CN107089946B - Norfloxacin and vanillin eutectic crystal and preparation method thereof - Google Patents
Norfloxacin and vanillin eutectic crystal and preparation method thereof Download PDFInfo
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- CN107089946B CN107089946B CN201710310135.1A CN201710310135A CN107089946B CN 107089946 B CN107089946 B CN 107089946B CN 201710310135 A CN201710310135 A CN 201710310135A CN 107089946 B CN107089946 B CN 107089946B
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- norfloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
- C07C47/58—Vanillin
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention belongs to the technical field of organic pharmaceutical co-crystals, and particularly relates to a norfloxacin and vanillin co-crystal and a preparation method thereof. The norfloxacin and vanillin eutectic crystal provided by the invention takes norfloxacin raw material medicines as API (active pharmaceutical ingredient), vanillin is a eutectic formation, and a series of characteristic peaks exist in XRD (x-ray diffraction) spectra 2 theta of the norfloxacin and vanillin, wherein the characteristic peaks are 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657 and 30.320. The preparation method of the eutectic crystal comprises the following steps: dissolving norfloxacin and vanillin in water at the temperature of 90-100 ℃, wherein the molar ratio of norfloxacin to vanillin is 1:1, and the mass ratio of norfloxacin to water is 1: 300-500, filtering the dissolved reaction solution, cooling the filtrate, separating out crystals, filtering, and drying to obtain the crystals, namely the norfloxacin and vanillin eutectic crystal. The invention further widens the solid form of norfloxacin, modifies the physical and chemical properties of the medicament, increases the solubility in water and provides possibility for improving the medicament effect and the bioavailability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a novel norfloxacin co-crystal and a preparation method thereof.
Background
"pharmaceutical co-crystals" are pharmaceutical active ingredients (APIs) and physiologically acceptable ligands (CCFs) that form specific crystal structures by molecular recognition through intermolecular forces (hydrogen bonding, halogen bonding, pi stacking, and van der waals forces) without breaking the chemical bonds of the APIs themselves. The crystal engineering-based pharmaceutical co-crystal is essentially a supramolecular self-assembly system and is a balanced result of thermodynamics, kinetics and molecular recognition. For a pharmaceutically active ingredient, its crystalline form may affect its many physicochemical properties, such as melting point, solubility, stability, bioavailability, and the like. The formation of the pharmaceutical co-crystal does not destroy the covalent bond of the pharmaceutical active ingredient, so that a better means for changing the physicochemical properties of the pharmaceutical active ingredient can be provided. The research on the crystal form of the medicine has great significance in the pharmaceutical industry. The U.S. Food and Drug Administration (FDA) issued Regulation Classification of pharmaceutical Co-Crystals guide for Industry in 2016.8 against the development trend of pharmaceutical co-Crystals. The guidelines suggest that when a drug and certain excipients form a co-crystal, the drug co-crystal can be managed and controlled as a "fixed dose combination product". Thus, the co-crystal need not be separately registered as a new drug substance (API). The European drug administration (EMA) issued a "Reflection paper on the use of active substructures in medical products" on 3.2015, which could be managed and controlled by using similar pharmaceutical salts as the raw material drugs (class II drug management files). For the pharmaceutical imitation company, how to develop a new crystal form of the drug so as to break the patent protection of the original pharmaceutical company on the crystal form and to put the pharmaceutical imitation into the market in advance is a crucial problem in recent years.
The research on the crystal form of the medicine is deeply valued by large pharmaceutical companies abroad, but still belongs to the starting stage in the pharmaceutical field at home. Norfloxacin (Norfloxacin, also known as Noroxin, Fulgram), a broad-spectrum antibiotic, particularly high in antibacterial activity against aerobic gram-negative bacilli, has good antibacterial effects in vitro against: most of the bacteria of the Enterobacteriaceae family include Enterobacter such as Citrobacter, Enterobacter cloacae, Enterobacter aerogenes, Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, Vibrio, Yersinia, and the like. The norfloxacin has antibacterial activity in vitro against multiple drug-resistant bacteria. Has good antibacterial effect on penicillin-resistant Neisseria gonorrhoeae, Haemophilus influenzae and Moraxella catarrhalis. Norfloxacin dissolves very slightly in water, resulting in low bioavailability. It is slightly soluble in dimethyl formamide and ethanol. In order to change the water solubility and increase the bioavailability, norfloxacin nicotinate and succinyl norfloxacin are synthesized in China sequentially.
The co-crystals and salts of norfloxacin were studied in detail in Basavoju et al (Basavoju et al, CrystalGrowth & Design, vol.6, No.12,2006). The research shows that the compound forms eutectic with isonicotinamide and forms salt with succinic acid, malonic acid and maleic acid. The co-crystal with isonicotinamide adopts chloroform as a solvent, and the co-crystal has one molecule of chloroform, so that the application of the co-crystal in the medicine is limited.
The invention selects norfloxacin as a raw material medicine as a medicine active component and edible vanillin as an eutectic formation. Norfloxacin used in the invention has a molecular formula of C16H18FN3O3The chemical name is 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid. The ligand used in the invention is vanillin with the molecular formula of C8H8O3The chemical name is 3-methoxy-4-hydroxybenzaldehyde.
The invention selects norfloxacin medicine and edible spice as active ingredients, takes water as solvent, and adopts a solution crystallization method which is most easy to operate industrially to prepare the eutectic crystal, thereby exploiting the diversity of medicine molecules.
Disclosure of Invention
The invention aims to provide a norfloxacin and vanillin eutectic with a novel structure and a preparation method thereof, and the crystal structure of the norfloxacin and vanillin eutectic is tested, characterized and tested. The co-crystal 2 theta of the ofloxacin and the vanillin prepared by the invention has a series of characteristic peaks at 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657 and 30.320,
the preparation method of the norfloxacin and vanillin eutectic crystal is characterized by comprising the following steps: dissolving norfloxacin and vanillin in water at the temperature of 90-100 ℃, wherein the molar ratio of norfloxacin to vanillin is 1:1, and the mass ratio of norfloxacin to water is 1: 300-500, filtering the dissolved reaction solution, cooling the filtrate, separating out crystals, and filtering to obtain the crystals, namely the norfloxacin and vanillin eutectic crystal.
The invention further widens the solid form of norfloxacin, modifies the physical and chemical properties of the medicament, increases the solubility in water and provides possibility for improving the medicament effect and the bioavailability.
Drawings
FIG. 1 norfloxacin XRD pattern;
FIG. 2 Vanillin XRD pattern;
FIG. 3 is an XRD diagram of co-crystal of norfloxacin and vanillin;
FIG. 4 is a DSC plot of norfloxacin;
FIG. 5 Vanillin DSC plot;
FIG. 6 is a DSC chart of co-crystal of norfloxacin and vanillin;
FIG. 7 is an infrared spectrum of norfloxacin;
FIG. 8 is a vanillin infrared spectrum;
FIG. 9 is an infrared spectrum of co-crystal norfloxacin and vanillin.
Detailed Description
As shown in figure 3, the XRD pattern of the norfloxacin and vanillin eutectic crystal is not the simple superposition of the XRD pattern (figure 1) of norfloxacin and vanillin (figure 2), and has obvious characteristic peaks, namely a series of characteristic peaks existing in the positions of 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657 and 30.320 in 2 theta, and the norfloxacin and vanillin eutectic crystal is a new crystal form.
The norfloxacin and vanillin eutectic crystal prepared by the invention has DSC showing the eutectic melting point of 217.1 ℃ (figure 6), the spectrum does not have melting point peaks of two raw materials, the norfloxacin melting point is 222.9 ℃ (figure 4), and the vanillin melting point is 86.3 ℃ (figure 5), but generates a new characteristic peak, which is also the mark of the eutectic formation.
The infrared spectrum (figure 9) of the norfloxacin and vanillin eutectic crystal prepared by the invention is not the simple superposition of the norfloxacin infrared spectrum (figure 7) and the vanillin infrared spectrum (figure 8) and is also a mark of a eutectic formation substance.
Detailed description of the preferred embodiment 1
Adding 104g of deionized water into a 250ml three-neck flask, slowly adding 348mg of norfloxacin and 166mg of vanillin, heating to 100 ℃, dissolving the norfloxacin and vanillin, quickly filtering the reaction solution after dissolving, placing the filtrate into a 250ml beaker, naturally cooling, standing for 24 hours, separating out crystals, filtering and drying to obtain 502 mg of needle-shaped white crystals, namely the co-crystal of norfloxacin and vanillin. The measured solubility of norfloxacin, norfloxacin and vanillin in pure water at 25 ℃ is shown in table 1, and it can be known from the table that compared with norfloxacin, the solubility of the co-crystal of the invention in water is greatly improved, and the bioavailability is greatly improved; and is also beneficial to the processing operation of the subsequent pharmaceutical process.
TABLE 1 solubility of norfloxacin, norfloxacin and vanillin co-crystals in pure water at 25 deg.C
| Compound (I) | Solubility (mg/mL) |
| Norfloxacin hydrochloride | 0.28 |
| Norfloxacin and vanillin cocrystal | 27.8 |
Specific example 2
Adding 174g of deionized water into a 250ml three-neck flask, slowly adding 348mg of norfloxacin and 166mg of vanillin, heating to 90 ℃, dissolving the norfloxacin and vanillin, quickly filtering the reaction solution after dissolving, placing the filtrate into a 250ml beaker, naturally cooling, standing for 24 hours, separating out crystals, filtering and drying to obtain 502 mg of needle-shaped white crystals, namely the norfloxacin and vanillin eutectic crystal. The measured solubility in eutectic water is shown in table 2.
TABLE 2 solubility of norfloxacin, norfloxacin and vanillin co-crystals in pure water at 25 deg.C
| Compound (I) | Solubility (mg/mL) |
| Norfloxacin hydrochloride | 0.28 |
| Norfloxacin and vanillin cocrystal | 27.9 |
Claims (1)
1. A preparation method of norfloxacin and vanillin eutectic crystal uses norfloxacin raw material as a pharmaceutical active ingredient API, vanillin is a eutectic formation, and characteristic peaks exist in XRD spectrogram 2 theta of 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657 and 30.320; the norfloxacin and vanillin eutectic crystal has a DSC (differential scanning calorimetry) display eutectic point of 217.1 ℃;
the preparation method comprises the following steps: dissolving norfloxacin and vanillin in water at the temperature of 90-100 ℃, wherein the molar ratio of norfloxacin to vanillin is 1:1, and the mass ratio of norfloxacin to water is 1: 300-500, filtering the dissolved reaction solution, cooling the filtrate, separating out crystals, filtering, and drying to obtain the crystals, namely the norfloxacin and vanillin eutectic crystal.
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| CN115536583A (en) * | 2021-08-15 | 2022-12-30 | 广东温氏大华农生物科技有限公司 | Enrofloxacin-vanillin eutectic crystal and preparation method thereof |
| CN114805046B (en) * | 2022-04-25 | 2023-05-12 | 东华理工大学 | Eutectic structure of vanillin and amide compound and preparation method thereof |
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| WO2009136408A1 (en) * | 2008-04-09 | 2009-11-12 | Institute Of Life Sciences | Synergistic pharmaceutical cocrystals |
| CN102188365B (en) * | 2011-05-11 | 2012-12-05 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN103265483A (en) * | 2013-05-24 | 2013-08-28 | 常州大学 | Co-crystal of norfloxacin and phthalic acid and preparation method thereof |
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