A hydrogen bond eutectic of aminoglutethimide and m-toluic acid and a synthesis method thereof

Abstract

The present invention discloses a hydrogen bond eutectic of aminoglutethimide and m-toluic acid and a synthesis method thereof. The molecular formula of the eutectic is [(C 13 H 16 N2O2)·(C8H8O2)], with a melting point of 122.8°C, is a molecular structure composed of an aminoglutethimide molecule and an m-toluic acid molecule bonded together by intermolecular hydrogen bonds, and belongs to the monoclinic system. The present invention is a hydrogen-bonded eutectic synthesized by a solution crystallization method. The eutectic of the present invention is a brand-new compound and has not been reported in the literature. The eutectic significantly improves the solubility and dissolution rate of the aminoglutethimide raw material drug in water. The novel hydrogen-bonded eutectic and its preparation method have commercial application value and clinical application prospects.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a novel co-crystal of adrenocortical hormone inhibitory anti-tumor drugs, in particular to a hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid and a method for synthesizing the same. Technical Background

[0002] A eutectic is a multi-component crystal, which includes both binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates. [1-4] . Advantages of pharmaceutical cocrystals: (1) Each component in a pharmaceutical cocrystal can be a neutral molecule, so pharmaceutical cocrystals can cover all APIs, including acids, bases, and non-ionized molecules. (2) There are many molecules that can potentially be used to form cocrystals with APIs. These substances may include food additives, preservatives, pharmaceutical excipients, vitamins, minerals, amino acids, other active molecules, and even other APIs. Cocrystals can be prepared using techniques such as solution crystallization, mechanical grinding and melt crystallization, rapid evaporation, supercritical fluids, hot melt extrusion, wet compression, and dry compression. [5-8] , among which solution crystallization is the most commonly used.

[0003] Aminoglutethimide (AG), also known as 3-ethyl-3-(-aminophenyl)-2,6-piperidinedione. It has the effect of blocking the cleavage of cholesterol side chains in the adrenal glands to convert into pregnenolone, inhibiting the action of aromatase in the body. It is mainly used clinically to treat advanced breast cancer (postmenopausal and estrogen receptor-positive patients have better efficacy), ovarian cancer, prostate cancer and adrenal cortical carcinoma. It is also used for hypercortisolism (Cushing's syndrome) and Cushing's syndrome-like syndrome caused by adrenal tumors. The drug is a slightly soluble substance (the limit of slightly soluble substances) in aqueous solution, with a solubility of about 0.2mg / ml [9] The poor solubility of aminoglutethimide in water not only affects the bioavailability of the drug, but also seriously affects the new drug development and clinical use of the drug. Summary of the invention

[0004] In order to solve the problem that aminoglutethimide has poor solubility in water and improve the solubility of aminoglutethimide in water, the present invention provides a hydrogen bond eutectic of aminoglutethimide and m-toluic acid and a synthesis method thereof.

[0005] In the present invention, the chemical name of aminoglutethimide is 3-ethyl-3-(4-aminophenyl)-2,6-piperidindione, and the molecular formula is C 13 H 16 N2O2, its structural formula is shown in Figure a, the molecular formula of m-toluic acid is C8H8O2, and the corresponding structural formula is shown in Figure b.

[0006]

[0007] The present invention is a hydrogen bond eutectic of aminoglutethimide and m-toluic acid synthesized by solution crystallization method. The synthesis method comprises the following steps:

[0008] (1) A certain molar ratio of aminoglutethimide and m-toluic acid is added to a 100 mL flask, a certain volume of an organic solvent is added to the flask, and the mixture is heated for a certain period of time until the raw materials are completely dissolved to obtain a reaction solution.

[0009] (2) The reaction solution was transferred into a 10 mL clean test tube, sealed with plastic wrap, and appropriate small holes were pierced in the plastic wrap with a needle. The mixture was evaporated at room temperature for a period of time to obtain a hydrogen bonded eutectic of aminoglutethimide and m-toluic acid.

[0010] (3) The above-mentioned certain molar ratio of aminoglutethimide to m-toluic acid is in the range of 1:0.2 to 0.2:1.

[0011] (4) The above-mentioned organic solvent preferably includes toluene, benzene, ethyl acetate, acetonitrile, methanol and ethanol, and the volume of the organic solvent is between 3mL and 5mL.

[0012] (5) The above-mentioned heating temperature is between 40°C and 70°C, and the heating time is between 3min and 10min.

[0013] (6) Use a needle to pierce the above test tube with an appropriate number of small holes, 1 to 10.

[0014] (7) The above reaction solution evaporates at room temperature for about 2-10 days.

[0015] A hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention has the following characteristics:

[0016] (1) The molecular formula is [(C 13 H 16 N2O2)·(C8H8O2)] is composed of an aminoglutethimide molecule and a m-toluic acid molecule bonded together by intermolecular hydrogen bonds (O2-H2…N2, 2.4148(28), <(DHA)=104.322(248)°), belonging to the monoclinic system, with a space group of P2(1) / n. The unit cell parameters are: α=90°, β=101.367(8)°, γ=90°, V=1913.3(9)A 3, Z = 4. Its PXRD characteristic diffraction peaks appear at 6.58°, 10.12°, 10.69°, 13.21°, 14.74°, 15.15°, 15.8°, 17.48°, 19.0°, 19.84°, 21.09°, 22.05°, 22.51°, 25.09°, 25.59°, 29.05°, 34.69°, 39.14°. The phase transition temperature is 122.8°C.

[0017] (2) The hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention was tested and verified by single crystal diffraction (SCXRD), X-ray powder diffraction (PXRD), differential scanning calorimeter (DSC), thermogravimetric analyzer (TG), and infrared spectroscopy (FTIR).

[0018] (3) The present invention measures the water solubility of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid by ultraviolet spectrophotometry, and the dissolution medium is a phosphate buffer solution at pH 7.2, and the solubility and intrinsic dissolution rate are measured.

[0019] The beneficial effects of the present invention are:

[0020] (1) The present invention adopts a co-crystal strategy, and the prepared compound can effectively modify the original active drug component-aminoglutethimide. After the co-crystal is formed, the water solubility and intrinsic dissolution rate of the co-crystal are significantly higher than those of the aminoglutethimide raw material, that is, the co-crystal significantly improves the water solubility of the aminoglutethimide raw material, thereby helping to significantly improve the bioavailability of aminoglutethimide;

[0021] (2) The hydrogen bonded eutectic of aminoglutethimide and m-toluic acid synthesized in the present invention is a completely new compound and has not been reported in the literature;

[0022] (3) The hydrogen bonded co-crystal of aminoglutethimide and m-methylbenzoic acid synthesized by the present invention is a new crystal form of aminoglutethimide anticancer drug, which prolongs the market cycle from the perspective of intellectual property protection and has very important clinical application prospects;

[0023] (4) The method for preparing a hydrogen bond eutectic compound of aminoglutethimide and m-toluic acid of the present invention is simple and easy, has good reproducibility, and the eutectic compound product has high purity, is easy to realize large-scale industrial production, and has low cost and high commercial application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The present invention is further described below in conjunction with the accompanying drawings and implementation examples.

[0025] Figure 1 It is a schematic diagram of the basic structural unit of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid of the present invention;

[0026] Figure 2 is a crystal cell stacking diagram of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention;

[0027] Figure 3 The figure is the X-ray powder diffraction (PXRD) spectrum of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention. Figure 3 1-PXRD spectrum of aminoglutethimide and m-toluic acid hydrogen bond co-crystal simulated by Mercury software; 2-PXRD spectrum of aminoglutethimide and m-toluic acid hydrogen bond co-crystal synthesized by the present invention;

[0028] Figure 4 The differential scanning calorimetry (DSC) spectrum of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention. Figure 4 The phase transition temperature of aminoglutethimide is 153.1℃; the phase transition temperature of m-toluic acid is 114.2℃; the phase transition temperature of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid is 122.8℃.

[0029] Figure 5 The infrared (FTIR) spectrum of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention;

[0030] Figure 6 The thermogravimetric analysis (TG) diagram of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid of the present invention;

[0031] Figure 7 The dissolution curve of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid in phosphate buffer solution of the present invention;

[0032] Figure 8 This is the intrinsic dissolution rate (IDR) diagram of the hydrogen-bonded co-crystal of aminoglutethimide and m-toluic acid of the present invention. DETAILED DESCRIPTION

[0033] [Example 1] Synthesis of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0034] Take aminoglutethimide and m-methylbenzoic acid in a molar ratio of 1:0.5 and add them to a 50 mL flask, add 10 mL of an organic solvent acetonitrile to the flask, heat at 50°C for 5 min until the raw materials are completely dissolved, and obtain a reaction solution. Transfer the reaction solution to a 10 mL clean test tube, seal it with plastic wrap, poke 10 small holes in the plastic wrap with a needle, and volatilize it at room temperature for 8 days to obtain a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid.

[0035] [Example 2] Synthesis of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0036] Take aminoglutethimide and m-methylbenzoic acid in a molar ratio of 1:1 and add them to a 50 mL flask. Add 5 mL of organic solvent toluene to the flask and heat at 50°C for 4 min until the raw materials are completely dissolved to obtain a reaction solution. Transfer the reaction solution to a 10 mL clean test tube, seal it with plastic wrap, poke 5 small holes in the plastic wrap with a needle, and volatilize it at room temperature for 10 days to obtain a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid.

[0037] [Example 3] Synthesis of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0038] Take aminoglutethimide and m-methylbenzoic acid in a molar ratio of 1:0.5 and add them to a 50 mL flask, add 10 mL of organic solvent methanol to the flask, heat at 60°C for 3 min until the raw materials are completely dissolved, and obtain a reaction solution. Transfer the reaction solution into a 10 mL clean test tube, seal it with plastic wrap, poke 8 small holes in the plastic wrap with a needle, and evaporate at room temperature for 5 days to obtain a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid.

[0039] [Example 4] Crystallographic data of hydrogen bonded co-crystal of aminoglutethimide and m-toluic acid

[0040] The schematic diagram of the basic structural unit of the hydrogen bond co-crystal of aminoglutethimide and m-toluic acid is shown in the attached figure. Figure 1 ; The unit cell stacking diagram of the hydrogen bonded co-crystal of aminoglutethimide and m-toluic acid is shown in the attached figure. Figure 2 .

[0041] The molecular formula is [(C 13 H 16 N2O2)·(C8H8O2)], an aminoglutethimide molecule and a m-toluic acid molecule are combined together by intermolecular hydrogen bonds (O2-H2...N2, 2.4148(28), <(DHA)=104.322(248)°), belonging to the monoclinic system, with a space group of P2(1) / n. The unit cell parameters are: α=90°, β=101.367(8)°, γ=90°, V=1913.3(9)A 3 , Z=4.

[0042] [Example 5] PXRD analysis of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0043] In the PXRD spectrum of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid of the present invention, characteristic diffraction peaks appear at 6.58°, 10.12°, 10.69°, 13.21°, 14.74°, 15.15°, 15.8°, 17.48°, 19.0°, 19.84°, 21.09°, 22.05°, 22.51°, 25.09°, 25.59°, 29.05°, 34.69° and 39.14°.

[0044] Theoretical PXRD spectrum of the co-crystal of the present invention simulated by Mercury software ( Figure 3 1) and the measured spectrum of the cocrystal ( Figure 3 2) is basically consistent, indicating that the co-crystal prepared by the present invention has high purity.

[0045] [Example 6] DSC analysis of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0046] The DSC of a hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention is as follows: Figure 4 .

[0047] Figure 4 The phase transition temperature of aminoglutethimide is 153.1°C; the phase transition temperature of m-toluic acid is 114.2°C; the phase transition temperature of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid is 122.8°C. The melting point of the hydrogen bond eutectic of the present invention is between the two starting materials, and the hydrogen bond eutectic of the present invention is a single crystal endothermic peak.

[0048] [Example 7] FTIR analysis of hydrogen bonded co-crystals of aminoglutethimide and m-toluic acid

[0049] The FTIR image of a hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention is as follows: Figure 5 . Figure 5 Displayed at 3344.5cm -1 , 1711.43cm -1 , 1521.91cm -1 , 1372.05cm -1 , 1182.53cm -1 The characteristic absorption peaks of the hydrogen bonded eutectic of the present invention are at 3344.5cm -1 It is the symmetric and asymmetric stretching vibration peak of -NH2 in the aminoglutethimide molecule. The eutectic is at 1711.43cm -1 A strong carbonyl -C=O stretching vibration absorption peak appears at 1521.91cm-1 and 1372.05cm-1, and asymmetric stretching vibration absorption peaks of nitro group appear at 1521.91cm-1 and 1372.05cm-1. In summary, the formation of aminoglutethimide drug cocrystal is proved.

[0050] [Example 8] TG analysis of hydrogen bonded co-crystals of aminoglutethimide and m-toluic acid

[0051] Figure 6 It is a thermogravimetric analysis (TG) diagram of the hydrogen bond eutectic of aminoglutethimide and m-toluic acid of the present invention. Figure 6 In the test conditions of nitrogen atmosphere, the hydrogen bond eutectic of aminoglutethimide and m-toluic acid began to lose weight at 116°C, the aminoglutethimide raw material began to lose weight at 194°C, and m-toluic acid began to lose weight at 104°C.

[0052] [Example 9] Dissolution experiment of hydrogen bonded eutectic of aminoglutethimide and m-toluic acid

[0053] The solubility and intrinsic dissolution rate (IDR) of the hydrogen bonded eutectic of aminoglutethimide and m-toluic acid of the present invention in a phosphate buffer solution at pH = 7.2 are shown in the attached Figure 7 and attached Figure 8 As shown. Figure 7 and attached Figure 8 It can be seen that the solubility and intrinsic dissolution rate of the hydrogen-bonded cocrystal of aminoglutethimide and m-toluic acid have been significantly improved compared with the raw material aminoglutethimide itself.

[0054] References

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[0056] [2]Liu, M., et al. Development of a pharmaceutical cocrystal with solution crystallization technology: Preparation, characterization, and evaluation of myricetin-proline cocrystals[J]. European Journal ofPharmaceutics&Biopharmaceutics, 2016.107:151-159.

[0057] [3]Mnguni,et al.Binary polymorphic cocrystals:an update on theavailable literature in the Cambridge Structural Database,including a newpolymorph of the pharmaceutical 1:1cocrystal theophylline–3,4-dihydroxybenzoic acid.Acta crystallographica.Section C[J],Structuralchemistry,2018.74.

[0058] [4]Syed,S.A.A.,et al.Sulfaguanidine cocrystals:Synthesis,structuralcharacterization and their antibacterial and hemolytic analysis[J].Journal ofPharmaceutical and Biomedical Analysis,2018.149.

[0059] [5]Childs S L,et al.Screening strategies based on solubility andsolution composition generate pharmaceutically acceptable cocrystals ofcarbamazepine[J].Crystengcomm,2008.10(7):856-864.

[0060] [6]Lu E,Rodríguez-Hornedo N,Suryanarayanan R.A rapid thermal methodfor cocrystalscreening[J].Crystengcomm,2008.10(6):665-668.

[0061] [7]Bag P P,M.Patni,C.Malla Reddy.A kinetically controlledcrystallization process for identifying new co-crystal forms:fast evaporationof solvent from solutions to dryness[J].Crystengcomm,2011.13(19):5650-5652.

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Claims

1. A hydrogen bond eutectic of aminoglutethimide and m-toluic acid, characterized in that: The molecular formula of the co-crystal is [(C 13 H 16 N2O2)·(C8H8O2)], with a melting point of 122.8°C; it is a molecular structure composed of an aminoglutethimide molecule and an m-toluic acid molecule bonded together by intermolecular hydrogen bonds, belonging to the monoclinic system, with a space group of P2(1) / n, and unit cell parameters of: α=90°, β=101.367(8)°, γ=90°, V=1913.3(9)A 3 , Z=4; its PXRD characteristic diffraction peaks appear at 6.58°, 10.12°, 10.69°, 13.21°, 14.74°, 15.15°, 15.8°, 17.48°, 19.0°, 19.84°, 21.09°, 22.05°, 22.51°, 25.09°, 25.59°, 29.05°, 34.69°, 39.14°, and the phase transition temperature is 122.8°C.

2. A method for preparing a hydrogen bonded eutectic of aminoglutethimide and m-toluic acid comprises the following steps: (1) adding aminoglutethimide and m-toluic acid in a set molar ratio into a 100 mL flask, adding a set volume of an organic solvent into the flask, and heating for a set time until the raw materials are completely dissolved to obtain a reaction solution; (2) The reaction solution was transferred into a 10 mL clean test tube, sealed with plastic wrap, and a small hole was made in the plastic wrap with a needle. The mixture was evaporated at room temperature for a set time to obtain a hydrogen bonded eutectic of aminoglutethimide and m-toluic acid.

3. The method for preparing the co-crystal according to claim 2, characterized in that: The molar ratio of aminoglutethimide to m-toluic acid is in the range of 1:0.2 to 0.2:

1.

4. The method for preparing a co-crystal according to claim 2, characterized in that: The organic solvent preferably includes toluene, benzene, ethyl acetate, acetonitrile, methanol and ethanol, and the volume of the organic solvent is between 3 mL and 5 mL.

5. The method for preparing a co-crystal according to claim 2, characterized in that: The heating temperature is between 40°C and 70°C, and the heating time is between 3min and 10min.

6. The method for preparing a co-crystal according to claim 2, characterized in that: Use a needle to poke 1 to 10 small holes in the test tube.

7. The method for preparing a co-crystal according to claim 2, characterized in that: The reaction solution evaporates at room temperature for 2-10 days.

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