L-valine abiraterone p-toluenesulfonic acid crystal form and preparation method thereof
By preparing the L-valine abiraterone p-toluenesulfonic acid crystal form, the problem of poor water solubility of abiraterone acetate was solved, resulting in improved solubility and stability, which promotes the manufacturing and clinical application of pharmaceutical formulations.
Patent Information
- Application Number
- CN202610175625.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-06
- Publication Date
- 2026-05-19
AI Technical Summary
Abiraterone acetate is a lipophilic compound with extremely poor water solubility. It is classified as a Class IV biopharmaceutical and has a slow in vitro dissolution rate, resulting in very low bioavailability and making it difficult to effectively treat prostate cancer.
A method for preparing the L-valine abiraterone p-toluenesulfonic acid crystal form is provided. The method involves reacting L-valine abiraterone with p-toluenesulfonic acid in a mixed solution of organic solvent and water in a specific ratio, followed by cooling and crystallization to prepare a crystal form with improved solubility, stability, and powder flowability.
This improves the solubility and stability of L-valine abiraterone, making it suitable for the manufacture and application of pharmaceutical formulations and potentially promoting the design and clinical application of abiraterone formulations.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to the crystal form of L-valine abiraterone p-toluenesulfonic acid and its preparation method. Background Technology
[0002] Prostate cancer is a common and fatal malignant cancer, and its incidence rate in my country has been on the rise in recent years, leading to continued rapid growth in market demand. Androgens are a key factor in the development of prostate cancer. Androgen biosynthesis first involves the activation of 17α-hydroxylase to convert pregnenolone and progesterone into 17α-hydroxy derivatives, followed by C17,20-lyase activity to form dehydroepiandrosterone and androstenedione, both precursors of testosterone. Cytochrome P450 is a key enzyme in this biosynthetic pathway. CYP17 is a cytochrome P450 enzyme that catalyzes the activities of two independently regulating steroid 17α-hydroxylases and C17,20-lyases, thereby regulating the in vivo synthesis of sex steroid precursors in the testes and other parts of the body.
[0003] Abiraterone acetate, a prodrug of abiraterone, is a CYP17 enzyme inhibitor approved for marketing in the United States in 2011 for the treatment of patients with recurrent prostate cancer (CRPC). The recommended dose is 1000 mg orally once daily in combination with prednisone 5 mg orally twice daily. However, abiraterone acetate is a lipophilic compound with extremely poor water solubility, classified as a Class IV biopharmaceutical (low solubility, low permeability), and has a slow in vitro dissolution rate. According to publicly available FDA data, the bioavailability of abiraterone acetate tablets is extremely low. Animal pharmacokinetics studies revealed a relative bioavailability of 37% in rats and only 1.6%–1.7% in monkeys and miniature pigs.
[0004] L-valine abiraterone, with the structure shown in Formula I, is a novel abiraterone prodrug with great application potential, providing new options for clinical use and possessing significant market value.
[0005]
[0006] Formula I
[0007] Different polymorphs of drugs can possess different chemical and physical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties directly affect the processing or production of active pharmaceutical ingredients and formulations, and influence the stability, solubility, and bioavailability of the formulations. Therefore, drug polymorphism is of great significance for the quality, safety, and efficacy of drug formulations. Summary of the Invention
[0008] This invention provides the p-toluenesulfonic acid crystal form of L-valine abiraterone and its preparation method. The crystal form has improved solubility, stability and powder flowability, which facilitates the manufacture and application of formulations.
[0009] Specifically, the technical content of this invention is as follows: In one aspect, the present invention provides a crystal form of L-valine abiraterone p-toluenesulfonic acid, wherein the molar ratio of L-valine abiraterone to p-toluenesulfonic acid and water in the crystal form is 1:1:2.
[0010] Preferably, the crystal form is subjected to Cu-Kα radiation, and the X-ray diffraction pattern represented by 2θ has characteristic peaks at 11.9±0.2°, 12.9±0.2°, 15.4±0.2°, 17.5±0.2°, and 21.5±0.2°.
[0011] Preferably, the crystal form is subjected to Cu-Kα radiation, and the X-ray diffraction pattern represented by 2θ has characteristic peaks at 7.1±0.2°, 11.9±0.2°, 12.9±0.2°, 13.8±0.2°, 14.6±0.2°, 15.4±0.2°, 17.5±0.2°, and 21.5±0.2°.
[0012] Preferably, the crystal form has Figure 1 The X-ray powder diffraction pattern shown.
[0013] Preferably, the crystallographic parameters of the crystal form are: orthorhombic crystal system, space group P212121, cell parameters: a=6.19450(10)Å, b=20.2852(4)Å, c=28.2373(6)Å, α=90°, β=90°, γ=90°, cell volume V=3548.21(12)Å. 3 .
[0014] Preferably, the crystal form has Figure 2 The TGA / DSC diagram shown.
[0015] In a second aspect, the present invention provides a method for preparing the L-valine abiraterone p-toluenesulfonic acid crystal form, comprising the following steps: adding L-valine abiraterone and p-toluenesulfonic acid to a mixed solution of organic solvent and water, stirring to dissolve and react, cooling to crystallize, filtering, and drying to obtain the crystal.
[0016] Preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, and butanone.
[0017] More preferably, the organic solvent is selected from one or more of butanone, ethanol, and acetone.
[0018] Preferably, the ratio of L-valine abiraterone to organic solvent is 1:40~90, g / ml.
[0019] More preferably, the ratio of L-valine abiraterone to organic solvent is 1:50~70, g / ml.
[0020] Preferably, the volume ratio of water to organic solvent is 1:4~10.
[0021] More preferably, the volume ratio of water to organic solvent is 1:6~8.
[0022] Preferably, the molar ratio of L-valine abiraterone to p-toluenesulfonic acid is 1:0.8~2.0, more preferably 1:1.1.
[0023] Preferably, the heating, dissolving, and reaction temperature is 50~60℃.
[0024] Preferably, the heating and dissolving reaction time is 1 to 3 hours.
[0025] Preferably, the cooling and crystallization temperature is 0~25℃.
[0026] More preferably, the cooling crystallization temperature is 10~20℃.
[0027] Preferably, the crystallization time is 48~72h.
[0028] Preferably, the drying temperature is 50~60℃ and the drying time is 8~10h.
[0029] The present invention also provides a pharmaceutical composition comprising the L-valine abiraterone p-toluenesulfonic acid crystal form and other pharmaceutically acceptable components.
[0030] Other pharmaceutically acceptable components include other active ingredients that can be used in combination, fillers, binders, disintegrants, lubricants, etc.
[0031] The filler is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, and sorbitol; the binder is selected from one or more of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, ethylcellulose, and povidone; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, croscarmellose sodium, and croscarmellose; and the lubricant is selected from one or more of magnesium stearate, micronized silica gel, talc, and sodium dodecyl sulfate.
[0032] The pharmaceutical composition is prepared by using standard and conventional techniques to combine the L-valine abiraterone p-toluenesulfonic acid crystal form of the present invention with other pharmaceutically acceptable components to prepare a usable dosage form.
[0033] The dosage forms of the pharmaceutical composition include, but are not limited to, tablets, capsules, granules, and pills.
[0034] Crystal structure confirmed:
[0035] (1) X-ray powder diffraction detection
[0036] PANalytical Empyrean X-ray powder diffractometer; light source: Cu target; flat sample stage; incident light path: BBHD; diffraction. Optical path: PIXCEL; voltage: 45 kV; current: 40 mA; divergence slit: 1 / 4°; anti-scattering slit: 1°; Solar slit: 0.04 rad; counting time per step: 0.5 s; scanning range: 3–50°. Specific results are shown in Table 1.
[0037] Table 1. Main X-ray powder diffraction characteristic peaks of L-valine abiraterone p-toluenesulfonic acid crystal form
[0038]
[0039] (2) Single crystal diffraction detection
[0040] The X-ray single crystal diffraction instrument and testing conditions involved in this invention are as follows: Rigaku XtaLAB Synergy X-ray single crystal diffractometer, testing temperature 293(2)K, CuKa radiation, data collection in ω-scan mode and Lp correction. The structure was resolved by direct method, and all non-hydrogen atoms were identified by difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was refined by least squares method. The crystallographic data of L-valine abiraterone p-toluenesulfonic acid crystal form are shown in Table 4.
[0041] Table 2 Crystallographic data of L-valine abiraterone p-toluenesulfonic acid crystal forms
[0042] The ORTEP diagram of the L-valine abiraterone p-toluenesulfonic acid crystal form of this invention shows that the crystal contains one molecule of L-valine abiraterone, one molecule of p-toluenesulfonic acid, and two molecules of water, as shown in the attached diagram. Figure 3 As shown, its hydrogen bond diagram is attached. Figure 4 As shown.
[0043] (3) TGA / DSC analysis The TGA / DSC thermal analysis instrument and test conditions in this invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30~300℃; heating rate: 10℃ / mIVn; programmed gas N2; gas flow rate: 50mL / mIVn; crucible: 40μL aluminum crucible.
[0044] The DSC-TGA spectrum of the L-valine abiraterone p-toluenesulfonic acid crystal form of this invention is as follows: Figure 2 As shown: there is an absorption peak at 43.70℃~117.98℃, corresponding to a weight loss of 5.2967%, which is approximately the loss of two water molecules; there is a strong absorption peak at 232.68℃~263.54℃, with a peak value of 254.15℃, which is the melting point of the L-valine abiraterone p-toluenesulfonic acid crystal form.
[0045] Compared with the prior art, the L-valine abiraterone p-toluenesulfonic acid crystal form of the present invention has the following advantages:
[0046] (1) This invention provides for the first time the crystal form of L-valine abiraterone p-toluenesulfonic acid and its preparation method. The process is simple, reproducible, and easy to scale up for industrial production.
[0047] (2) The L-valine abiraterone p-toluenesulfonic acid crystal form of the present invention has improved stability, solubility and flow properties compared with L-valine abiraterone, making it suitable for the manufacture and application of pharmaceutical preparations, and is expected to promote the design of abiraterone preparations and their clinical application. Attached Figure Description
[0048] Figure 1 PXRD pattern of L-valine abiraterone p-toluenesulfonic acid crystal form;
[0049] Figure 2 TGA / DSC image of L-valine abiraterone p-toluenesulfonic acid crystal form;
[0050] Figure 3 ORTEP diagram of L-valine abiraterone p-toluenesulfonic acid crystal form;
[0051] Figure 4 Hydrogen bond diagram of L-valine abiraterone p-toluenesulfonic acid crystal form. Detailed Implementation
[0052] The present invention will be further described below through specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.
[0053] All raw materials used in this invention are commercially available or prepared using conventional techniques known in the art.
[0054] Example 1
[0055] 44.8 mg of L-valine abiraterone and 19.0 mg of p-toluenesulfonic acid were added to a mixed solution of 4 ml acetone and 0.5 ml water. The mixture was heated to 55 °C and stirred to dissolve for 1 h. After slowly cooling to 15-20 °C, the mixture was allowed to stand at a controlled temperature for 48 h to crystallize. The mixture was then filtered, the filter cake was washed with acetone, and dried under vacuum at 55 °C for 8 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 91.18% and a purity of 99.25%.
[0056] Example 2
[0057] 44.8 mg of L-valine abiraterone and 19.0 mg of p-toluenesulfonic acid were added to a mixed solution of 2 ml acetone, 2 ml ethanol and 0.5 ml water. The mixture was heated to 50 °C and stirred to dissolve for 2 h. After slowly cooling to 10-15 °C, the mixture was allowed to stand at a controlled temperature for 60 h to crystallize. The mixture was then filtered, the filter cake was washed with acetone and dried under vacuum at 55 °C for 8 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 92.88% and a purity of 99.41%.
[0058] Example 3
[0059] 44.8 mg of L-valine abiraterone and 19.0 mg of p-toluenesulfonic acid were added to a mixed solution of 3.0 ml ethanol and 0.5 ml water. The mixture was heated to 60 °C and stirred to dissolve for 2 h. After slowly cooling to 10-15 °C, the mixture was allowed to stand at a controlled temperature for 48 h to crystallize. The mixture was then filtered, the filter cake was washed with ethanol, and dried under vacuum at 55 °C for 8 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 94.05% and a purity of 99.45%.
[0060] Example 4
[0061] 44.8 mg of L-valine abiraterone and 25.8 mg of p-toluenesulfonic acid were added to a mixed solution of 2.5 ml of butanone and 0.6 ml of water. The mixture was heated to 50 °C and stirred to dissolve for 2 h. After slowly cooling to 15-20 °C, the mixture was allowed to stand at a controlled temperature for 48 h to crystallize. The mixture was then filtered, the filter cake was washed with butanone, and dried under vacuum at 55 °C for 10 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 90.23% and a purity of 98.71%.
[0062] Example 5
[0063] 1.0 g of L-valine abiraterone and 0.42 g of p-toluenesulfonic acid were added to a mixed solution of 58 ml acetone and 7.5 ml water. The mixture was heated to 55 °C and stirred to dissolve for 3 h. After slowly cooling to 10-15 °C, the mixture was allowed to stand at a controlled temperature for 72 h to crystallize. The mixture was then filtered, the filter cake was washed with acetone, and dried under vacuum at 55 °C for 10 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 93.95% and a purity of 99.21%.
[0064] Example 6
[0065] 44.8 mg of L-valine abiraterone and 19.0 mg of p-toluenesulfonic acid were added to a mixed solution of 3.0 ml isopropanol and 0.5 ml water. The mixture was heated to 60 °C and stirred to dissolve for 2 h. After slowly cooling to 10-15 °C, the mixture was allowed to stand at a controlled temperature for 48 h to crystallize. The mixture was then filtered, the filter cake was washed with ethanol, and dried under vacuum at 55 °C for 8 h to obtain L-valine abiraterone p-toluenesulfonic acid crystals with a yield of 83.25% and a purity of 98.66%.
[0066] Comparative Example 1
[0067] Under a nitrogen atmosphere at 0°C, N-Boc-L-valine (4.50 g) and EDC-HCl (7.90 g) were added to 55 ml of DCM containing abiraterone (4.80 g) under stirring. Then, DMAP (335.0 mg) was added. The reaction temperature was gradually raised to room temperature and stirred overnight. After the reaction was completed, the reactants were diluted with DCM and water, separated, and the organic layer was washed with salt water and dried with Na2SO4. The solution was then concentrated under vacuum to obtain N-Boc-L-valine abiraterone ester (7.41 g, yield 98.3%).
[0068] At 0°C and under a nitrogen atmosphere, a solution of isopropanol hydrochloride (27 ml, 0.5 M) containing 7.41 g of N-Boc-L-valine abiraterone ester was slowly added to isopropanol (55 ml) under stirring. The reaction temperature was then gradually raised to room temperature and stirred for 3 h. After the reaction was completed, the reaction mixture was concentrated and the pH was adjusted with hydrochloric acid until a solid was obtained. The solid was dried under vacuum to obtain L-valine abiraterone hydrochloride (6.20 g, yield 94.9%) with an HPLC purity of 98.92%.
[0069] Comparative Example 2
[0070] A mixture of 20.02 g abiraterone, 13.12 g N-Boc-L-valine, 7.22 g DIC, and 6.99 g DMAP was added to 500 mL of dichloromethane and stirred at room temperature for 5 h. The reaction solution was concentrated under vacuum, and 300 mL of ethyl acetate was added with stirring. The suspension was filtered and washed with 1 M potassium bisulfate aqueous solution (150 mL × 3), saturated sodium bicarbonate aqueous solution (150 mL × 3), and water (150 mL), respectively. The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to obtain N-Boc-L-valine abiraterone ester. Subsequently, at room temperature, 30% TFA / CH2Cl (300 mL) was added and stirred for 1 h. The mixture was then concentrated under vacuum, 100 mL of water was added, and the pH of the solution was adjusted to 9-10 with 10% Na2CO3. The mixture was extracted with CH2Cl2 (150 mL × 3). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated to obtain a yellow solid residue. Column chromatography (PE / EA = 2:1) yielded 20.01 g of white solid product with an HPLC purity of 99.23%.
[0071] Verification of Examples
[0072] Stability test
[0073] The tests were conducted according to the methods outlined in Appendix 9001, "Guidelines for Stability Testing of Raw Materials and Preparations," of the Chinese Pharmacopoeia, Part IV. Each crystal form of L-valine abiraterone was evenly distributed into open petri dishes, with a thickness ≤5 mm. The distance was adjusted to ensure a light intensity of 4500±500 Lx. Alternatively, each crystal form was placed in a sealed, clean glass bottle and stored in a 60℃ constant temperature drying oven. Another method involved evenly distributing each crystal form of L-valine abiraterone into open petri dishes, with a thickness ≤5 mm, and storing them in a constant temperature and humidity incubator at room temperature (approximately 25℃) and a relative humidity of 92±5%. Samples were taken for testing at 5 and 10 days. The results are shown in Table 3.
[0074] Table 3 Results of Experimental Measurement of Influencing Factors
[0075] Experiments showed that the L-valine abiraterone p-toluenesulfonic acid crystal form prepared by this invention exhibited almost no change in purity under high temperature, high humidity, and strong light conditions, demonstrating significant stability.
[0076] Solubility test
[0077] 10 ml of each of the following media (0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer) was measured into a vial. An excess of the test sample was added, and the vial was sealed and placed in a 25°C water bath with stirring for 30 min. The solution was then filtered through an aqueous microporous membrane. The filtrate was collected, and the concentration of the active ingredient in the solution was determined by high-performance liquid chromatography (HPLC). The solubility (expressed as L-valine abiraterone) was obtained. The results are shown in Table 4.
[0078] Table 4 Solubility Test Results
[0079] Experiments have shown that the L-valine abiraterone p-toluenesulfonic acid crystal form prepared by this invention has improved solubility compared to L-valine abiraterone.
[0080] Hygroscopicity test
[0081] The hygroscopicity of each crystal form of L-valine abiraterone in Example 3 and Comparative Examples 1 and 2 was evaluated by DVS test at 25°C between 0%RH and 90%RH. The hygroscopicity test results at 80%RH and 90%RH are shown in Table 5.
[0082] Table 5 Results of hygroscopicity test
[0083] Experiments have shown that the L-valine abiraterone p-toluenesulfonic acid crystal form prepared by this invention has low hygroscopicity.
[0084] Liquidity test
[0085] A 7cm diameter petri dish was used. Two glass funnels were stacked alternately on an iron stand, with the outlet of the lower funnel 3.5-6.0cm from the base. Samples of each crystal form of L-valine abiraterone from Example 3 and Comparative Examples 1 and 2 were taken and slowly added from the upper funnel, allowing the sample to gradually accumulate on the base through the buffer between the two funnels, forming a cone, until the tallest cone was obtained. The height H of the cone was measured three times for each sample, and the average value was taken.
[0086] The angle of repose is calculated using the following formula: a = arctg (H / R), where a is the angle of repose and R is the chassis radius.
[0087] When the angle of repose of the powder is less than or equal to 30 degrees, its flowability is good; when it is less than or equal to 40 degrees, it can meet the flowability requirements in the production process; and when it is greater than 40 degrees, its flowability is poor. The results are shown in Table 6.
[0088] Table 6 Results of fluidity measurement
[0089] Through testing, the L-valine abiraterone p-toluenesulfonic acid crystal form of this application has a repose angle of less than 30°, exhibiting good flowability and facilitating formulation manufacturing.
Claims
1. A crystal form of L-valine abiraterone p-toluenesulfonic acid, characterized in that, In the crystal form, the molar ratio of L-valine abiraterone to p-toluenesulfonic acid and water is 1:1:
2.
2. The crystal form as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 11.9±0.2°, 12.9±0.2°, 15.4±0.2°, 17.5±0.2°, and 21.5±0.2°.
3. The crystal form as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 7.1±0.2°, 11.9±0.2°, 12.9±0.2°, 13.8±0.2°, 14.6±0.2°, 15.4±0.2°, 17.5±0.2°, and 21.5±0.2°.
4. The crystal form as described in claim 1, characterized in that, It has the X-ray powder diffraction pattern shown in Figure 1.
5. The crystal form as described in claim 1, characterized in that, Its crystallographic parameters are: orthorhombic crystal system, space group P212121, cell parameters: a=6.19450(10)Å, b=20.2852(4)Å, c=28.2373(6)Å, α=90°, β=90°, γ=90°, cell volume V=3548.21(12)Å. 3 .
6. The crystal form as described in claim 1, characterized in that, It has the TGA / DSC diagram shown in Figure 2.
7. A method for preparing the L-valine abiraterone p-toluenesulfonic acid crystal form according to any one of claims 1-6, characterized in that, Includes the following steps: L-valine abiraterone and p-toluenesulfonic acid are added to a mixed solution of organic solvent and water, heated and stirred to dissolve and react, cooled to crystallize, filtered, and dried to obtain the final product.
8. The preparation method according to claim 7, characterized in that, The organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, and butanone.
9. The preparation method according to claim 7, characterized in that, The heating and melting temperature is 50~60℃; the cooling and crystallization temperature is 0~25℃, preferably 10~20℃.
10. A pharmaceutical composition, characterized in that, It includes the L-valine abiraterone p-toluenesulfonic acid crystal form of any one of claims 1-6 and other pharmaceutically acceptable excipients.