AU2021105917A4 - Ornidazole medicine eutectic and preparation method thereof - Google Patents
Ornidazole medicine eutectic and preparation method thereof Download PDFInfo
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- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 title claims abstract description 127
- 229960002313 ornidazole Drugs 0.000 title claims abstract description 127
- 230000005496 eutectics Effects 0.000 title claims abstract description 93
- 239000003814 drug Substances 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 83
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- NJESAXZANHETJV-UHFFFAOYSA-N 4-methylsalicylic acid Chemical compound CC1=CC=C(C(O)=O)C(O)=C1 NJESAXZANHETJV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000013078 crystal Substances 0.000 claims abstract description 22
- 230000009471 action Effects 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims description 42
- 238000002156 mixing Methods 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 29
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000007789 sealing Methods 0.000 claims description 13
- 238000000227 grinding Methods 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000013638 trimer Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000010586 diagram Methods 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002243 precursor Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000884 anti-protozoa Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004323 axial length Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides ornidazole drug eutectic and a preparation method
thereof, belonging to the technical field of drug eutectic. According to the ornidazole
drug eutectic provided by the invention, the basic structural units comprise an
ornidazole molecule and a 4- methylsalicylic acid molecule, and the ornidazole
molecule and the 4- methylsalicylic acid molecule are connected by hydrogen bonds;
The ornidazole drug eutectic belongs to orthogonal crystal system, and the space
group is P212 12 1. The unit cell parameters are: a=7.0484(8), b=9.4098(13),
c=25.566(3),a=90°, 0=90°, y=90°. Unit cell volume V=1695.7(4)A3, Z=4. On the
basis of inheriting various pharmacological actions of the raw material medicine
ornidazole, the ornidazole medicine eutectic provided by the invention has obviously
improved thermodynamic stability and stable chemical properties.
Description
Ornidazole medicine eutectic and preparation method thereof
TECHNICAL FIELD The invention relates to the technical field of drug eutectic, in particular to ornidazole drug eutectic and a preparation method thereof.
BACKGROUND Drug research and development is a long, expensive and arduous process in pharmaceutical industry, usually accompanied by high risk and low success rate, and less than 1% of pharmaceutical active ingredients (API) have been successfully developed and appeared in the market. The main challenge of successful drug development is the physical and chemical properties of API, such as solubility, permeability, bioavailability and stability. Generally, the properties of materials depend on their solid structure, so the change of solid structure can improve the properties of drug molecules. Crystal engineering is defined as the application of supramolecular chemistry concept in crystalline solids, which is considered as the actual manifestation of molecular recognition and self-assembly. It involves changing the molecular noncovalent interactions to change the crystal stacking of solid materials, such as hydrogen bonding, van der Waals force, -rr-stacking and electrostatic interaction. Eutectic crystal is a crystal engineering method that uses complementary molecules based on supramolecular chemistry and molecular recognition principle to produce new multi-component crystalline solid materials. Based on the principle of crystal engineering, it can be used to prepare drug eutectic with the aim of improving the solid properties of API without changing its inherent covalent structure. At present, the application of drug eutectic in modifying the physical and chemical properties of API has begun to gain attention, and many drugs on the market have been studied by eutectic, such as acetaminophen, aspirin, ibuprofen, flurbiprofen tablets, etc. It has also been reported that a dicarboxylic acid antituberculous drug is prepared by using carboxylic acid and pyrimidine through eutectic technology. However, the eutectic of ornidazole has not been reported.
SUMMARY The invention aims to provide an ornidazole drug eutectic and a preparation method thereof. In the invention, the ornidazole drug eutectic is formed by hydrogen bonding with 4-methylsalicylic acid as a precursor. On the basis of inheriting various pharmacological effects of the ornidazole drug eutectic, its thermodynamic stability is obviously improved and its chemical properties are stable. In order to achieve the above object of the invention, the present invention provides the following technical scheme: This invention provides Ornidazole drug eutectic, which is characterized in that the basic structural unit comprises an ornidazole molecule and a 4-methylsalicylic acid molecule, and the ornidazole molecule and the 4-methylsalicylic acid molecule are connected by hydrogen bonds. The ornidazole drug eutectic belongs to orthogonal crystal system, and the space group is P212121. The unit cell parameters are: a=7.0484(8), b=9.4098(13), c=25.566(3), a=900 , @=900, y=90°. Unit cell volume
V=1695.7(4)A, Z=4. Preferably, the occurrence positions of XRD characteristic diffraction peaks of the ornidazole drug eutectic includel1.530 , 14.090, 16.260, 17.060, 18.770, 19.800, 23.460, 25.05°, 28.02° and 32.01°. Preferably,the ornidazole drug eutectic has a three-dimensional supramolecular network structure, wherein in the A-axis direction, oxygen atoms of hydroxyl groups in ornidazole molecules act as hydrogen bond donors and oxygen atoms of nitro groups in ornidazole molecules act as hydrogen bond receptors to form 06-H6.. .05 hydrogen bonds, and two ornidazole molecules and one 4- methylsalicylic acid molecule pass through 06-H6 .... The trimer forms a one-dimensional supramolecular chain structure through the action of O-H-O hydrogen bond; Adjacent one-dimensional supramolecular chain structures form a two-dimensional supramolecular layered structure through Cl H1B...01 hydrogen bonding; The two-dimensional supramolecular layered structure forms the three-dimensional supramolecular network structure through 03-H3 ... N1 hydrogen bonding. Preferably, the ornidazole drug eutectic is colorless and rod-shaped with a density of 1.456g/cm 3
The invention provide a preparation method of ornidazole drug eutectic according to that technical scheme, which comprise the following steps: (1) Grinding and mixing ornidazole and 4methylsalicylic acid to obtain a first mixed material. (2) Mixing the first mixed material with a methanol-water solvent to obtain a second mixed material. (3) Standing the second mixed material at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. Preferably, the grinding and mixing time is 20-30 min. Preferably, the volume ratio of methanol to water in the methanol-water solvent is 1: (1-2). Preferably, the consumption ratio of the first mixed material to the methanol-water solvent is (0.0186-0.0372) g: 5ml. Preferably, the steps (2) and (3) are specifically: (2) Placing the first mixed material and methanol-water solvent in a mixing container, sealing the mixing container with a sealing film, and mixing to obtain a second mixed material. (3) Standing the mixing container filled with the second mixed material and sealed by the sealing film at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. Preferably, the mixing treatment is carried out in a shaker, and the operating conditions of the mixing treatment include room temperature, 1.5-2.5h, and the rotating speed of the shaker is 180-220rpm. (4) The invention provides an ornidazole drug eutectic, the basic structural unit comprises an ornidazole molecule and a 4- methylsalicylic acid molecule, and the ornidazole molecule and the 4- methylsalicylic acid molecule are connected by hydrogen bonds; The ornidazole drug eutectic belongs to orthogonal crystal system, and the space group is P212121. The unit cell parameters are:The unit cell parameters are: a=7.0484(8), b=9.4098(13), c=25.566(3), a=90°, P=90°, y=90°. Unit cell volume
V=1695.7(4)A3, Z=4.
According to the invention, ornidazole as a pharmaceutical active ingredient (API) and 4-methylsalicylic acid as a precursor (CCF) are connected by hydrogen bonds to form ornidazole pharmaceutical eutectic, and the basic structural units of the ornidazole pharmaceutical eutectic comprise an ornidazole molecule and a 4- methylsalicylic acid molecule, namely the molar ratio of ornidazole to 4-methylsalicylic acid is 1: 1. On the basis of inheriting various pharmacological actions of the raw material medicine ornidazole, the thermodynamic stability of the ornidazole eutectic provided by the invention is obviously improved, and the skeleton structure of the crystal can still be maintained after being placed at room temperature for one year, and the chemical properties are stable. The invention provides a preparation method of ornidazole drug eutectic, which comprises the following steps: (1) grinding and mixing ornidazole and 4methylsalicylic acid to obtain a first mixed material; (2) mixing the first mixed material with a methanol water solvent to obtain a second mixed material; (3) standing the second mixed material at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. According to the invention, methanol and water are used as solvents, and ornidazole drug eutectic is prepared by a grinding-solvent slow volatilization method; the method is simple and feasible, the operating conditions are mild and easy to control, and the reproducibility is good; and the method is convenient to be widely popularized in industrial pharmacy, thereby greatly reducing the production cost and cycle, avoiding the problems of too long eutectic synthesis time, complicated process and the like in the existing method for preparing drug eutectic, greatly improving the success rate of drug eutectic formation, and having great commercial application value.
BRIEF DESCRIPTION OF THE FIGURES Fig. 1 is a physical diagram of ornidazole drug eutectic. Fig. 2 is a schematic diagram of asymmetric structural units of ornidazole drug eutectic. Fig. 3 is a schematic diagram of one-dimensional supramolecular chain structure of ornidazole drug eutectic.
Fig. 4 is a schematic diagram of the two-dimensional supramolecular layered structure of ornidazole drug eutectic. Fig. 5 is a schematic diagram of the three-dimensional supramolecular network structure of ornidazole drug eutectic. Fig. 6 is an x-ray powder diffraction (XRD) diagram of ornidazole drug eutectic. Fig. 7 is an infrared spectrum of ornidazole drug eutectic.
DESCRIPTION OF THE INVENTION This invention provides Ornidazole drug eutectic, which is characterized in that the basic structural unit comprises an ornidazole molecule and a 4-methylsalicylic acid molecule, and the ornidazole molecule and the 4-methylsalicylic acid molecule are connected by hydrogen bonds. The ornidazole drug eutectic belongs to orthogonal crystal system, and the space group is P212121. The unit cell parameters are: a=7.0484(8), b=9.4098(13),
c=25.566(3), a=900 , P=90 0 , y=90 0. Unit cell volume V=1695.7(4)A , Z=4. Ornidazole (ORL for short) is the third generation nitroimidazole solid drug with anti protozoan and anti-bacterial effects, which is widely used in clinic after metronidazole and tinidazole. It has anti-protozoan and anti-bacterial properties against anaerobic bacteria, and is mainly used to treat severe liver and intestinal amoebic diseases, and to treat and prevent susceptible anaerobic bacteria infection in gastric surgery. It is also sold as a combined preparation with fluoroquinolone antibiotic ofloxacin for the treatment of bacterial infections; In addition, it is also suitable for treating Crohn's disease and poultry infection. However, due to the complete and rapid absorption and short biological half-life of ornidazole after oral administration, it is necessary to deliver the drug in a more durable way to improve bioavailability. On the basis of inheriting various pharmacological actions of the raw material medicine ornidazole, the ornidazole medicine eutectic provided by the invention has obviously improved thermodynamic stability and stable chemical properties. According to the invention, ornidazole is used as a pharmaceutical active ingredient and 4- methylsalicylic acid is used as a precursor; ornidazole contains a functional group capable of forming hydrogen bonds, and has the capability of forming strong hydrogen bonds with the precursor 4-methylsalicylic acid; the ornidazole drug eutectic is formed by hydrogen bonding; and the basic structural unit comprises an ornidazole molecule and a 4-methylsalicylic acid molecule, namely the molar ratio of ornidazole to 4 methylsalicylic acid is 1: 1. Particularly, the molecular formula of ornidazole drug eutectic is (C7HioO3N3C)-(CH803), wherein the molecular formula of ornidazole is C7H101CIN303. In this invention , the occurrence positions of XRD characteristic diffraction peaks of the ornidazole drug eutectic include 11.530, 14.090, 16.260, 17.060, 18.770, 19.800, 23.460, 25.050, 28.020 and 32.010. In the present invention, the ornidazole drug eutectic preferably has a three dimensional supramolecular network structure, wherein in the A-axis direction, the oxygen atom of hydroxyl in ornidazole molecule as hydrogen bond donor and the oxygen atom of nitro in ornidazole molecule as hydrogen bond acceptor form 06-H6.. .05 hydrogen bond, and two ornidazole molecules and one 4- methylsalicylic acid molecule pass through 06-H6...05 and C15-H15B The trimer forms a one-dimensional supramolecular chain structure through the action of 0-H-0 hydrogen bond; Adjacent one-dimensional supramolecular chain structures form a two-dimensional supramolecular layered structure through C1-H1B...01 hydrogen bonding; The two dimensional supramolecular layered structure forms the three-dimensional supramolecular network structure through 03-H3...N1 hydrogen bonding. In the present invention, the ornidazole drug eutectic is colorless and rod-shaped, and the density is preferably 1.456g/cm3. The invention provide a preparation method of ornidazole drug eutectic according to that technical scheme, which comprise the following steps: (1) Grinding and mixing ornidazole and 4methylsalicylic acid to obtain a first mixed material. (2) Mixing the first mixed material with a methanol-water solvent to obtain a second mixed material. (3) Standing the second mixed material at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. According to the invention, ornidazole and 4methylsalicylic acid are ground and mixed to obtain a first mixed material. In the present invention, the molar ratio of ornidazole to 4methylsalicylic acid is preferably 1:(1-2), more preferably 1: 1. In the present invention, the grinding and mixing time is preferably 20-30 min, more preferably min. In the present invention, the grinding mixing is preferably carried out in an agate mortar. According to the invention, reactants can be fully contacted by grinding to realize uniform mixing, which is beneficial to generating hydrogen bond precursors (i.e., first mixed materials). After obtaining a first mixed material, the invention mixes the first mixed material with a methanol-water solvent to obtain a second mixed material. In the present invention, the volume ratio of methanol to water in the methanol-water solvent is preferably 1: (1-2), more preferably 1:1. In the present invention, the consumption ratio of the first mixed material to the methanol-water solvent is preferably (0.0186-0.0372) g: ml, more preferably 0.0186 g:5ml. In the invention, the methanol-water solvent is used as a reaction medium, so that the polarity of the solution can be adjusted, which is beneficial to the dissolution of organic molecules and the generation of ornidazole drug eutectic. According to the invention, the first mixed material and the methanol-water solvent are preferably placed in a mixing container, the mixing container is sealed by a sealing film, and the second mixed material is obtained after mixing treatment. In the present invention, there is no special limitation on the specific operation mode of sealing the mixing container with the sealing film, and it is only necessary to adopt a mode well known to those skilled in the art. In the present invention, the mixing container is preferably a beaker. In the present invention, the mixing treatment is preferably performed in a shaking table, specifically, a mixing container containing the first mixed material and the methanol-water solvent and sealed by a sealing film is placed in the shaking table for mixing treatment. In the present invention, the operating conditions of the mixing treatment include: the temperature is room temperature, that is, no additional heating or cooling is needed, and in the embodiment of the present invention, the room temperature is specifically 25 0C.The time is preferably 1.5-2.5h, more preferably 2h. The rotate speed of that shaking table is preferably 180-220rpm, more preferably 200rpm. After obtaining the second mixed material, the invention stands the second mixed material at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. According to the invention, the mixing container filled with the second mixed material and sealed by the sealing film is preferably left standing at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic. According to the invention, the methanol-water solvent is slowly volatilized by standing at room temperature, so that the drug eutectic grows and precipitates out of the solvent, and finally the ornidazole drug eutectic is obtained. In the embodiment of the invention, a second mixed material based on 0.011Og of ornidazole, 0.0076g of 4 methylsalicylic acid and 5mL of methanol-water solvent (the volume ratio of methanol to water is 1: 1) is allowed to stand at room temperature for 7 days, and colorless rod crystals are precipitated, namely ornidazole drug eutectic. In the following, the technical scheme of the present invention will be described clearly and completely in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative labor belong to the scope of protection of the present invention. In the embodiment of the invention, the instruments for detecting the eutectic structure and performance of ornidazole drugs are as follows: Single crystal diffraction characterization: Agilent Technologies Gemini A Ultra Atlas CCD single crystal diffractometer, using Mo-Ka ray, radiation wavelength 0.71073A, crystal structure using SHELXL software package, structure analysis by direct method, and F2 finishing by least square method; Use Diamond and MerCury software to obtain the structure diagram. Powder X- ray diffraction (XRD) characterization: RINT2000 vertical goniometer X ray diffractometer; Power 40kV/150mA, scanning range 2°~50°. Step width 0.020. Scanning speed is 10/min. Infrared spectrum characterization: Nicolet Impact 410 FTIR spectrometer, measuring range 4000-400cm1, KBr tabletting. Embodiment 1 Accurately weigh 0.011Og of ornidazole and 0.0076g of 4-methylsalicylic acid in an agate mortar with an analytical balance, and grind for 25min to obtain a first mixed material. Transfer all the first mixed materials in agate mortar to a 25mL beaker, accurately add 2.5mL methanol and 2.5mL water with a pipette gun, and seal the beaker with a sealing film; Put the beaker in a shaking table and shake it at room temperature (25 0C) for 2h at 200r/min to obtain a second mixed material; Take the beaker containing the second mixed material and sealed by the sealing film out of the shaking table, and let it stand at room temperature to volatilize methanol and water slowly. After 7 days, colorless rod crystals are precipitated, which is ornidazole drug eutectic. Fig. 1 is a physical diagram of the ornidazole drug eutectic. It can be seen from fig. 1 that the ornidazole drug eutectic has a colorless rod structure with a size of 0.06mmxO.02nmxO.02nm. Fig. 2 is a schematic diagram of asymmetric structural unit of ornidazole drug eutectic. It can be seen from Fig.2 that ornidazole and 4-methylsalicylic acid successfully react to form ornidazole drug eutectic. The eutectic structure of ornidazole prepared in this example was characterized and its properties were tested as follows: 1. The crystal structure of ornidazole drug eutectic is analyzed. The results show that the basic structural unit of ornidazole drug eutectic is composed of one ornidazole molecule (1) and one 4- methylsalicylic acid (2). In the A-axis direction, the oxygen atom of hydroxyl in ornidazole molecule as hydrogen bond donor and the oxygen atom of nitro in ornidazole molecule as hydrogen bond acceptor form 06-H6.. .05 hydrogen bond, and two ornidazole molecules and one 4- methylsalicylic acid molecule interact through 06-H6 ... 05,C15-H15B ... 01 and C9-H9 ... 02 hydrogen bonds to form one. The trimer forms a one-dimensional supramolecular chain structure (as shown in Fig.3). Through O-H . --Ohydrogen bonding; Adjacent one-dimensional supramolecular chain structures form a two-dimensional supramolecular layered structure through hydrogen bonding C1-H1B- -. 01(as shown in Fig.4); The two-dimensional supramolecular layered structure continues to form a three-dimensional supramolecular network structure by weak 03-H3 ... n1 hydrogen bonding (as shown in Fig. 5). 2. The ornidazole drug eutectic was characterized by X-ray single crystal diffraction. The X-ray single crystal diffraction data showed that the ornidazole drug eutectic belongs to orthogonal crystal system, with space group P212121, and its axial length a=7.0484(8), b=9.4098(13), c=25.566(3), axial angle a=90°, 0=90°, y=9 0 ° The unit cell volume V=1695.7(4)A3 , Z=4 , density Dx=1.456g/cm3, and its molecular formulaic (C 7 HoO 3N 3Cl)-(C 8H 80 3). The ornidazole drug eutectic was characterized by powder X-ray diffraction (XRD). As shown in Figure 6, the XRD characteristic diffraction peaks of ornidazole drug eutectic appeared at 11.530,14.090,16.260,17.060,18.770,19.800,23.460,25.050,28.020 and 32.01°. At the same time, it can be seen from Fig. 6 that the theoretical XRD data is consistent with the experimental XRD data, indicating that the ornidazole drug eutectic prepared by the invention is relatively pure. The crystallographic parameters of the ornidazole drug eutectic are shown in Table 1, the hydrogen bond geometry size is shown in Table 2, and the atomic coordinates and temperature factors are shown in Table 3. Table 1 Crystallization parameters of ornidazole drug eutectic crystal system orthorhombic system space groups P212 12 1 molecular formula (C 7H 1 00 3N 3 Cl)-(C 8H 80 3
) molecular weight 371.77 a=7.0484(8) b=9.4098(13) c=25.566(3) cell parameters a=90°
p=90° y=90° Cell volume V=1695.7(4)A3
Z=4 Z (molecular/cell)
Density (g/cm 3) Dx=1.456
Table 2 Hydrogen bond geometry size of ornidazole drug eutectic D-H---A(A) (symmetry code) D-H(A) H - A(A) D---A(A) D-H---A(deg)
06-H6---05(1-x, 0.5+y, 1.5- 0.820 2.221 3.028 168.124
z)
C15-H15B---01(x, y, z) 0.969 2.528 3.372 145.518
C9-H9- --02(-0.5+x, 0.5-y, 0.931 2.395 3.280 158.639
1-z)
C1-H1B. 01(x, y, z) 0.960 2.703 3.545 146.719
03-H3---N1(x, y, z) 0.820 1.847 2.644 163.453
Table 3 Atomic coordinates and temperature factors of ornidazole drug eutectic Atom x y z U(eq)
C1I 11693.9(16) 3169.5(15) 7237.2(5) 77.3(4) 03 2644(4) 4491(3) 5091.2(11) 54.2(7) 02 4940(4) 4865(3) 4514.5(11) 61.4(8) N2 6465(4) 1963(3) 6323.0(11) 37.0(7) N3 4085(5) 362(3) 6726.2(13) 48.8(8) 01 4403(4) 6701(4) 3771.1(12) 67.7(8) 04 2488(4) -127(3) 6679.5(12) 68.8(9) 06 7548(5) 4066(3) 7048.7(12) 69.5(9) NI 4742(4) 2746(3) 5658.8(12) 46.2(8) 05 5114(4) 68(3) 7097.9(13) 71.1(9) C5 2066(5) 6141(4) 4425.2(13) 39.1(8)
C1O 4701(5) 1330(4) 6340.6(14) 38.7(8) C8 3348(5) 5120(4) 4677.4(14) 43.4(9) C6 2647(5) 6871(4) 3979.0(14) 45.3(9) C11 6410(5) 2828(4) 5901.3(14) 41.7(9) C9 3689(5) 1809(4) 5930.7(15) 44.3(9) C2 -373(5) 8039(4) 3915.3(15) 47.4(10) C13 8099(5) 1802(4) 6675.2(14) 42.9(9) C7 1436(6) 7806(4) 3732.2(16) 49.9(10) C3 -960(6) 7315(4) 4361.3(16) 49.0(10) C4 227(5) 6387(4) 4609.1(14) 44.3(9) C14 7892(5) 2638(4) 7175.3(15) 44.0(9) C15 9602(5) 2448(4) 7519.6(15) 49.4(10) C12 7987(6) 3733(5) 5719.4(16) 58.4(11) C1 -1684(7) 9041(5) 3638.3(18) 65.7(12)
3. Fig.7 shows the infrared spectrum of ornidazole drug eutectic. It can be seen from Fig.7 that ornidazole and 4- methylsalicylic acid are contained in eutectic molecules, which proves that ornidazole and 4- methylsalicylic acid are both involved in the formation of eutectic. 4. The ornidazole drug eutectic prepared in Example 1 was placed at room temperature and air atmosphere, and the skeleton structure of the crystal could still be maintained after one year, with stable chemical properties. The above is only the preferred embodiment of the present invention, and it should be pointed out that for ordinary people in the technical field, without departing from the principle of the present invention, several improvements and embellishments can be made, and these improvements and embellishments should also be regarded as the protection scope of the present invention.
Claims (9)
- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Ornidazole drug eutectic, which is characterized in that the basic structural unit comprises an ornidazole molecule and a 4-methylsalicylic acid molecule, and the ornidazole molecule and the 4-methylsalicylic acid molecule are connected by hydrogen bonds. The ornidazole drug eutectic belongs to orthogonal crystal system, and the space group is P212121. The unit cell parameters are: a=7.0484(8), b=9.4098(13),c=25.566(3), a=900 , P=900, y=900 . Unit cell volume V=1695.7(4)A3, Z=4. The ornidazole drug eutectic according to claim 1, which is characterized in that the occurrence positions of XRD characteristic diffraction peaks of the ornidazole drug eutectic include 11.530,14.090,16.260,17.060,18.770,19.800,23.460,25.050,28.02° and 32.010.
- 2. The ornidazole drug eutectic according to claim 1, characterized in that the ornidazole drug eutectic has a three-dimensional supramolecular network structure, wherein in the A-axis direction, oxygen atoms of hydroxyl groups in ornidazole molecules act as hydrogen bond donors and oxygen atoms of nitro groups in ornidazole molecules act as hydrogen bond receptors to form 06-H6 ... 05 hydrogen bonds, and two ornidazole molecules and one 4- methylsalicylic acid molecule pass through 06-H6 .... The trimer forms a one-dimensional supramolecular chain structure through the action of 0-H-0 hydrogen bond; Adjacent one-dimensional supramolecular chain structures form a two-dimensional supramolecular layered structure through C1-H1B ... 01 hydrogen bonding; The two-dimensional supramolecular layered structure forms the three-dimensional supramolecular network structure through 03-H3 ... N1 hydrogen bonding.
- 3. The ornidazole drug eutectic according to any one of claims 1 to 3, which is characterized in that the ornidazole drug eutectic is colorless and rod-shaped with a density of 1.456g/cm 3
- 4. The preparation method of ornidazole drug eutectic according to any one of claims 1 to 4 is characterized by comprising the following steps: (1) Grinding and mixing ornidazole and 4methylsalicylic acid to obtain a first mixed material. (2) Mixing the first mixed material with a methanol-water solvent to obtain a second mixed material.(3) Standing the second mixed material at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic.
- 5. The preparation method according to claim 5, wherein the grinding and mixing time is 20-30 min.
- 6. The preparation method according to claim 5, wherein the volume ratio of methanol to water in the methanol-water solvent is 1: (1-2).
- 7. The preparation method according to claim 7, wherein the consumption ratio of the first mixed material to the methanol-water solvent is (0.0186 ~ 0.0372) g: 5ml.
- 8. The preparation method according to claim 5, wherein the steps (2) and (3) specifically comprise: (2) placing the first mixed material and methanol-water solvent in a mixing container, sealing the mixing container with a sealing film, and mixing to obtain a second mixed material; And (3) standing the mixing container filled with the second mixed material and sealed by the sealing film at room temperature to volatilize the methanol-water solvent and precipitate the ornidazole drug eutectic.
- 9. The preparation method according to claim 9, wherein the mixing treatment is carried out in a shaking table, and the operating conditions of the mixing treatment include room temperature, time of 1.5-2.5h, and the rotating speed of the shaking table of 180-220 rpm.
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