A preparation method of progesterone co-crystal and its application
By forming eutectics with nitrobenzoic acid, the problem of poor solubility of progesterone is solved, its water solubility and stability are improved, local irritability and side effects are reduced, and the effective delivery and stability of progesterone is achieved.
Patent Information
- Application Number
- CN202210235964.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-03-10
- Publication Date
- 2025-01-03
- Estimated Expiration
- 2042-03-10
AI Technical Summary
Poor solubility of progesterone leads to local irritation, nodules and sterile abscesses during intramuscular injection, and requires frequent injections, and lacks effective treatment methods.
Nitrobenzoic acid is used as eutectic reagent to form eutectic crystals with progesterone, and through hydrogen bonding, progesterone-nitrobenzoic acid eutectic crystals are prepared to improve its water solubility and stability, and the ball milling method and single crystal culture method are used to improve its water solubility and stability. A stable eutectic is obtained.
It significantly improves the solubility and stability of progesterone, reduces local irritation and side effects, extends drug delivery time, reduces dose and side effects, and has a lower preparation cost.
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Figure CN114644669B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of drug co-crystal preparation, and in particular relates to a preparation method of a progesterone co-crystal and an application thereof. Background Art
[0002] Drug cocrystals are "supermolecules" with fixed composition and single melting point formed by drug molecules and cocrystal reagents through intermolecular forces such as hydrogen bonds. Existing research results show that the use of cocrystal reagents with good water solubility and poorly soluble drugs to form drug cocrystals can significantly improve the water solubility and bioavailability of poorly soluble drugs without changing the molecular structure of the drugs. It is the latest key technology to improve the physical and chemical properties of drugs such as water solubility, permeability and stability. In 2013, the US FDA issued the industry guidelines for drug cocrystals, which listed drug cocrystals as drug excipients; in 2016, the guidelines were revised to further classify drug cocrystals as "solid-state" drug solvates, providing guidelines for the approval and marketing of cocrystal drugs. In 2014, two cocrystal drugs for the treatment of diabetes, Farxiga and Suglat, were approved for marketing. In 2015, Novartis' blockbuster cocrystal drug LCZ696 for the treatment of heart failure was approved for marketing.
[0003] Progesterone (C 21 H 30 Progesterone (O2) is the main biologically active progestogen secreted by the ovary. Progesterone can not only induce the endometrium to transition to the secretory phase, increase endometrial receptivity to facilitate the implantation of the fertilized egg, but also act on the local part of the uterus to provide a good internal environment for the maintenance of pregnancy.
[0004]
[0005] Because progesterone has poor solubility, progesterone oily injection is often used in clinical practice. Its advantages are mainly accurate efficacy and low price. Its disadvantages are mainly pain and irritation at the injection site, easy formation of local nodules, and the absorption and recovery of local nodules and sterile abscesses takes a long time. These are all normal phenomena of intramuscular progesterone injection, and there is no special and effective treatment method. In addition, intramuscular progesterone injections need to be injected daily.
[0006] The drug co-crystal method provides a new idea and attempt to improve the water solubility and stability of poorly soluble oral contraceptives such as steroid hormones. Summary of the invention
[0007] The purpose of the present invention is to provide a method for preparing a progesterone co-crystal and its application. Since the nitro group is an electron-withdrawing group, nitrobenzoic acid is not a good hydrogen bond donor and cannot be used as a co-crystal reagent for the preparation of drug co-crystals. In the present invention, a co-solvent is added when preparing the progesterone co-crystal, and the progesterone-nitrobenzoic acid co-crystal is successfully prepared, which expands the selection range of the co-crystal reagent.
[0008] The progesterone co-crystal is formed by the active ingredient progesterone and the co-crystal former nitrobenzoic acid, wherein the progesterone and the nitrobenzoic acid are connected by hydrogen bonds, wherein the molar ratio of the progesterone to the nitrobenzoic acid is 1:1.
[0009] The nitrobenzoic acid is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
[0010] The progesterone-o-nitrobenzoic acid eutectic belongs to the orthorhombic system, the space group is P212121, and the unit cell parameters are: α=90°,β=90°,γ=90°,Z=4,the unit cell volume is The progesterone-m-nitrobenzoic acid eutectic belongs to the triclinic system, the space group is P1, and the unit cell parameters are: α=62.763(7)°,β=86.884(6)°,γ=77.261(6)°,Z=2,the unit cell volume is The progesterone-p-nitrobenzoic acid eutectic belongs to the orthorhombic system, the space group is P212121, and the unit cell parameters are: α=90°,β=90°,γ=90°,Z=4,the unit cell volume is
[0011] The X-ray powder diffraction pattern of progesterone-o-nitrobenzoic acid expressed in 2θ angles has characteristic peaks at 4.1°, 6.5°, 9.2°, 10.1°, 10.4°, 10.5°, 21.7°, and 23.2°, wherein the error range of 2θ for each characteristic peak is ±0.2°; the X-ray powder diffraction pattern of progesterone-m-nitrobenzoic acid expressed in 2θ angles has characteristic peaks at 3.5°, 4.6°, 5.7°, 6 .9°, 8.4°, 8.6°, 12°, and 21°, wherein the error range of 2θ for each characteristic peak is ±0.2°; the X-ray powder diffraction pattern of progesterone-p-nitrobenzoic acid expressed in 2θ angles has characteristic peaks at 2.2°, 2.8°, 3.4°, 3.5°, 5.4°, 7.7°, 9.1°, and 38.7°, wherein the error range of 2θ for each characteristic peak is ±0.2°.
[0012] The melting point of progesterone-o-nitrobenzoic acid is 143.08±0.1°C; the melting point of progesterone-m-nitrobenzoic acid is 95.06±0.1°C; the melting point of progesterone-o-nitrobenzoic acid is 157.03±0.1°C.
[0013] The preparation method of the progesterone eutectic is as follows: progesterone, nitrobenzoic acid, ethyl acetate or methanol are placed in a ball mill and ball-milled for 20-60 minutes, and the obtained white solid powder is the progesterone-nitrobenzoic acid eutectic; the nitrobenzoic acid is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
[0014] The preparation method of the progesterone eutectic single crystal is as follows: adding progesterone-nitrobenzoic acid eutectic powder into methanol to dissolve, and evaporating the solvent to obtain colorless block crystals, which are the progesterone-nitrobenzoic acid eutectic single crystals.
[0015] A pharmaceutical composition comprises the above-mentioned progesterone cocrystal and a pharmaceutically acceptable carrier or adjuvant.
[0016] The progesterone-nitrobenzoic acid eutectic (o-nitrobenzoic acid, m-nitrobenzoic acid, p-nitrobenzoic acid) prepared by the present invention has good stability and significantly improved solubility. Increasing the solubility of progesterone can reduce the irritation and adverse reactions of progesterone. Moreover, the eutectic technology can control the release of progesterone and prolong the delivery of progesterone, which has the application value of reducing the dosage and related side effects. The eutectic reagent used in the preparation method is cheap, and the preparation adopts a method with low production cost such as ball milling, which will not significantly increase the production cost of the drug when improving the water solubility of the drug, and can ensure the basic stability of the price of the eutectic drug. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 This is the powder X-ray diffraction (PXRD) spectrum of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0018] Figure 2 This is a graph showing the results of simultaneous thermal analysis (TG-DSC) of the progesterone-o-nitrobenzoic acid cocrystal prepared in Example 1.
[0019] Figure 3 This is the Fourier transform infrared spectrum (FT-IR) of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0020] Figure 4 This is the SEM photograph of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0021] Figure 5 The H NMR spectrum of the progesterone-o-nitrobenzoic acid cocrystal prepared in Example 1 ( 1 H-NMR).
[0022] Figure 6 This is a structural analysis diagram of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0023] Figure 7 This is a graph showing the stability evaluation results of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0024] Figure 8 This is a graph showing the results of the water solubility evaluation of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0025] Fig. 9 This is a graph showing the bioavailability evaluation results of the progesterone-o-nitrobenzoic acid co-crystal prepared in Example 1.
[0026] Fig.10 This is the powder X-ray diffraction (PXRD) spectrum of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0027] Fig.11 This is a graph showing the results of simultaneous thermal analysis (TG-DSC) of the progesterone-m-nitrobenzoic acid cocrystal prepared in Example 1.
[0028] Fig.12 This is the Fourier transform infrared spectrum (FT-IR) of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0029] Fig.13 This is the SEM photograph of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0030] Fig.14 The H NMR spectrum of the progesterone-m-nitrobenzoic acid cocrystal prepared in Example 1 ( 1 H-NMR).
[0031] Fig.15 This is a structural analysis diagram of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0032] Fig.16 This is a graph showing the stability evaluation results of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0033] Fig.17 This is a graph showing the results of the water solubility evaluation of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0034] Fig.18 This is a graph showing the bioavailability evaluation results of the progesterone-m-nitrobenzoic acid co-crystal prepared in Example 1.
[0035] Fig.19 This is the powder X-ray diffraction (PXRD) spectrum of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0036] Fig. 20 This is a graph showing the results of simultaneous thermal analysis (TG-DSC) of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0037] Fig.21 This is the Fourier transform infrared spectrum (FT-IR) of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0038] Fig. 22 This is the SEM photograph of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0039] Fig.23 The H NMR spectrum of the progesterone-p-nitrobenzoic acid cocrystal prepared in Example 1 ( 1 H-NMR).
[0040] Fig.24 This is a structural analysis diagram of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0041] Fig.25 This is a graph showing the stability evaluation results of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0042] Fig.26 This is a graph showing the results of the water solubility evaluation of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1.
[0043] Fig. 27 This is a graph showing the bioavailability evaluation results of the progesterone-p-nitrobenzoic acid co-crystal prepared in Example 1. DETAILED DESCRIPTION
[0044] Example 1
[0045] 943.4 mg (3.0 mmol) of progesterone and 501.4 mg (3.0 mmol) of o-nitrobenzoic acid were weighed and added into a ball mill (planetary ball mill, Nanjing Chishun Technology Development Co., Ltd.), 0.2 mL of ethyl acetate as a cosolvent was added, and ball milling was performed at 28 Hz for 40 min. The obtained white powder was progesterone-o-nitrobenzoic acid eutectic.
[0046] Single crystal culture method: Take 100 mg of the above-mentioned progesterone-o-nitrobenzoic acid eutectic powder, add 15 ml of methanol to dissolve it, and the solvent evaporates slowly. Colorless block crystals will be obtained in about 1 week.
[0047] Example 2
[0048] 943.4 mg (3.0 mmol) of progesterone and 501.4 mg (3.0 mmol) of m-nitrobenzoic acid were weighed and added into a ball mill (planetary ball mill, Nanjing Chishun Technology Development Co., Ltd.), 0.2 mL of ethyl acetate as a cosolvent was added, and ball milling was performed at 28 Hz for 40 min. The obtained white powder was progesterone-m-nitrobenzene eutectic.
[0049] Single crystal culture method: Take 100 mg of the above-mentioned progesterone-m-nitrobenzoic acid eutectic powder, add 15 ml of methanol to dissolve it, and the solvent evaporates slowly. Colorless block crystals will be obtained in about 1 week.
[0050] Example 3
[0051] 943.4 mg (3.0 mmol) of progesterone and 501.4 mg (3.0 mmol) of p-nitrobenzoic acid were weighed and added into a ball mill (planetary ball mill, Nanjing Chishun Technology Development Co., Ltd.), 0.2 mL of ethyl acetate as a cosolvent was added, and ball milling was performed at 28 Hz for 40 min. The obtained white powder was progesterone-p-nitrobenzene eutectic.
[0052] Single crystal culture method: Take 100 mg of the above-mentioned progesterone-p-nitrobenzoic acid eutectic powder, add 15 ml of methanol to dissolve it, and the solvent evaporates slowly. Colorless block crystals will be obtained in about 1 week.
[0053] The co-crystals and single crystals prepared in Examples 1-3 were subjected to characterization tests:
[0054] Experimental conditions
[0055] 1. Thermal analysis (TG-DSC)
[0056] Instrument model: TGA / DSC 3+
[0057] Heating rate: 10℃ / min
[0058] Temperature range: 40-400℃
[0059] Gas atmosphere: Nitrogen
[0060] 2. Infrared absorption spectrum (IR)
[0061] Instrument model: Bruker EQUINOX 55 FT-IR
[0062] Experimental method: Take an appropriate amount of sample and place it in the middle of the probe for testing
[0063] 3. 1 H-NMR nuclear magnetic resonance spectrum
[0064] Instrument model: AVANCE III HD 400 / 500MHz NMR spectrometer
[0065] Solvent: d 6 -DMSO (TMS internal standard)
[0066] 4. Single crystal X-ray diffraction (SXRD)
[0067] Instrument model: Rigaku AFC-10
[0068] Experimental method: Select a colorless crystal of 0.31mm×0.22mm×0.18mm in size, use graphite monochromatized Mo-K rays, and radiate wavelength The measurement temperature was 173.00 (15) K. The structure was solved and refined using SHELXT-14 and Olex2 programs. The atomic positions were determined using the direct method, and then the coordinates of all non-hydrogen atoms were calculated using the difference function method and the least squares method. The structure was modified using the least squares method.
[0069] 5. Powder X-ray diffraction (PXRD)
[0070] Instrument model: D8 ADVANCE X-ray powder analyzer from Bruker, Germany.
[0071] Measurement conditions: copper target, 40KV / 40mA, start angle 5°, end angle 40° / 60°, step width 0.02, scanning speed 17.7 seconds / step. Wavelength Graphite monochromator.
[0072] 6. Scanning electron microscope images
[0073] Instrument model: Jeol JSM-6100
[0074] 7. Stability test
[0075] Instrument model: Comprehensive drug stability test chamber (Shanghai Yiheng Scientific Instrument Co., Ltd.)
[0076] Experimental method: The stability experiment examines the stability and transformation law of the sample under high temperature, high humidity and light conditions. Take 100 mg of the test sample powder and put it into a weighing bottle. Place the sample opening under high temperature (60±2℃), high humidity (90%±5%) and light (4500±500lx) conditions for 10 days. Take samples on the 0th day, 5th day and 10th day for powder X-ray diffraction analysis.
[0077] 8. Solubility test
[0078] Instrument model: Tianda Tianfa RC806D dissolution tester
[0079] Experimental method: The sample was passed through a 100-mesh sieve, 2 g of each test sample was weighed and added into 1000 mL of deionized water respectively. The mixture was stirred at 37 °C and 100 rpm. 2 mL of samples were taken at 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min and 360 min respectively. The filtrate was filtered and taken as the test sample. Two injections were made for HPLC detection.
[0080] Liquid phase conditions: HPLC: Waters; chromatographic column: Waters XBridge C18 4.6*150mm, 3.5μm chromatographic column; mobile phase: acetonitrile: water = 45:55; detection wavelength: 280nm; flow rate: 0.8mL / min; column temperature: 40℃; injection volume: 20μL; running time: 15min.
[0081] 9. Bioavailability test
[0082] 9.1 Animals: Healthy female SD rats (7-9 weeks old, weighing 220±30 g, 5 rats per group) were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
[0083] 9.2 Animal Dosing Method: All animals were housed under a 12-hour / 12-hour light / dark cycle, 5 per cage, and were allowed to eat freely. Progesterone and its cocrystals were prepared with PBS (phosphate buffered solution, containing 0.1% DMSO) to prepare a solution, and the dose was equivalent to 5.0 mg / kg of progesterone, and administered by intramuscular injection.
[0084] 9.3 Biological sample preparation method: 50 μL jugular blood samples were collected in batches into heparinized tubes at the specified time (15, 30 min and 1, 1.5, 2, 3, 5, 7, 12, 24, 48 h). The blood was then centrifuged for 15 min. Plasma samples were stored at -20°C. 50 μL rat plasma, 5 μL methanol and 200 μL internal standard solution (buspirone, 5 ng / mL) were added to 1 mL methanol: acetonitrile (1:1, v / v). The above plasma samples were vortexed for 1 min, centrifuged at 4000 rpm for 15 min, and the supernatant was diluted 20 times with methanol: water (1:1, v / v, 0.1% trifluoroacetic acid) for injection.
[0085] 9.4 Biological sample analysis method: LC-MS / MS instrument model: AB Sciex 5500; LC-MS / MS quantitative analysis software: 1.6.3; ionization mode: electrospray positive ion; scanning mode: multiple reaction monitoring (MRM); analyte MRM: EE-DNS, 530.4 / 171.0; internal standard MRM: buspirone, 386.2 / 122.2;
[0086] Liquid phase conditions: Shimadzu LC-30AD, ACE Excel 5C4 (50 mm*2.1 mm), injection volume 10 μL; mobile phase: A: 5 mM ammonium acetate (0.05% trifluoroacetic acid), B: acetonitrile (0.1% trifluoroacetic acid), flow rate 0.8 mL / min, the gradient of mobile phase A and B are shown in the table below.
[0087] Gradient of mobile phase A and B
[0088] Time (min) A(％) B(％) 0.4-1.8 80.0 20.0 1.8-2.7 5.00 95.0 2.7-3.5 80.0 20.0
[0089] Characterization results
[0090] 1. Progesterone-o-nitrobenzoic acid eutectic
[0091] (1) Powder X-ray diffraction (PXRD) test: The absorption peak data are as follows.
[0092]
[0093]
[0094]
[0095] (2) Synchronous thermal analysis (TG-DSC): Differential scanning calorimetry (DSC) showed that the eutectic melting point was 143.08°C; thermogravimetric analysis (TGA) showed that the decomposition of o-nitrobenzoic acid and progesterone was observed within the test temperature range.
[0096] (3) Fourier transform infrared spectroscopy (FT-IR) test: The main infrared absorption peak data are as follows.
[0097] <![CDATA[Wave number ν / cm -1 > Transmittance / % 3101.40 99.4 3077.21 99.4 2612.78 98.3 2514.00 98.4 1727.62 86.6 1698.29 82.3 1611.78 85.5 1530.72 77.6 1416.62 97.7 1299.67 92.3 1266.56 79.0 1195.43 95.9 1073.74 94.4 947.36 92.9 893.76 97.5 803.15 86.9 784.25 91.6 742.62 90.4 681.43 91.6 664.20 98.9 640.96 91.9
[0098] (4) H NMR spectrum ( 1 H-NMR) test: chemical shift data is 1 H-NMR (400MHz, d 6 -DMSO)δ=13.85(s,1H),7.99(d,1H),7.88(d,1H),7.80(d,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25-2.23(m,2 H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H).
[0099] (5) Single crystal X-ray diffraction (SXRD) test: From the single crystal structure analysis results, it can be seen that the molecular ratio of progesterone-o-nitrobenzoic acid eutectic is 1:1, and the two are connected by hydrogen bonds.
[0100]
[0101] (6) Stability experimental results show that progesterone-o-nitrobenzoic acid eutectic is stable under high temperature, high humidity and light conditions.
[0102] (7) Solubility test results show that the formation of eutectic significantly increases the water solubility of progesterone.
[0103] (8) Bioavailability test: From the drug-time curves of progesterone and cocrystal, it can be seen that the peak time of progesterone is 1 hour, the peak time of cocrystal is 1.5 hours, and the Cmax of cocrystal is 1.8 times that of progesterone.
[0104] 2. Progesterone-m-nitrobenzoic acid eutectic
[0105] (1) Powder X-ray diffraction (PXRD) test: The absorption peak data are as follows.
[0106]
[0107]
[0108] (2) Synchronous thermal analysis (TG-DSC): Differential scanning calorimetry (DSC) showed that the eutectic melting point was 95.06°C; thermogravimetric analysis (TGA) showed that the decomposition of m-nitrobenzoic acid and progesterone was observed within the test temperature range.
[0109] (3) Fourier transform infrared spectroscopy (FT-IR) test: The main infrared absorption peak data are as follows.
[0110] <![CDATA[Wavenumber ν / cm -1 > Transmittance / % 2933.0 89.1 1714.3 88.0 1622.5 87.6 1526.6 89.6 1468.5 92.8 1431.5 92.6 1345.0 87.1 1292.9 90.1 1233.5 86.1 1144.2 91.2 1076.6 92.9 898.0 91.9 688.8 92.3
[0111] (4) H NMR spectrum ( 1 H-NMR) test: chemical shift data is 1 H-NMR (400MHz, d 6-DMSO)δ=13.75(s,1H),8.63(d,1H),8.49(d,1H),8.34(d,1H),7.80(t,1H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25-2.2 3(m,2H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H).
[0112] (5) Single crystal X-ray diffraction (SXRD) test: From the single crystal structure analysis results, it can be seen that the molecular ratio of progesterone-m-nitrobenzoic acid eutectic is 1:1, and the two are connected by hydrogen bonds.
[0113]
[0114]
[0115] (6) Stability experimental results show that progesterone-m-nitrobenzoic acid eutectic is stable under high temperature, high humidity and light conditions.
[0116] (7) Solubility test results show that the formation of eutectic significantly increases the water solubility of progesterone.
[0117] (8) Bioavailability test: From the drug-time curves of progesterone and cocrystal, it can be seen that the peak time of progesterone is 1 hour, the peak time of cocrystal is 1.5 hours, and the Cmax of cocrystal is 2.1 times that of progesterone.
[0118] 3. Progesterone-p-nitrobenzoic acid eutectic
[0119] (1) Powder X-ray diffraction (PXRD) test: The absorption peak data are as follows.
[0120]
[0121]
[0122] (2) Synchronous thermal analysis (TG-DSC): Differential scanning calorimetry (DSC) showed that the melting point of the eutectic was 157.03°C; thermogravimetric analysis (TGA) showed that decomposition of the eutectic was observed within the test temperature range.
[0123] (3) Fourier transform infrared spectroscopy (FT-IR) test: The main infrared absorption peak data are as follows.
[0124]
[0125]
[0126] (4) H NMR spectrum ( 1 H-NMR) test: chemical shift data is 1 H-NMR (400MHz, d 6 -DMSO)δ=14.40-12.90(s,1H),8.34(d,2H),8.16(d,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25-2.23(m,2H), 2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H).
[0127] (5) Single crystal X-ray diffraction (SXRD) test: From the single crystal structure analysis results, it can be seen that the molecular ratio of progesterone-p-nitrobenzoic acid eutectic is 1:1, and the two are connected by hydrogen bonds.
[0128]
[0129] (6) Stability experimental results show that progesterone-p-nitrobenzoic acid eutectic is stable under high temperature, high humidity and light conditions.
[0130] (7) Solubility test results show that the formation of eutectic significantly increases the water solubility of progesterone.
[0131] (8) Bioavailability test: From the drug-time curves of progesterone and cocrystal, it can be seen that the peak time of progesterone is 1 hour, the peak time of cocrystal is 1.5 hours, and the Cmax of cocrystal is 2.0 times that of progesterone.
Claims
1. A progesterone co-crystal, characterized in that: It is formed by an active ingredient progesterone and a cocrystal former nitrobenzoic acid, wherein progesterone and nitrobenzoic acid are connected by hydrogen bonds, and the nitrobenzoic acid is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid; the molar ratio of progesterone to nitrobenzoic acid is 1:1; Progesterone-2-nitrobenzoic acid cocrystal It belongs to the orthorhombic system, with space group P212121. The unit cell parameters are: a = 7.6491(3)Å, b = 17.0219(7)Å, c = 19.3106 (16)Å, α = 90°, β = 90°, γ = 90°, Z = 4, and the unit cell volume is 2514.30(19)Å. 3 ; Progesterone-m-nitrobenzoic acid cocrystal It belongs to the triclinic system, space group is P1, unit cell parameters are: a = 7.6835(6)Å, b = 13.4703(9)Å, c = 13.9188(10)Å, α = 62.763(7)°, β = 86.884(6)°, γ = 77.261(6)°, Z = 2, unit cell volume is 1247.51(16)Å 3 ; Progesterone-p-nitrobenzoic acid cocrystal It belongs to the orthorhombic system, the space group is P212121, the unit cell parameters are: a = 7.6538(7)Å, b = 11.6876(9)Å, c = 27.4019(19)Å, α = 90°, β = 90°, γ = 90°, Z = 4, and the unit cell volume is 2451.2(3)Å 3 ; Progesterone-2-nitrobenzoic acid The X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 10.442°, 12.403°, 13.437°, 16.078°, 17.841°, 20.481°, 20.979°, 24°, 26.078°, 27.261°, and 29.699°, wherein the error range of 2θ for each characteristic peak is ±0.2°; Progesterone-m-nitrobenzoic acid The X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 13.059°, 15.081°, 15.82°, 17.038°, 19.359°, 20.121°, 20.799°, 22.422°, 22.902°, 26.617°, and 30.041°, wherein the error range of 2θ for each characteristic peak is ±0.2°; Corpus luteum Keto-4-nitrobenzoic acid The X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 6.34°, 13.14°, 14.74°, 16.739°, 17.16°, 18.742°, 19.081°, 20.519°, 23.558°, 26.658°, and 29.798°, wherein the error range of 2θ for each characteristic peak is ±0.2°; Progesterone-2-nitrobenzoic acid The melting point is 143.08 ± 0.1 °C; Progesterone- Nitrobenzoic acid The melting point is 95.06±0.1℃; Progesterone-p-nitrobenzoate The melting point is 157.03±0.1 ℃.
2. A method for preparing the progesterone co-crystal according to claim 1, characterized in that: The specific operation of the preparation method is: placing progesterone, nitrobenzoic acid, ethyl acetate or methanol in a ball mill for 20-60 minutes, and the obtained white solid powder is the progesterone-nitrobenzoic acid eutectic; the nitrobenzoic acid is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
3. A method for preparing a single crystal of the progesterone co-crystal according to claim 1, characterized in that: The specific operation of the preparation method is: adding progesterone-nitrobenzoic acid eutectic powder into methanol to dissolve, and the solvent evaporates to obtain colorless block crystals, which are single crystals of progesterone-nitrobenzoic acid eutectic.
4. A pharmaceutical composition, characterized in that It comprises the progesterone co-crystal according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.