A hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid and a synthesis method thereof

Abstract

The invention discloses a hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid and a synthesis method thereof. The molecular formula of the eutectic is [(C13H16N2O2)·(C7H4N2O6)], the melting point is 166.39°C, and the molecular structure is composed of an aminoglutethimide molecule and a 3,5-dinitrobenzoic acid molecule bonded together by intermolecular hydrogen bonds, and belongs to the triclinic system. The present invention is a hydrogen bond 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 water dissolution rate and solubility of the eutectic are significantly higher than those of the aminoglutethimide raw material drug, that is, the eutectic significantly improves the water solubility of the aminoglutethimide raw material drug, thereby contributing to significantly improving the bioavailability of aminoglutethimide. The novel hydrogen bond eutectic and its preparation method have high 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 3,5-dinitrobenzoic acid and a method for synthesizing the same. Technical Background

[0002] In recent years, with the development of combinatorial chemistry and high-throughput screening technology, the discovery rate of new active compounds has greatly accelerated. According to the US FDA biopharmaceutical classification system, 40% of these new compounds belong to Class II (high permeability and low solubility) and Class IV (low permeability and low solubility). In order to improve their drugability, it is necessary to modify these compounds to improve their physicochemical properties and physical and mechanical properties. [1] .

[0003] A cocrystal is a multi-component crystal, which includes both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between neutral solids and salts or solvates. In recent years, crystal engineering has attracted increasing attention by controlling intermolecular interactions to improve the physicochemical properties of APIs without changing their chemical structures. [2,3] Cocrystal synthesis belongs to the category of crystal engineering. It is the result of the mutual recognition and assembly of molecules between the active components of the drug and the ligands through non-covalent interactions under the premise of kinetic and thermodynamic equilibrium. [4] . Pharmaceutical cocrystals have two advantages: (1) The components in a pharmaceutical cocrystal can be neutral molecules, 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, and other active molecules, and even other APIs. To date, solution crystallization, mechanical grinding, and melt crystallization are the general techniques for preparing cocrystals, as well as rapid evaporation, supercritical fluids, antisolvent addition, hot melt extrusion, wet compression, dry compression, and other techniques. [5,6-8] , among which solution crystallization is the most commonly used.

[0004] Aminoglutethimide (AG), also known as 3-ethyl-3-(-aminophenyl)-2,6-piperidinedione, can block the cleavage of cholesterol side chains in the adrenal glands to convert them into pregnenolone. At the same time, it also has the effect of 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 0.2 mg / 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

[0005] 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 3,5-dinitrobenzoic acid and a synthesis method thereof.

[0006] The present invention is a hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid synthesized by solution crystallization method. The synthesis method comprises the following steps:

[0007] (1) A certain molar ratio of aminoglutethimide and 3,5-dinitrobenzoic 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.

[0008] (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 3,5-dinitrobenzoic acid.

[0009] (3) The above-mentioned certain molar ratio of aminoglutethimide to 3,5-dinitrobenzoic acid, the molar ratio is in the range of 1:0.2 to 0.2:1.

[0010] (4) The above-mentioned organic solvent preferably includes acetonitrile, methanol and ethanol, and the volume of the organic solvent is between 3mL and 5mL.

[0011] (5) The above-mentioned heating temperature is between 40°C and 70°C, and the heating time is between 3min and 10min.

[0012] (6) Use a needle to pierce the above test tube with an appropriate number of small holes, 1 to 10.

[0013] (7) The above reaction solution evaporates at room temperature for about 2-10 days.

[0014] The aminoglutethimide and 3,5-dinitrobenzoic acid hydrogen bond eutectic of the present invention has the following characteristics:

[0015] (1) The molecular formula is [(C13H16N2O2)·(C7H4N2O6)], which is a eutectic formed by an aminoglutethimide molecule and a 3,5-dinitrobenzoic acid molecule bonded together by intermolecular hydrogen bonds. It belongs to the monoclinic crystal system, the space group is P-1, and the unit cell parameters are: α=74.156(3)°, β=88.190(3)°, γ=72.032(3)°, Its XRD characteristic diffraction peaks appear at 6.271, 11.493, 12.674, 13.401, 14.082, 16.488, 17.624, 18.668, 19.077, 19.758, 20.166, 20.439, 20.848, 21.302, 21.665, 22.164, 23.027, 23.572, 23.890, 24.299, 24.753, 26.160, 26.433, 26.978, 28.022, 29.203, 31.155, and 32.654.

[0016] (2) A hydrogen bonded co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention was tested and verified by means of single crystal diffraction (SCXRD), X-ray powder diffraction (PXRD), differential scanning calorimeter (DSC), thermogravimetric analyzer (TG), and infrared spectroscopy (FTIR).

[0017] (3) The present invention measures the water solubility of aminoglutethimide and 3,5-dinitrobenzoic acid hydrogen bonded co-crystals by ultraviolet spectrophotometry, the dissolution medium is a phosphate buffer solution at pH 7.2, and the measurement indicators are drug dissolution rate and dissolution rate.

[0018] The beneficial effects of the present invention are:

[0019] (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 dissolution rate and solubility 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;

[0020] (2) The hydrogen-bonded co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid synthesized by the present invention is a completely new compound and has not been reported in the literature;

[0021] (3) The aminoglutethimide and 3,5-dinitrobenzoic acid hydrogen bond co-crystal 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 a very important clinical application prospect;

[0022] (4) The preparation method of the co-crystal compound of the present invention is simple and easy, has good reproducibility, and the co-crystal compound product has high purity, is easy to realize large-scale industrial production, and has low cost, and has high commercial application value and clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The present invention is further described below in conjunction with the accompanying drawings and implementation examples.

[0024] Figure 1 Schematic diagram of the asymmetric basic structural unit of the hydrogen bond co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention;

[0025] Figure 2 is a unit cell stacking diagram of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention;

[0026] Figure 3a is the interaction diagram of intramolecular CH…O type hydrogen bonds (bond length 2.569, bond angle 113.87) of the co-crystal of the present invention, Figure 3b It is the interaction diagram of the intramolecular NH…O type hydrogen bond (bond length 2.157, bond angle 162.81) of the co-crystal of the present invention;

[0027] Figure 4 The X-ray powder diffraction (PXRD) spectrum of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention; Figure 4 1. PXRD spectrum of the co-crystal of the present invention, Figure 4 2. PXRD spectrum of the co-crystal of the present invention simulated by Mercury software;

[0028] Figure 5 is a differential scanning calorimetry (DSC) spectrum of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention;

[0029] Figure 6 The infrared (FTIR) spectrum of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention;

[0030] Figure 7 is a solubility diagram of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid in a phosphate buffer solution of the present invention;

[0031] Figure 8It is the intrinsic dissolution rate (IDR) diagram of the hydrogen-bonded co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention. DETAILED DESCRIPTION

[0032] [Example 1] Synthesis of hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid

[0033] Take aminoglutethimide and 3,5-dinitrobenzoic acid in a molar ratio of 1:0.2 and add them to a 100 mL flask. Add 3 mL of organic solvent methanol to the flask and heat at 40°C for 5 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 10 small holes in the plastic wrap with a needle, and evaporate it at room temperature for 8 days to obtain a hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid.

[0034] [Example 2] Synthesis of hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid

[0035] Take aminoglutethimide and 3,5-dinitrobenzoic acid in a molar ratio of 1:1 and add them to a 100 mL flask. Add 3 mL of organic solvent ethanol 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 evaporate it at room temperature for 5 days to obtain a hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid.

[0036] [Example 3] Synthesis of hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid

[0037] Take aminoglutethimide and 3,5-dinitrobenzoic acid in a molar ratio of 1:1 and add them to a 100 mL flask. Add 3 mL of organic solvent methanol to the flask and heat at 60°C for 3 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 8 small holes in the plastic wrap with a needle, and evaporate it at room temperature for 10 days to obtain a hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid.

[0038] [Example 4] Crystallographic data of hydrogen bonded co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid

[0039] The hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid was determined by single crystal diffractometer (SCXRD). The unit cell data are shown in Table 1 and the unit cell diagram is shown in the attached figure. Figure 1 , the unit cell stacking diagram is as shown in the attached Figure 2 , the intramolecular interaction diagrams are shown in Figures 3a and 3b.

[0040] Table 1 Unit cell data of aminoglutethimide drug co-crystal

[0041]

[0042] [Example 5] PXRD spectrum of hydrogen bonded eutectic synthesized from aminoglutethimide and 3,5-dinitrobenzoic acid In the PXRD spectrum of hydrogen bonded eutectic synthesized from aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention ( Figure 4 In 1), the characteristic diffraction peaks appear at 6.271, 11.493, 12.674, 13.401, 14.082, 16.488, 17.624, 18.668, 19.077, 19.758, 20.166, 20.439, 20.848, 21.302, 21.665, 22.164, 23.027, 23.572, 23.890, 24.299, 24.753, 26.160, 26.433, 26.978, 28.022, 29.203, 31.155, and 32.654.

[0043] Theoretical PXRD spectrum of the co-crystal of the present invention simulated by Mercury software ( Figure 4 2) and the measured spectrum of the cocrystal ( Figure 4 1) is basically consistent, indicating that the co-crystal prepared by the present invention has high purity.

[0044] [Example 6] DSC graph of hydrogen bonded co-crystal of aminoglutethimide and 3,5-dinitrobenzoic acid

[0045] The DSC of a hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention is as follows: Figure 5 . The DSC analysis results show that there is only one strong endothermic peak in the range of room temperature to 250°C, and the melting point (peak value) is 166.39°C, which is the single crystal endothermic peak of the hydrogen-bonded eutectic of the present invention. The melting point of aminoglutethimide raw material is 153.44°C, and the melting point of 3,5-dinitrobenzoic acid is 206.18°C. The melting point of the hydrogen-bonded eutectic of the present invention is between the two starting materials.

[0046] [Example 7] FTIR image of hydrogen bonded co-crystal synthesized from aminoglutethimide and 3,5-dinitrobenzoic acid

[0047] The FTIR of a hydrogen bonded eutectic synthesized from aminoglutethimide and 3,5-dinitrobenzoic acid of the present invention is as follows: Figure 6 .exist Figure 6 The characteristic absorption peaks of the hydrogen bond eutectic of the present invention are shown at 1696.3345cm-1, 1621.5352cm-1, 1537.1002cm-1, 1338.4861cm-1, 1187.8465cm-1 and 536.3539cm-1.

[0048] The absorption peaks of amino (-NH2)-NH2, carbonyl (-C=O) and nitro (-NO2) in the aminoglutethimide raw material molecule have all changed. The symmetric and asymmetric stretching vibration peaks of -NH2 in the aminoglutethimide molecule at 2800-3000 cm-1 disappeared, and the strong absorption peak of the stretching vibration of the carbonyl (-C=O) in the molecule shifted to 1696.3345 cm-1. The asymmetric stretching vibration absorption peak of the nitro (-NO2) in 3,5-dinitrobenzoic acid shifted to 1621.5352 cm-1 and 1537.1002 cm-1.

[0049] [Example 8] Test of co-crystal solubility

[0050] The solubility and intrinsic dissolution rate (IDR) of the hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid synthesized by 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 cocrystal have been significantly improved compared with the raw material aminoglutethimide itself.

[0051] References

[0052] [1]Wermuth C G.The practice of medicinal chemistry(3rd Ed.).AcademicPress,2009.

[0053] [2]Song,J.,et al.Improving the Solubility of Lenalidomide viaCocrystals[J].Crystal growth&design,2014.14(6):3069-3077.

[0054] [3]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.

[0055] [4]Aakeroy C B.Crystal Engineering:Strategies and Architectures[J].Acta Crystallographica Section B.1997,53(4):569-586

[0056] [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.

[0057] [6]Lu E,Rodríguez-Hornedo N,Suryanarayanan R.A rapid thermal methodfor cocrystal screening[J].Crystengcomm,2008.10(6):665-668.

[0058] [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.

[0059] [8]Bag P P,C.M.Reddy.Screening and Selective Preparation ofPolymorphs by Fast Evaporation Method:A Case Study of Aspirin,AnthranilicAcid,and Niflumic Acid[J].Crystal Growth&Design,2012.12(6):2740-2743.

[0060] [9]Remenar J F,et al.Crystal engineering of novel cocrystals of atriazole drug with 1,4-dicarboxylic acids[J].Journal of the American ChemicalSociety,2003.125(28)。

Claims

1. A hydrogen bond eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid, characterized in that: The molecular formula of the co-crystal is [(C 13 H 16 N2O2)·(C7H4N2O6)], with a melting point of 166.39°C; it is a molecular structure composed of an aminoglutethimide molecule and a 3,5-dinitrobenzoic acid molecule bonded together by intermolecular hydrogen bonds, belonging to the triclinic system, with a space group of P-1 and unit cell parameters of: α=74.156(3)°, β=88.190(3)°, γ=72.032(3)°, Its XRD characteristic diffraction peaks appear at 6.271, 11.493, 12.674, 13.401, 14.082, 16.488, 17.624, 18.668, 19.077, 19.758, 20.166, 20.439, 20.848, 21.302, 21.665, 22.164, 23.027, 23.572, 23.890, 24.299, 24.753, 26.160, 26.433, 26.978, 28.022, 29.203, 31.155, and 32.

654.

2. A method for preparing a hydrogen bonded eutectic of aminoglutethimide and 3,5-dinitrobenzoic acid, using a solution crystallization method, the preparation method comprising the following steps: (1) adding aminoglutethimide and 3,5-dinitrobenzoic 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 3,5-dinitrobenzoic acid.

3. The method for preparing the co-crystal according to claim 2, characterized in that: The molar ratio of aminoglutethimide to 3,5-dinitrobenzoic 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 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 1-10 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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