CN112174888A - Enrofloxacin single crystal form and preparation method thereof - Google Patents

Enrofloxacin single crystal form and preparation method thereof Download PDF

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CN112174888A
CN112174888A CN201910598009.XA CN201910598009A CN112174888A CN 112174888 A CN112174888 A CN 112174888A CN 201910598009 A CN201910598009 A CN 201910598009A CN 112174888 A CN112174888 A CN 112174888A
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enrofloxacin
single crystal
powder
crystal form
preparation
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CN112174888B (en
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杨雪
崔志刚
王建
程雪娇
王猛
于小婷
张磊
刘紫薇
宋秀梅
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Tianjin Zhongsheng Challenge Biotechnology Co ltd
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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
    • 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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Abstract

The invention relates to an enrofloxacin single crystal form and a preparation method thereof, wherein enrofloxacin is a fluoroquinolone broad-spectrum antibacterial drug, and the application numbers of CCDC are as follows: 1920356, respectively; the crystal system is monoclinic system, P21The method comprises the following specific steps: (1) putting each 0.2g of enrofloxacin powder with the purity of more than 98 percent into 20-30ml of organic solvent, and heating and dissolving the enrofloxacin powder, wherein the organic solvent is methanol, ethanol, acetone, ethyl acetate, chloroform, acetonitrile, dichloromethane and the like; (2) and cooling and standing the enrofloxacin powder after the enrofloxacin powder is completely dissolved, separating out crystals, and filtering to obtain the enrofloxacin crystal. The enrofloxacin single crystal form substance is a single crystal form compound, and has high stability and more obvious bioavailability than a polycrystalline effect due to single crystal form; the preparation method breaks through the technical bottleneck that technicians in the field cannot obtain the enrofloxacin single crystal form at the present stage, is simple and easy to obtain, and meets the requirement of large-scale industrial production.

Description

Enrofloxacin single crystal form and preparation method thereof
Technical Field
The invention relates to the field of compound production, in particular to an enrofloxacin single crystal form substance and a preparation method thereof.
Background
Enrofloxacin (Enrofloxacin, ENR) as a yellowish or pale yellow crystalline powder; bitter taste and water insolubility; is easy to dissolve in sodium hydroxide solution, methanol, methyl cyanide and other organic solvents; the molecular formula is as follows: c19H22FN3O3Molecular weight: 359.40, melting point: 225 ℃, CAS number: 93106-60-6. Enrofloxacin can combine with bacterial DNA gyrase subunit A, thus inhibiting the cutting and connecting functions of enzyme, preventing the replication of bacterial DNA and presenting antibacterial action. The antibacterial agent has the characteristics of strong antibacterial activity, wide antibacterial spectrum, difficult generation of drug resistance, effectiveness to drug-resistant bacteria of other antibacterial agents, relatively less adverse reaction and the like, and has small toxic and side effects. Enrofloxacin has good effects on Escherichia coli, salmonella, Klebsiella, Pasteurella, Actinomyces pleuropneumoniae, erysipelas bacillus, Proteus, Serratia marcescens, Corynebacterium pyogenes, Bordetella septica, Staphylococcus aureus, streptococcus, mycoplasma, chlamydia and the like. Enrofloxacin is a quinolone drug of the third generation, which is initially put on the market by Bayer corporation in Germany in 1987, has a trade name of Baytral and Baixiao, is known as a new weapon for preventing and treating diseases of livestock and poultry in 90 years, is approved by FDA in 10 months in 1996, is a special antibacterial drug for livestock and poultry, is widely applied to prevention and treatment of various animal infectious diseases, and has already entered most of countries and markets in the world at present.
For a compound used as a pharmaceutical ingredient, the crystal structure has an important influence on the stability, bioavailability and other indexes of the compound, and the most common and more accurate method for researching the crystal structure is the X-ray diffraction method at present. The single crystal form has good stability, high bioavailability and good solubility, while the polymorphism has relatively poor properties. Although enrofloxacin has been used, the crystal structure of the compound has not been reported.
Disclosure of Invention
The invention aims to provide an enrofloxacin single crystal form.
The invention aims to provide a preparation method of the enrofloxacin single crystal form.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a monocrystaline enrofloxacin compound, P2, is monoclinic system1The/n space group has chirality and unit cell parameters as follows:
Figure BDA0002117972340000021
a R1＝Σ||Fo|–|Fc||/|Fo|.b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2
the preparation method of the enrofloxacin single crystal form substance comprises the following specific steps:
(1) putting each 0.2g of enrofloxacin powder with the purity of more than 98 percent into 20-30ml (such as 20ml, 21ml, 22ml, 23ml, 24ml, 25ml, 26ml, 27ml, 28ml, 29ml and 30ml) of organic solvent, and heating to dissolve the solid powder, wherein the organic solvent is any one of methanol, ethanol, acetone, ethyl acetate, chloroform, acetonitrile and dichloromethane;
(2) and (4) cooling to room temperature (25 ℃) after the solid is completely dissolved, standing, precipitating crystals, and filtering to obtain the product.
In the above production method, as a preferable embodiment, the purity of the altrenogest powder is 98% or more.
In the above production method, as a preferred embodiment, the heating temperature is 35 to 70 ℃ (e.g., 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃).
In the above production method, as a preferred embodiment, the organic solvent is methanol.
In the above production method, as a preferable embodiment, the enrofloxacin powder of 0.2g in the step (1) is put in 20ml of methanol.
The invention has the beneficial effects that:
the enrofloxacin single crystal form substance is a single crystal form compound, and has high stability and more obvious bioavailability than a polycrystalline effect due to single crystal form; the preparation method breaks through the technical bottleneck that technicians in the field cannot obtain the enrofloxacin single crystal form at the present stage, is simple and easy to obtain, and meets the requirement of large-scale industrial production.
Drawings
FIG. 1 is a structural formula diagram of enrofloxacin single crystal form;
FIG. 2 is a single crystal structure diagram of enrofloxacin single crystal;
FIG. 3 is a pharmacokinetic profile of single crystal enrofloxacin preparation and a common preparation in porcine plasma.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description will be given with reference to specific embodiments.
Example 1
A preparation method of enrofloxacin single crystal form substance comprises the following specific steps:
(1) placing 0.2g of enrofloxacin powder with the purity of 98 percent in 20ml of methanol, and heating and dissolving the solid powder at 40 ℃;
(2) after the powder is completely dissolved, the solution is cooled and placed statically, crystals are separated out, and the product is obtained by filtering, wherein the yield is 75 percent, and the purity is 99.8 percent.
The structural formula of enrofloxacin in the example is shown in figure 1, the crystal structure of the obtained product is shown in figure 2 through X-ray diffraction method, the product is a monoclinic system, and P21N 1 nullUnit cell parameters are as follows in table 1:
TABLE 1
Figure BDA0002117972340000041
a R1＝Σ||Fo|–|Fc||/|Fo|.b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2
Example 2
A preparation method of enrofloxacin single crystal form substance comprises the following specific steps:
(1) putting 0.2g of enrofloxacin solid powder with the purity of 98 percent into 20ml of organic solvent, and heating and dissolving the solid powder at 70 ℃, wherein the organic solvent is acetonitrile mixture;
(2) after the powder is completely dissolved, the solution is cooled and placed statically, crystals are separated out, and the product is obtained by filtering, wherein the yield is 60 percent, and the purity is 98.7 percent.
Example 3
A preparation method of enrofloxacin single crystal form substance comprises the following specific steps:
(1) placing 0.2g of enrofloxacin solid powder with the purity of 98 percent in 20ml of acetone, and heating and dissolving the solid powder at 40 ℃;
(2) after the powder is completely dissolved, the solution is cooled and placed statically, crystals are separated out, and the product is obtained by filtering, wherein the yield is 75 percent, and the purity is 99.7 percent.
Example 4
A preparation method of enrofloxacin single crystal form substance comprises the following specific steps:
(1) putting 0.2g of enrofloxacin solid powder with the purity of 98.5 percent into 20ml of ethanol, and heating and dissolving the solid powder at 70 ℃;
(2) after the powder is completely dissolved, the solution is cooled and placed statically, crystals are separated out, and the product is obtained by filtering, wherein the yield is 75 percent, and the purity is 98.5 percent.
Example 5
A preparation method of enrofloxacin single crystal form substance comprises the following specific steps:
(1) putting 0.2g of enrofloxacin solid powder with the purity of 98 percent into 30ml of ethanol, and heating and dissolving the solid powder at 50 ℃;
(2) after the powder is completely dissolved, the solution is cooled and placed statically, crystals are separated out, and the product is obtained by filtration, wherein the yield is 65 percent, and the purity is 98.6 percent.
Test example 1 pharmacokinetics study of enrofloxacin single crystal injection and enrofloxacin injection in sow
1 materials and methods
1.1 materials
1.1.1 medicine
The test drugs are: the enrofloxacin single crystal injection with the content of 20 percent is provided by Zhongsheng challenge biotechnology limited company in Tianjin city.
Control drugs: the enrofloxacin injection with the content of 20 percent is provided by Zhongsheng challenge biotechnology limited company in Tianjin city.
1.1.2 test animals
The healthy hybrid sow with the long white and the big white has 16 heads and the weight of about 20kg, and is provided by Ninghe breeder pig farm in Tianjin. The test pigs are identified by ear numbers. The test animals had not been administered the relevant drug for at least 2 weeks prior to the trial and had passed through an adaptation period of at least 1 week. During the test period, the tested animals are fed according to the conventional conditions, drinking water and ingestion are performed freely, and the feed is complete feed without any medicine. 1.2 test methods
1.2.1 test design
16 sows, randomly divided into 2 groups A and B, each group having 8 sows. Before the test, the animals are raised according to the conventional method, water and food are freely drunk, the feed is full-value daily ration (without antibacterial drugs), and the animals are observed for two weeks. After clinical observation of health, the test was performed. The administration methods of the two groups of sows are respectively as follows: injecting enrofloxacin injection into neck muscles of group A and injecting enrofloxacin single crystal injection into neck muscles of group B; the groups were fasted 16h before administration and had free access to water.
1.2.2 administration and blood sample Collection
Administration: according to the weight ratio of 2.5 mg.kg-1Body weight was given in a single dose.
Sampling time: the sampling time was determined on a pilot basis, blank plasma was taken prior to dosing, and blood samples were taken 0.083, 0.167, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72h, 96h post-dosing, respectively.
Blood collection approach: the pig stands for fixation, and the anterior vena cava is used for blood collection, wherein the blood collection is about 5mL each time.
And (3) sample preservation: collecting venous blood, placing in a centrifuge tube containing 0.5% heparin sodium, mixing, centrifuging at 3000rpm for 10min, separating plasma, storing in a refrigerator at-20 deg.C, and testing.
1.2.3 measurement of plasma concentration in pigs following administration in different ways
And (3) after the plasma samples collected at each time point are processed, a verified HPLC detection method for the enrofloxacin content in the pig plasma is adopted for determination, the chromatographic peak area of the enrofloxacin is recorded, and the concentration of the enrofloxacin in the plasma is calculated by a standard curve regression equation.
1.2.4 data analysis processing
Pharmacokinetic data were processed using a non-compartmental model of pharmacokinetic software winnonlin5.2.1, Pharsight, inc, to calculate pharmacokinetic parameters for the test sows, and to generate a drug-time curve with blood drug concentration versus time.
2, results:
the enrofloxacin is injected and administered according to the dose of 2.5mg/kg body weight, and the result of the pharmacokinetic research in the pig body shows that the blood concentration-time data of the enrofloxacin in the pig body are suitable to be fitted by a non-atrioventricular model, and the elimination half-life period T of the enrofloxacin single crystal injection and the enrofloxacin injection1/2βThe total time is 32.39h and 22.82h respectively, which shows that the enrofloxacin single crystal injection has slower elimination rate in the body than the enrofloxacin injection. Enrofloxacin single crystal injection and time T of peak of enrofloxacin injection in blood plasmamaxThe concentration of the enrofloxacin is 1.5h and 3h respectively, which shows that the enrofloxacin can reach the peak concentration in a shorter time. Enrofloxacin single crystal injection and AUC of enrofloxacin injection0→∞47.25h ug/mL and 38.36h ug/mL respectively, and the apparent distribution volumes V/F are 2.08L/kg and 1.99L/kg respectively, which indicates that the enrofloxacin is widely distributed in the body. In conclusion, the enrofloxacin single crystal injection can be faster than the enrofloxacin injectionThe peak concentration of the compound is wide in distribution, slower in elimination, and capable of maintaining effective concentration in the organism for a longer time. The time curve chart of the enrofloxacin single crystal injection in the pig plasma is shown in figure 3.
The above detailed description of the single crystalline form of enrofloxacin and the method for preparing the same with reference to the specific embodiments is illustrative and not restrictive, and several examples are listed according to the limited scope, therefore, variations and modifications without departing from the general concept of the present invention shall fall within the protection scope of the present invention.

Claims (7)

1. A monocrystaline enrofloxacin compound, P2, is monoclinic system1The/n space group has chirality and unit cell parameters as follows:
Figure FDA0002117972330000011
aR1＝Σ||Fo|–|Fc||/|Fo|.bwR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2。
2. the method for preparing enrofloxacin single crystal form according to claim 1, wherein the method comprises the following steps: the method comprises the following steps:
(1) putting each 0.2g of enrofloxacin powder with the purity of more than 98 percent into 20-30ml of organic solvent, and heating to dissolve the powder;
(2) and cooling and standing the enrofloxacin powder after the enrofloxacin powder is completely dissolved, separating out crystals, and filtering to obtain the enrofloxacin crystal.
3. The method of claim 2, wherein: the organic solvent is any one of methanol, ethanol, acetone, ethyl acetate, chloroform, acetonitrile and dichloromethane.
4. The production method according to claim 2 or 3, wherein the enrofloxacin powder has a purity of 98% or more.
5. The production method according to any one of claims 2 to 4, wherein the heating temperature is 35 to 70 ℃.
6. The production method according to claim 3, characterized in that: the organic solvent is methanol.
7. The production method according to any one of claims 2 to 6, characterized in that: in the step (1), every 0.2g of enrofloxacin powder is put into 20ml of methanol.
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Publication number Priority date Publication date Assignee Title
CN101810569A (en) * 2010-05-22 2010-08-25 鼎正动物药业（天津）有限公司 Enrofloxacin injection liquid and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101810569A (en) * 2010-05-22 2010-08-25 鼎正动物药业（天津）有限公司 Enrofloxacin injection liquid and preparation method thereof

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