obviously beneficial for drug release in vivo.

[0083] Example 8: Stability investigation of crystal form / eutectic of Examples 1-5

[0084] Influencing factor tests were conducted in accordance with the Guidelines for Stability Testing of Raw Materials and Preparations in the 2015 Edition of the Pharmacopoeia of the People's Republic of China. The crystal forms / eutectic crystals of Examples 1-1, 2, 3, 4, and 5 of this invention were placed under conditions of 40℃, 60℃, 75% humidity, and light exposure for a period of time. The purity and changes of the crystal forms after placement are shown in Table 3.

[0085] Table 3. Stability results of deuterated butylbenazine crystal forms / eutectic.

[0086]

[0087]

[0088] Note: " / " indicates the initial state before processing in each embodiment.

[0089] Table 3 shows that the L-malic acid eutectic of the present invention has better stability. Under the conditions of high temperature, high humidity and light, the crystal purity changes little and there is less single impurity generated, making it more suitable for drug development and use.

[0090] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A eutectic of deuterated butylbenazine, characterized in that, The eutectic is a eutectic formed by deuterated benzoxazine and L-malic acid.

2. The eutectic of deuterated butylbenazine as described in claim 1, characterized in that, The molar ratio of deuterated benzodiazepine to L-malic acid is 1:

1.

3. The eutectic of deuterated butylbenazine as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the deuterated benzoxazine L-malic acid eutectic exhibits characteristic peaks at diffraction angles 2θ: 14.1±0.2°, 15.8±0.2°, 17.8±0.2°, 21.2±0.2°, and 24.6±0.2°; more preferably, it also exhibits characteristic peaks at diffraction angles 2θ: 10.7±0.2°, 14.1±0.2°, 15.8±0.2°, 17.8±0.2°, 18.9±0.2°, 20.0±0.2°, 21.2±0.2°, 21.6±0.2°, and 23.5±0.2°. A characteristic peak is observed at 4.6±0.2°. Further optimization yields peaks at diffraction angles of 2θ: 6.8±0.2°, 10.7±0.2°, 14.1±0.2°, 14.6±0.2°, 15.8±0.2°, 17.3±0.2°, 17.8±0.2°, 18.9±0.2°, 20.0±0.2°, 21.2±0.2°, 21.6±0.2°, 22.4±0.2°, 22.8±0.2°, 23.5±0.2°, 24.2±0.2°, 24.6±0.2°, and 25.1°. Characteristic peaks are observed at diffraction angles ±0.2°, 25.8±0.2°, 29.0±0.2°, and 29.3±0.2°. Further optimization yields characteristic peaks at diffraction angles 2θ: 6.8±0.2°, 7.5±0.2°, 10.7±0.2°, 11.2±0.2°, 12.2±0.2°, 14.1±0.2°, 14.6±0.2°, 15.8±0.2°, 16.5±0.2°, 17.3±0.2°, 17.8±0.2°, 18.9±0.2°, 20.0±0.2°, and 21.2±0.2°. Characteristic peaks are observed at 21.6±0.2°, 22.4±0.2°, 22.8±0.2°, 23.5±0.2°, 24.2±0.2°, 24.6±0.2°, 25.1±0.2°, 25.8±0.2°, 27.0±0.2°, 27.6±0.2°, 29.0±0.2°, 29.3±0.2°, 30.4±0.2°, 31.2±0.2°, 33.3±0.2°, and 36.7±0.2°, and the X-ray powder diffraction pattern shown in Figure 1 is further preferred.

4. The eutectic of deuterated butylbenazine as described in claim 1, characterized in that, The differential scanning calorimetry (DSC) curve of the deuterated benzoxazine L-malic acid eutectic has an endothermic peak and an initial temperature of 211.6 ± 3 °C. More preferably, it has the differential scanning calorimetry curve shown in Figure 2.

5. The eutectic of deuterated butylbenazine as described in claim 1, characterized in that, The thermogravimetric analysis curve of the deuterated benzoxazine L-malic acid eutectic is shown in Figure 3.

6. A method for preparing a deuterated benzoxazine L-malic acid eutectic, the method comprising: L-malic acid and deuterated benzoxazine were dissolved in a good solvent. After complete dissolution, the mixture was cooled to crystallize, stirred, filtered, and dried.

7. The method for preparing a deuterated benzoxazine L-malic acid eutectic as described in claim 6, characterized in that, The molar ratio of L-malic acid to deuterated benzodiazepine is 0.5 to 2:1; more preferably, the molar ratio of L-malic acid to deuterated benzodiazepine is 1 to 1.2:

1.

8. The method for preparing a deuterated benzophenone L-malic acid eutectic as described in claim 6, characterized in that, The good solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, and tetrahydrofuran. More preferably, the good solvent is selected from any one of methanol, ethanol, and tetrahydrofuran.

9. A pharmaceutical composition comprising a deuterated benzoxazine L-malic acid cocrystal and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of a deuterated benzoxazine L-malate eutectic or a pharmaceutical combination thereof in the preparation of a medicament for treating chorea associated with Huntington's disease and diseases associated with tardive dyskinesia in adults.

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