CN116444422A - Hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid and synthesis method thereof - Google Patents
Hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid and synthesis method thereof Download PDFInfo
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- CN116444422A CN116444422A CN202210011760.7A CN202210011760A CN116444422A CN 116444422 A CN116444422 A CN 116444422A CN 202210011760 A CN202210011760 A CN 202210011760A CN 116444422 A CN116444422 A CN 116444422A
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- aminoglutethimide
- methylbenzoic acid
- hydrogen bond
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- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960003437 aminoglutethimide Drugs 0.000 title claims abstract description 69
- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 57
- 239000001257 hydrogen Substances 0.000 title claims abstract description 57
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 239000013078 crystal Substances 0.000 title claims abstract description 49
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 230000005496 eutectics Effects 0.000 claims abstract description 36
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008018 melting Effects 0.000 claims abstract description 3
- 238000002844 melting Methods 0.000 claims abstract description 3
- 238000012360 testing method Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
- 239000003755 preservative agent Substances 0.000 claims description 11
- 230000002335 preservative effect Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 230000007704 transition Effects 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 11
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 description 6
- 229960002972 glutethimide Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000014311 Cushing syndrome Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 238000004080 punching Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UVBMFLQXZPETMM-UHFFFAOYSA-N 3-(2-aminophenyl)-3-ethylpiperidine-2,6-dione Chemical compound C=1C=CC=C(N)C=1C1(CC)CCC(=O)NC1=O UVBMFLQXZPETMM-UHFFFAOYSA-N 0.000 description 1
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000037171 Hypercorticoidism Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000002454 adrenal cortex cancer Diseases 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 201000005255 adrenal gland hyperfunction Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 208000025854 malignant tumor of adrenal cortex Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960000249 pregnenolone Drugs 0.000 description 1
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/14—Monocyclic dicarboxylic acids
- C07C63/15—Monocyclic dicarboxylic acids all carboxyl groups bound to carbon atoms of the six-membered aromatic ring
- C07C63/24—1,3 - Benzenedicarboxylic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid and a synthesis method thereof. The molecular formula of the eutectic is [ (C) 13 H 16 N 2 O 2 )·(C 8 H 8 O 2 )]The melting point is 122.8 ℃, and the molecular structure is formed by combining an aminoglutethimide molecule and an m-methylbenzoic acid molecule together through intermolecular hydrogen bonds, and belongs to a monoclinic system. The invention relates to a hydrogen bond eutectic synthesized by a solution crystallization method. The co-crystal of the invention is a brand new compound, which is not reported in the literature. The eutectic obviously improves the water dissolution and dissolution rate of the aminoglutethimide raw material medicine. The novel hydrogen bond eutecticThe preparation method has commercial application value and clinical application prospect.
Description
Technical Field
The invention relates to a synthesis method of a novel co-crystal of adrenocortical hormone inhibition antitumor drugs, in particular to a hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid and a synthesis method thereof.
Technical Field
The eutectic is a multicomponent crystal comprising both a binary eutectic formed between two neutral solids and a polynary eutectic formed between a neutral solid and a salt or solvate [1-4] . Advantages of the pharmaceutical co-crystal (1) the components of the pharmaceutical co-crystal may be neutral molecules, thus the pharmaceutical co-crystal may encompass all APIs, including acids, bases and non-ionized molecules. (2) Potentially can be used to prepareMany molecules that form co-crystals with API, which may include food additives, preservatives, pharmaceutical excipients, vitamins, minerals, amino acids, and other active molecules, and even other API. Can be prepared into eutectic by solution crystallization, mechanical grinding and melt crystallization, rapid evaporation, supercritical fluid, hot melt extrusion, wet compression, dry compression, etc [5-8] Among them, the solution crystallization method is most commonly used.
Aminoglutethimide (AG), also known as 3-ethyl-3- (-aminophenyl) -2, 6-piperidinedione. The composition has the effects of blocking cholesterol side chain cleavage in adrenal gland to be converted into pregnenolone and inhibiting in vivo aromatase, and is clinically used for treating advanced breast cancer (postmenopausal and estrogen receptor positive patients with better curative effects), ovarian cancer, prostate cancer and adrenal cortex cancer, and also used for hypercortisolism (cushing's syndrome) and cushing's syndrome caused by adrenal tumor. The medicine is slightly soluble (limit of slightly soluble substances) in water solution, and has solubility of about 0.2mg/ml [9] . The dissolubility of the aminoglutethimide in water is poor, which not only affects the bioavailability of the medicine, but also seriously affects the development and clinical use effects of the new medicine.
Disclosure of Invention
The invention provides a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid and a synthesis method thereof, which aim to solve the problem that the aminoglutethimide has poor water solubility and improve the water solubility of aminoglutethimide.
In the invention, the chemical name of the aminoglutethimide is 3-ethyl-3- (4-aminophenyl) -2, 6-piperidinedione, and the molecular formula is C 13 H 16 N 2 O 2 The structural formula is shown in figure a, and the molecular formula of the m-methylbenzoic acid is C 8 H 8 O 2 The corresponding structural formula is shown in the figure b.
The invention relates to a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid synthesized by adopting a solution crystallization method. The synthesis method comprises the following steps:
(1) Adding a certain molar ratio of aminoglutethimide and m-methylbenzoic acid into a 100mL flask, adding a certain volume of organic solvent into the flask, and heating for a certain time until the raw materials are completely dissolved to obtain a reaction solution.
(2) And (3) transferring the reaction solution into a 10mL clean test tube, sealing the test tube by using a preservative film, pricking a proper amount of small holes on the preservative film by using a needle tube, and volatilizing for a period of time at room temperature to obtain the hydrogen bond eutectic of the aminoglutethimide and the m-methylbenzoic acid.
(3) The molar ratio of the aminoglutethimide to the m-methylbenzoic acid is in the range of 1:0.2 to 0.2:1.
(4) The organic solvent comprises toluene, benzene, ethyl acetate, acetonitrile, methanol and ethanol, and the volume of the organic solvent is 3mL-5 mL.
(5) The heating temperature is between 40 ℃ and 70 ℃ and the heating time is between 3min and 10min.
(6) The test tube is pricked with a needle tube to form 1-10 holes.
(7) The reaction solution was volatilized at room temperature for about 2 to 10 days.
The hydrogen bond co-crystal of the aminoglutethimide and the m-methylbenzoic acid has the following characteristics:
(1) The molecular formula is [ (C) 13 H 16 N 2 O 2 )·(C 8 H 8 O 2 )]Is that one aminoglutethimide molecule and one m-methylbenzoic acid molecule pass through intermolecular hydrogen bond (O 2 -H 2 …N 2 ，2.4148(28)，<(DHA) = 104.322 (248) °) is a monoclinic system, and the space group is 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 peak appears 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 was 122.8 ℃.
(2) The hydrogen bond co-crystal of the aminoglutethimide and the m-methylbenzoic acid is detected and verified by means of single crystal diffraction (SCXRD), X-ray powder diffraction (PXRD), a Differential Scanning Calorimeter (DSC), a thermogravimetric analyzer (TG) and an infrared spectrum (FTIR).
(3) The invention detects the water solubility of hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid. The measuring means is ultraviolet spectrophotometry, the dissolution medium is phosphate buffer solution with pH of 7.2, and the dissolution degree and the intrinsic dissolution rate are measured.
The beneficial effects of the invention are as follows:
(1) The compound prepared by adopting the eutectic strategy can effectively modify the original active pharmaceutical ingredient-aminoglutethimide, and after the eutectic is formed, the dissolution rate and the intrinsic dissolution rate of the eutectic in water are obviously higher than those of the aminoglutethimide bulk drug, namely the eutectic obviously improves the water solubility of the aminoglutethimide bulk drug, thereby being beneficial to obviously improving the bioavailability of the aminoglutethimide;
(2) The hydrogen bond eutectic of the aminoglutethimide and the m-methylbenzoic acid synthesized by the invention is a brand new compound, and is not reported in the literature;
(3) The hydrogen bond eutectic of the aminoglutethimide and the m-methylbenzoic acid synthesized by the invention is used as a novel crystal form of the aminoglutethimide anticancer drug, prolongs the market period from the aspect of intellectual property protection, and has very important clinical application prospect;
(4) The preparation method for synthesizing the hydrogen bond eutectic compound of the aminoglutethimide and the m-methylbenzoic acid is simple and easy to implement, has good reproducibility, high purity of the eutectic compound product, is easy to realize large-scale industrial production, has low cost and has higher commercial application value.
Drawings
The invention is further described below with reference to the drawings and examples of implementation.
FIG. 1 is a schematic diagram of the basic structural unit of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid according to the present invention;
FIG. 2 is a diagram of hydrogen bond eutectic unit cell stacks of aminoglutethimide and m-methylbenzoic acid according to the present invention;
FIG. 3 is a graph of the hydrogen bonding co-crystal X-ray powder diffraction (PXRD) patterns of aminoglutethimide and m-methylbenzoic acid of the present invention. FIG. 3 is a graph of the 1-Mercury software modeling the PXRD spectrum of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid; 2-synthesizing a PXRD spectrum of the hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid;
FIG. 4 is a Differential Scanning Calorimeter (DSC) spectrum of a hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid of the present invention. The aminoglutethimide phase transition temperature in fig. 4 is 153.1 ℃; the phase transition temperature of the m-methylbenzoic acid is 114.2 ℃; the hydrogen bond eutectic phase transition temperature of aminoglutethimide and m-methylbenzoic acid is 122.8 ℃.
FIG. 5 is a hydrogen bond co-crystal infrared (FTIR) spectrum of aminoglutethimide and m-methylbenzoic acid of the present invention;
FIG. 6 is a graph of the thermogravimetric analysis (TG) of hydrogen bonding co-crystals of aminoglutethimide and m-methylbenzoic acid of the present invention;
FIG. 7 is a graph showing the dissolution of hydrogen bond co-crystals of aminoglutethimide and m-methylbenzoic acid in phosphate buffer solution in accordance with the present invention;
FIG. 8 is a graph of Intrinsic Dissolution Rate (IDR) of aminoglutethimide and m-methylbenzoic acid hydrogen bond co-crystals in accordance with the present invention.
Detailed Description
Example 1 Synthesis of Hydrogen bond Co-crystals of Ammonia Lumide and Methylbenzoic acid
Ammonia glutethimide and m-methylbenzoic acid with the molar ratio of 1:0.5 are taken to be added into a 50mL flask, 10mL of organic solvent acetonitrile is added into the flask, and the mixture is heated at 50 ℃ for 5min until the raw materials are completely dissolved, so as to obtain a reaction solution. And (3) transferring the reaction solution into a 10mL clean test tube, sealing the test tube by using a preservative film, punching 10 small holes on the preservative film by using a needle tube, and volatilizing the test tube for 8 days at room temperature to obtain the hydrogen bond eutectic of the aminoglutethimide and the m-methylbenzoic acid.
Example 2 Synthesis of Hydrogen bond Co-crystals of Ammonia Lumide and Methylbenzoic acid
Ammonia glutethimide and m-methylbenzoic acid with the molar ratio of 1:1 are taken to be added into a 50mL flask, 5mL of organic solvent toluene is added into the flask, and the mixture is heated for 4min at 50 ℃ until the raw materials are completely dissolved, so as to obtain a reaction liquid. And (3) transferring the reaction solution into a 10mL clean test tube, sealing the test tube by using a preservative film, punching 5 small holes on the preservative film by using a needle tube, and volatilizing the test tube at room temperature for 10 days to obtain the hydrogen bond co-crystal of the aminoglutethimide and the m-methylbenzoic acid.
Example 3 Synthesis of Hydrogen bond Co-crystals of Ammonia Lumide and Methylbenzoic acid
Ammonia glutethimide and m-methylbenzoic acid with the molar ratio of 1:0.5 are taken to be added into a 50mL flask, 10mL of organic solvent methanol is added into the flask, and the mixture is heated at 60 ℃ for 3min until the raw materials are completely dissolved, so as to obtain a reaction solution. And (3) transferring the reaction solution into a 10mL clean test tube, sealing the test tube by using a preservative film, punching 8 small holes on the preservative film by using a needle tube, and volatilizing the test tube for 5 days at room temperature to obtain the hydrogen bond co-crystal of the aminoglutethimide and the m-methylbenzoic acid.
Example 4 crystallographic data of Hydrogen bond co-crystals of aminoglutethimide and Methylbenzoic acid
The basic structural unit diagram of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid is shown in figure 1; the unit cell stacking diagram of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid is shown in figure 2.
The molecular formula is [ (C) 13 H 16 N 2 O 2 )·(C 8 H 8 O 2 )]One aminoglutethimide molecule and one m-methylbenzoic acid molecule are bonded through intermolecular hydrogen bonds (O 2 -H 2 …N 2 ，2.4148(28)，<(DHA) = 104.322 (248) °) is a monoclinic system, and the space group is P2 (1)/n. The unit cell parameters are: α＝90°，β＝101.367(8)°，γ＝90°，V＝1913.3(9)A 3 ，Z＝4。
EXAMPLE 5 PXRD analysis of Hydrogen-bonded co-crystals of aminoglutethimide and m-methylbenzoic acid
In the hydrogen bond co-crystal PXRD spectrogram of the aminoglutethimide and the m-methylbenzoic acid, characteristic diffraction peaks appear at 6.58 degrees, 10.12 degrees, 10.69 degrees, 13.21 degrees, 14.74 degrees, 15.15 degrees, 15.8 degrees, 17.48 degrees, 19.0 degrees, 19.84 degrees, 21.09 degrees, 22.05 degrees, 22.51 degrees, 25.09 degrees, 25.59 degrees, 29.05 degrees, 34.69 degrees and 39.14 degrees.
The theoretical spectrogram (1 in figure 3) of the eutectic PXRD simulated by Mercury software is basically matched with the actual measurement spectrogram (2 in figure 3) of the eutectic, which shows that the purity of the eutectic prepared by the invention is higher.
Example 6 Hydrogen bond eutectic DSC analysis of Ammonia Lumide and Methylbenzoic acid
The DSC of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid is shown in figure 4.
The aminoglutethimide phase transition temperature in fig. 4 is 153.1 ℃; the phase transition temperature of the m-methylbenzoic acid is 114.2 ℃; the phase transition temperature of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid is 122.8 ℃. The melting point of the hydrogen bond eutectic is between two starting materials, and the hydrogen bond eutectic is a single crystal form endothermic peak.
Example 7 FTIR analysis of Hydrogen bond co-crystals of Ammonia glutethimide and Methylbenzoic acid
The FTIR of a hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid according to the invention is shown in FIG. 5. FIG. 5 shows the measurement at 3344.5cm -1 ，1711.43cm -1 ，1521.91cm -1 ，1372.05cm -1 ，1182.53cm -1 The characteristic absorption peak of the hydrogen bond eutectic of the present invention is at 3344.5cm -1 Is the symmetrical and asymmetrical stretching vibration peak of-NH 2 in the aminoglutethimide molecule, and the eutectic is 1711.43cm -1 Strong carbonyl-C=O telescopic vibration absorption peak appears at the position, and asymmetric telescopic vibration absorption peak of nitro appears at 1521.91cm < -1 > and 1372.05cm < -1 >, which proves that the ammonia glutethimide drug eutectic is formed.
EXAMPLE 8 TG analysis of Hydrogen bond co-crystals of Ammonia glutethimide and Methylbenzoic acid
FIG. 6 is a thermogravimetric analysis (TG) plot of the hydrogen bonding co-crystals of aminoglutethimide and m-methylbenzoic acid of the present invention. In fig. 6, under the nitrogen atmosphere test condition, the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid starts to lose weight at 116 ℃, the aminoglutethimide bulk drug starts to lose weight at 194 ℃, and the m-methylbenzoic acid starts to lose weight at 104 ℃.
Example 9 dissolution experiment of Hydrogen bond Co-crystals of Ammonia Lumide and Methylbenzoic acid
The dissolution and Intrinsic Dissolution Rate (IDR) of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid of the present invention in phosphate buffer solution at ph=7.2 are shown in fig. 7 and 8. As can be seen from fig. 7 and fig. 8, the dissolution rate and the intrinsic dissolution rate of the hydrogen bond co-crystal of aminoglutethimide and m-methylbenzoic acid are remarkably improved relative to those of the aminoglutethimide as a raw material medicine.
Reference to the literature
[1]Song,J.,et al.Improving the Solubility of Lenalidomide via Cocrystals[J].Crystal growth&design,2014.14(6):3069-3077.
[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 of Pharmaceutics&Biopharmaceutics,2016.107:151-159.
[3]Mnguni,et al.Binary polymorphic cocrystals:an update on the available literature in the Cambridge Structural Database,including a new polymorph of the pharmaceutical 1:1cocrystal theophylline–3,4-dihydroxybenzoic acid.Acta crystallographica.Section C[J],Structural chemistry,2018.74.
[4]Syed,S.A.A.,et al.Sulfaguanidine cocrystals:Synthesis,structural characterization and their antibacterial and hemolytic analysis[J].Journal of Pharmaceutical and Biomedical Analysis,2018.149.
[5]Childs S L,et al.Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine[J].Crystengcomm,2008.10(7):856-864.
[6]Lu E,Rodríguez-Hornedo N,Suryanarayanan R.A rapid thermal method for cocrystalscreening[J].Crystengcomm,2008.10(6):665-668.
[7]Bag P P,M.Patni,C.Malla Reddy.A kinetically controlled crystallization process for identifying new co-crystal forms:fast evaporation of solvent from solutions to dryness[J].Crystengcomm,2011.13(19):5650-5652.
[8]Bag P P,C.M.Reddy.Screening and Selective Preparation of Polymorphs by Fast Evaporation Method:A Case Study of Aspirin,Anthranilic Acid,and Niflumic Acid[J].Crystal Growth&Design,2012.12(6):2740-2743.
[9]Remenar J F,et al.Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids[J].Journal of the American Chemical Society,2003.125(28):8456-8457.
Claims (7)
1. A hydrogen bond eutectic of aminoglutethimide and m-methyl benzoic acid is characterized in that the molecular formula of the eutectic is [ (C) 13 H 16 N 2 O 2 )·(C 8 H 8 O 2 )]The melting point was 122.8 ℃. Is a molecular structure formed by combining an aminoglutethimide molecule and a m-methylbenzoic acid molecule through intermolecular hydrogen bonds, belongs to a monoclinic system, and has 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. The 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 was 122.8 ℃.
2. The invention relates to a hydrogen bond eutectic of aminoglutethimide and m-methylbenzoic acid synthesized by adopting a solution crystallization method. The synthesis method comprises the following steps:
(1) Adding a certain molar ratio of aminoglutethimide and m-methylbenzoic acid into a 100mL flask, adding a certain volume of organic solvent into the flask, and heating for a certain time until the raw materials are completely dissolved to obtain a reaction solution.
(2) And (3) transferring the reaction solution into a 10mL clean test tube, sealing the test tube by using a preservative film, pricking a proper amount of small holes on the preservative film by using a needle tube, and volatilizing for a period of time at room temperature to obtain the hydrogen bond eutectic of the aminoglutethimide and the m-methylbenzoic acid.
3. The method for preparing a pharmaceutical co-crystal of aminoglutethimide according to claim 2, wherein the molar ratio of aminoglutethimide to m-methylbenzoic acid is in the range of 1:0.2 to 0.2:1.
4. The method for preparing the aminoglutethimide pharmaceutical co-crystal according to claim 2, wherein the organic solvent comprises toluene, benzene, ethyl acetate, acetonitrile, methanol and ethanol, and the volume of the organic solvent is 3-5 mL.
5. The method for preparing aminoglutethimide pharmaceutical co-crystals according to claim 2, wherein the heating temperature is between 40 ℃ and 70 ℃ and the heating time is between 3min and 10min.
6. The method for preparing the aminoglutethimide pharmaceutical co-crystal according to claim 2, wherein a proper amount of small holes are punched in the test tube by needle tubes, and the number of the small holes is 1-10.
7. The method of claim 2, wherein the reaction solution is volatilized at room temperature for about 2-10 days.
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