CN106588953B - A kind of anti-infectives cefadroxil crystal-form compound and combinations thereof - Google Patents
A kind of anti-infectives cefadroxil crystal-form compound and combinations thereof Download PDFInfo
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- CN106588953B CN106588953B CN201610977283.4A CN201610977283A CN106588953B CN 106588953 B CN106588953 B CN 106588953B CN 201610977283 A CN201610977283 A CN 201610977283A CN 106588953 B CN106588953 B CN 106588953B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
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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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Abstract
The invention belongs to pharmaceutical technology field, a kind of anti-infectives cefadroxil crystal compound and combinations thereof is disclosed.Shown in the structural formula such as formula (I) of the cefadroxil crystal-form compound, which is measured with powder x-ray diffraction measuring method, as shown in Figure 1 with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction indicate.Crystal-form compound purity is high, impurity content is low, and stability is good, and not easy to moisture absorption, good fluidity, substantially increases its dissolubility.Capsule can be made with direct packaging using the crystal-form compound, without adding any auxiliary material, and manufactured capsule dissolution rate is high, impurity content is low, stability is good.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of anti-infectives cefadroxil crystal-form compound and combinations thereof
Object.
Background technique
Cefadroxil, chemical name are (6R, 7R) -3- methyl -7- [(R) -2- amino -2- (4- hydroxy phenyl) acetyl
Amino] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid monohydrate, it is a kind of well-known
The antibiotic with antibacterial activity, be by the second generation oral cephalosporin of U.S.'s Bristol Laboratories-Meyer company exploitation, knot
Shown in structure formula such as formula (I)：
Cefadroxil has stronger resisting gram-positive bacteria effect and certain anti-Gram-negative bacteria effect, to blueness
Mycin enzyme is more stable, and allergic reaction is less.With oral absorption is good, antimicrbial power is strong, resistance to enzyme, curative effect are high, blood concentration is maintained
Time length is low with toxicity, long half time and the features such as not by food effect and few side effects.Clinically it is widely used in treatment breathing
The sensitive bacteria at the positions such as road, the urinary tract, oral cavity and skin soft tissue infects.
It is very widely used at home and abroad since cefadroxil has the above advantages, after 1984 enter China market,
Market sales volume rises year by year, and has become one of widest oral anti-infective drugs of clinical application.The cephalo of domestic listing at present
Amoxycillin preparation has the dosage forms such as capsule, dispersible tablet, tablet, particle, dry suspensoid agent.
CN 105534937A and CN 105640895A disclose a kind of cefadroxil crystal-form compound, X-ray powder
Last diffraction pattern is as shown in Figure 3.Compared with prior art, not only under high temperature, high humidity and intense light conditions impurity content without significantly changing
Become, stability greatly improves；And the bioavilability of preparation is also obtained and significantly improves.
104447795 B of CN discloses a kind of cefadroxil benzyl compound and its pharmaceutical composition, cephalo hydroxyl of the invention
Ammonia benzyl compound contains 3.5 water, has the advantages that significantly improve its water solubility and hygroscopic, X-ray powder diffraction figure such as figure
Shown in 4.
However, due to unstable, the degradation easy to moisture absorption under the conditions ofs high temperature and humidity etc. of existing cefadroxil raw material, dissolution
Property is bad, causes its mobility poor, to cause the quality stability of formulation products poor, is unfavorable for storing for a long time, to facing
Safety, validity in bed use bring hidden danger.It is all by addition stabilizer, inclusion agents and correlation in existing preparation preparation
Auxiliary material improves its stability etc..
The present inventor, by a large number of experiments, has been made one kind and has been totally different from using existing cefadroxil crude product as raw material
The cefadroxil crystal compound of the prior art, and by test, surprisingly find crystal-form compound purity is high, impurity
Content is low, and stability is good, and not easy to moisture absorption, good fluidity, substantially increases its dissolubility.It can be straight using the crystal-form compound
It connects packing and capsule is made, without adding any auxiliary material, and manufactured capsule dissolution rate is high, impurity content is low, stability is good.
Summary of the invention
The first object of the present invention is to provide a kind of anti-infectives cefadroxil crystal-form compound, the crystal form chemical combination
Object is not only with high purity, and impurity content is low, and stability is good, and it is not easy to moisture absorption, and mobility, dissolubility etc. are substantially better than existing skill
Art.
The second object of the present invention is to provide the preparation method of the cefadroxil crystal-form compound, this method work
Skill is simple, high income, and repeatability is strong, is suitable for industrialized production.
The third object of the present invention is to provide a kind of Products of Cefadroxil Capsules, and the capsule contains provided by the present invention
Cefadroxil crystal-form compound or preparation method of the invention made from cefadroxil crystal-form compound.The capsule by
Cefadroxil direct packaging is made, and without adding any auxiliary material, and manufactured capsule dissolution rate is high, impurity content is low, steady
It is qualitative good.
The first purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of anti-infectives cefadroxil crystal-form compound, which is characterized in that the cefadroxil is order
Shown in the structural formula such as formula (I) for closing object, which is measured with powder x-ray diffraction measuring method, with 2 θ ± 0.2 ° diffraction
Angle indicate X-ray powder diffraction pattern as shown in Figure 1,
The second purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of preparation method of anti-infectives cefadroxil crystal-form compound of the present invention, which is characterized in that
This method comprises the following steps：
Cefadroxil bulk pharmaceutical chemicals are taken, is added in the mixed solvent A of the water of certain temperature, methanol, dimethylformamide, obtains
To solution；Then apply stationary magnetic field in the horizontal direction of the liquid level of acquired solution, and under conditions of the stationary magnetic field to
The mixed solvent B of acetone, ethyl acetate, ether is added dropwise in solution；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake second
Alcohol washing, is dried in vacuo 2-4 hours, obtains the cefadroxil crystals compound.
In the present invention, the cefadroxil bulk pharmaceutical chemicals can be cephalo hydroxyl disclosed in the method using the prior art
It is former to be also possible to commercially available cefadroxil monohydrate for the cefadroxil monohydrate that the synthetic method of ammonia benzyl is prepared
Expect medicine.
In preparation method of the present invention, wherein the temperature is 35-45 DEG C.The water, methanol, dimethylformamide it is mixed
The volume of bonding solvent A is 6-8 times of cefadroxil weight, and water, methanol and dimethylformamide volume ratio are 1：1:2.5.It is described
Magnetic field strength is 0.8T-1.5T.The acetone, ethyl acetate, ether mixed solvent B volume be cefadroxil weight 8-
10 times.The volume ratio of the acetone, ethyl acetate and ether is 2:3:5.
Third purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of Products of Cefadroxil Capsules, which is characterized in that the capsule contains cefadroxil provided by the present invention
Cefadroxil crystal-form compound made from crystal-form compound or preparation method of the invention.
The Products of Cefadroxil Capsules contains 100% cefadroxil.
The Products of Cefadroxil Capsules is prepared by following preparation method：
(1) raw material (cefadroxil) crosses 60 meshes, and observation has foreign after sieving.
(2) it is filled, is dispensed with capsule, controlled content uniformity and disintegration time, must meet the quality standard.
The preparation of capsule is not limited to preparation method of the present invention, and art methods preparation can also be used.
Compared with prior art, the invention has the advantages that：
(1) cefadroxil crystal-form compound provided by the present invention is not only with high purity, and impurity content is low, and stability is good,
And it is not easy to moisture absorption, and mobility, dissolubility etc. are substantially better than the prior art.
(2) the preparation method simple process of cefadroxil provided by the present invention, high income, repeatability is strong, is suitable for
Industrialized production.
(3) capsule provided by the present invention containing the cefadroxil crystal-form compound is by cefadroxil direct packaging
It is made, without adding any auxiliary material, and manufactured capsule dissolution rate is high, impurity content is low, stability is good.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of cefadroxil crystal-form compound of the invention.
Fig. 2 is the heat analysis map of cefadroxil crystal-form compound of the invention.
Fig. 3 is that the X- of the cefadroxil crystallization of patent CN105534937A and CN 105640895A embodiment preparation is penetrated
Line powder diffraction spectrum.
Fig. 4 is the X-ray powder diffraction collection of the cefadroxil crystallization of patent CN 104447795B embodiment preparation.
Specific embodiment
Technical solution of the present invention is described in detail with embodiment below, it will help to technical side of the invention
, there are further understanding in the advantages of case, effect, and the scope of protection of the present invention is not limited for embodiment, protection scope of the present invention by
Claim determines.
The preparation of 1 cefadroxil crystal-form compound of embodiment
Cefadroxil bulk pharmaceutical chemicals are taken, water, methanol, dimethyl of 35 DEG C of the volume for 6 times of cefadroxil weight is added
In the mixed solvent A of formamide, water, methanol and dimethylformamide volume ratio are 1:1:2.5, obtain solution；Then in gained
Apply the stationary magnetic field that magnetic field strength is 0.8T in the horizontal direction of the liquid level of solution, and to molten under conditions of the stationary magnetic field
The mixed solvent B of acetone, ethyl acetate, ether that volume is 8 times of cefadroxil weight, acetone, ethyl acetate are added dropwise in liquid
Volume ratio with ether is 2:3:5；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake ethanol washing is dried in vacuo 2-4
Hour, obtain the cefadroxil crystals compound.
It is measured with powder x-ray diffraction measuring method, is existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
9.1, characteristic diffraction peak is shown at 10.8,12.3,20.8,22.0,22.3,23.4,29.6.
It uses Cattell aquametry measurement moisture content for 4.72wt%, coincide substantially with theoretical value.
It is measured using thermogravimetric analysis, as a result as shown in Fig. 2, crystal water content is 4.72wt%, is coincide substantially with theoretical value.
The preparation of 2 cefadroxil crystal-form compound of embodiment
Cefadroxil bulk pharmaceutical chemicals are taken, water, methanol, dimethyl of 40 DEG C of the volume for 7 times of cefadroxil weight is added
In the mixed solvent A of formamide, water, methanol and dimethylformamide volume ratio are 1：1:2.5, obtain solution；Then in gained
Apply the stationary magnetic field that magnetic field strength is 1.1T in the horizontal direction of the liquid level of solution, and to molten under conditions of the stationary magnetic field
The mixed solvent B of acetone, ethyl acetate, ether that volume is 9 times of cefadroxil weight, acetone, ethyl acetate are added dropwise in liquid
Volume ratio with ether is 2:3:5；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake ethanol washing is dried in vacuo 2-4
Hour, obtain the cefadroxil crystals compound.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 3 cefadroxil crystal-form compound of embodiment
Cefadroxil bulk pharmaceutical chemicals are taken, water, methanol, dimethyl of 45 DEG C of the volume for 8 times of cefadroxil weight is added
In the mixed solvent A of formamide, water, methanol and dimethylformamide volume ratio are 1：1:2.5, obtain solution；Then in gained
Apply the stationary magnetic field that magnetic field strength is 1.5T in the horizontal direction of the liquid level of solution, and to molten under conditions of the stationary magnetic field
The mixed solvent B of acetone, ethyl acetate, ether that volume is 10 times of cefadroxil weight, acetone, ethyl acetate are added dropwise in liquid
Volume ratio with ether is 2:3:5；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake ethanol washing is dried in vacuo 2-4
Hour, obtain the cefadroxil crystals compound.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 4 cefadroxil crystal-form compound of embodiment
Cefadroxil bulk pharmaceutical chemicals are taken, water, methanol, dimethyl of 35 DEG C of the volume for 7 times of cefadroxil weight is added
In the mixed solvent A of formamide, water, methanol and dimethylformamide volume ratio are 1：1:2.5, obtain solution；Then in gained
Apply the stationary magnetic field that magnetic field strength is 1.5T in the horizontal direction of the liquid level of solution, and to molten under conditions of the stationary magnetic field
The mixed solvent B of acetone, ethyl acetate, ether that volume is 10 times of cefadroxil weight, acetone, ethyl acetate are added dropwise in liquid
Volume ratio with ether is 2:3:5；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake ethanol washing is dried in vacuo 2-4
Hour, obtain the cefadroxil crystals compound.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 5 cefadroxil crystal-form compound of embodiment
Cefadroxil bulk pharmaceutical chemicals are taken, water, methanol, dimethyl of 45 DEG C of the volume for 6 times of cefadroxil weight is added
In the mixed solvent A of formamide, water, methanol and dimethylformamide volume ratio are 1：1:2.5, obtain solution；Then in gained
Apply the stationary magnetic field that magnetic field strength is 1.1T in the horizontal direction of the liquid level of solution, and to molten under conditions of the stationary magnetic field
The mixed solvent B of acetone, ethyl acetate, ether that volume is 8 times of cefadroxil weight, acetone, ethyl acetate are added dropwise in liquid
Volume ratio with ether is 2:3:5；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake ethanol washing is dried in vacuo 2-4
Hour, obtain the cefadroxil crystals compound.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
【Example of formulations 1】Products of Cefadroxil Capsules
Products of Cefadroxil Capsules (0.125g)
Cefadroxil is that cefadroxil crystal-form compound provided by the present invention or preparation method of the invention are made
Cefadroxil crystal-form compound.
Preparation method：
(1) raw material (cefadroxil) crosses 60 meshes, and observation has foreign after sieving.
(2) it is filled, is dispensed with capsule, controlled content uniformity and disintegration time, must meet the quality standard.
【Example of formulations 2】Products of Cefadroxil Capsules
Products of Cefadroxil Capsules (0.125g)
Cefadroxil is that cefadroxil crystal-form compound provided by the present invention or preparation method of the invention are made
Cefadroxil crystal-form compound.
Preparation method：With example of formulations 1, except that cefadroxil used is head prepared by embodiment 2
Spore amoxycillin crystal form.
【Example of formulations 3】Products of Cefadroxil Capsules
Products of Cefadroxil Capsules (0.125g)
Cefadroxil is that cefadroxil crystal-form compound provided by the present invention or preparation method of the invention are made
Cefadroxil crystal-form compound.
Preparation method：With example of formulations 1, except that cefadroxil used is head prepared by embodiment 3
Spore amoxycillin crystal form.
【Example of formulations 4】Products of Cefadroxil Capsules
Products of Cefadroxil Capsules (0.125g)
Cefadroxil is that cefadroxil crystal-form compound provided by the present invention or preparation method of the invention are made
Cefadroxil crystal-form compound.
Preparation method：With example of formulations 1, except that cefadroxil used is head prepared by embodiment 4
Spore amoxycillin crystal form.
【Example of formulations 5】Products of Cefadroxil Capsules
Products of Cefadroxil Capsules (0.125g)
Cefadroxil is that cefadroxil crystal-form compound provided by the present invention or preparation method of the invention are made
Cefadroxil crystal-form compound.
Preparation method：With example of formulations 1, except that cefadroxil used is head prepared by embodiment 5
Spore amoxycillin crystal form.
Trial target 1：Cefadroxil crystal-form compound prepared by the embodiment of the present invention 1.
Trial target 2：Cefadroxil crystal-form compound prepared by the embodiment of the present invention 4.
Reference substance 1：Cefadroxil is made according to the method for CN105534937A and CN 105640895A embodiment 1.
Reference substance 2：Cefadroxil crystals are made according to the method for CN 104447795B embodiment 3.
Reference substance 3：Cefadroxil is made according to the method for CN 101448842A embodiment 2.
Reference substance 4：Cefadroxil is made according to the method for CN 102134250B embodiment 2.
Reference substance 5：Cefadroxil is made according to the method for CN 103360412B embodiment one.
Reference substance 6：Cefadroxil is made according to the method for CN 1016607B embodiment 7.
Reference substance 7：Cefadroxil is made according to the method for CN 102268019B embodiment 2.
Experimental example 2：Fluidity test
This experimental example evaluates the mobility of sample by measuring the angle of repose of sample, and the specific method is as follows：Take sample
Grain, flows into circular surface plate from fixed small funnel, until obtaining highest cone, measure cone height H and
Radius R calculates angle of repose α by tan α=H/R, the results are shown in Table 2, angle of repose is bigger, and mobility is poorer.
2 fluidity test result of table
As known from Table 1, compared with cefadroxil in the prior art, cefadroxil benzyl compound prepared by the present invention
Mobility significantly improves, and is conducive to the preparation of preparation, the raising of dissolution rate, bioavilability.
Experimental example 3：Dissolubility test
Suitable distilled water is added in the low capacity bottle with constant temperature jacket, cefadroxil is added at 25 DEG C to not
Until redissolution, starts magnetic stirrer, persistently stirred under constant temperature, system is in the shape of two-phase coexistent always during the experiment
State, the solubility of the concentration of cefadroxil as at this temperature in the liquid phase of system after 70 minutes.It is sampled after 2 hours
Analysis, takes average value similar in adjacent two times result as measured value of experiment, before sampling, in order to be sufficiently separated solid-liquid, stops
After stirring, not molten cefadroxil is deposited to the bottom of low capacity bottle, extracts a small amount of upper clear supernate with syringe, micro- with 0.45
The filter filtering of rice, sample is taken from filtrate, the content (concentration (mg/ml)) of cefadroxil is measured by HPLC.As a result see
Table 3.
Cefadroxil crystal compound of the present invention and the water-soluble of prior art crystal form compare table 3 at room temperature
| Sample | First time content | Second of content | Average value |
| Trial target 1 | 24.5 | 24.3 | 24.4 |
| Trial target 2 | 24.6 | 24.4 | 24.5 |
| Reference substance 1 | 3.7 | 3.7 | 3.7 |
| Reference substance 2 | 18.4 | 18.3 | 18.35 |
| Reference substance 3 | 4.1 | 3.9 | 4.0 |
| Reference substance 4 | 4.6 | 4.7 | 4.65 |
| Reference substance 5 | 4.5 | 4.5 | 4.5 |
| Reference substance 6 | 5.2 | 5.3 | 5.25 |
| Reference substance 7 | 4.9 | 4.8 | 4.85 |
From table 2 it can be seen that the water solubility of cefadroxil crystal compound of the present invention is compared with prior art, have aobvious
It writes and improves.
Experimental example 4：Draws moist test
According to 2015 editions general rules of Chinese Pharmacopoeia, 9103 drug draws moist test guideline.
Specific test method is as follows：
Dry stuffed glass weighing bottle (outer diameter 50mm, a height of 15mm) is taken, is placed in suitable 25 in test the previous day
(set temperature is 25 DEG C for DEG C of ± 1 DEG C thermostatic drier (placing ammonium chloride or ammonium sulfate saturated solution in lower part) or growth cabinet
± 1 DEG C, relative humidity is 80% ± 2%) in, accurately weighed weight (m1).
It takes test sample appropriate, is laid in above-mentioned weighing bottle, test sample thickness is about 1mm, accurately weighed weight (m2).
By weighing bottle opening, and with bottle cap with being placed under the conditions of above-mentioned constant temperature and humidity 24 hours.
Cover weighing bottle lid, accurately weighed weight (m3).
Percentage weight increase=(m3-m2)/(m2-m1) × 100%
Draw moist feature description and draws defining for moist weight gain
It deliquesces：It absorbs enough moisture and forms liquid.
It is great draw it is moist：Draw wet weight gain not less than 15%.
Have draw it is moist：Draw wet weight gain less than 15% but not less than 2%.
Slightly draw moist：Draw wet weight gain less than 2% but not less than 0.2%.
Nothing is moist almost without drawing：Draw wet weight gain less than 0.2%.
Test result is shown in Table 4
4 draws moist test result of table
As can be seen from the above table, cefadroxil crystal-form compound prepared by the present invention is moist almost without drawing, and is significantly better than
The prior art.
Experimental example 5：Influence factor test
By trial target and reference substance simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity (RH75% ± 5%)
Under the conditions of place 10 days, detected by stability high spot reviews project, compared with 0 day sample, the results are shown in Table 4.Related substance
Detection is detected referring to the related substance detecting method of 2015 editions cefadroxils of Chinese Pharmacopoeia.
5 influence factor test result of table
The height of drug quality is directly related to the health of millions upon millions of working people's bodies, is also related to economic construction of China
Effect, national defence consolidation and nationality it is flourishing；It has been far from the thing of medical industry enterprise range itself, but entire
National, the world the major issue.Those skilled in the art clearly know, in the present age of pharmaceutical technology prosperity, drug safety standard quilt
Constantly being promoted, the purity of prepared drug is also higher and higher, it is effectively reduced impurity content, even the several percentages of zero point
Point, can also be effectively reduced the generation of adverse reaction, thus impurity content to drug quality and people's drug safety to closing weight
It wants.Drug needs to store and transport into the process of circulation from production can just cure the sickness to save the patient, therefore, drug in storage and transportational process
Quality be particularly important, stability be the key that determine drug quality quality, drug storage and transportational process in, stablize
Property it is bad, impurity variation directly affects people's drug safety greatly.
As can be seen from the above table, the list using cefadroxil crystal-form compound made from method of the invention is miscellaneous, total miscellaneous
Equal size is very low, and stability is significantly better than the cefadroxil of the prior art, and drug safety is effectively promoted and deposits
The stability of storage reduces the generation of adverse reaction.
Above-mentioned experimental example 2-5 has also been carried out to the cefadroxil crystal-form compound of other embodiments of the present invention, has been obtained
Result it is similar.
Experimental example 6：Preparation dissolution determination
Formulation test product 1：Products of Cefadroxil Capsules prepared by invention formulation embodiment 1.
Formulation test product 2：Products of Cefadroxil Capsules prepared by invention formulation embodiment 3.
Preparations. Control product 1：Commercial product (Haosen Pharmaceutical Co., Ltd., Lianyungang)
Preparations. Control product 2：Commercial product (Shangdong Hualu Pharmaceutical Co., Ltd.)
Preparations. Control product 3：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to CN105534937A and CN 105640895A embodiment 1；
Preparations. Control product 4：According to cefadroxil made from 104447795 B example of formulations of CN, 4 prescription and preparation method
Benzyl capsule.
Preparations. Control product 5：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to CN 101448842A embodiment 2；
Preparations. Control product 6：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to 102134250 B embodiment 2 of CN；
Preparations. Control product 7：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to 103360412 B embodiment one of CN；
Preparations. Control product 8：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to 1016607 B embodiment 7 of CN；
Preparations. Control product 9：Using the prescription and preparation method of invention formulation embodiment 1, except that head used
Spore amoxycillin is cefadroxil made from the method according to 102268019 B embodiment 2 of CN.
Dissolution determination method：Trial target and reference substance are taken respectively, according to dissolution rate and drug release determination method (general rule 0,931 the
One method), using water 900ml as dissolution medium, revolving speed is 100 turns per minute, operates according to methods, when through 30 minutes, takes solution appropriate, is filtered
It crosses, precision measurement subsequent filtrate is appropriate, is quantitatively diluted and is made in every 1ml containing about cefadroxil with water (based on C16H17N3O5S)
The solution of 25 μ l measures absorbance according to UV-VIS spectrophotometry (general rule 0401) at the wavelength of 263nm；Separately take cephalo
Amoxycillin reference substance is appropriate, is dissolved with water and quantifies dilution and is made in every 1ml containing about the solution of 25 μ l, is measured in the same method, calculates every
The amount of dissolution of grain.Limit is the 80% of labelled amount, should meet regulation.
6 dissolution determination result of table
| Dissolution rate (%) | |
| Formulation test product 1 | 99.8 |
| Formulation test product 2 | 99.9 |
| Preparations. Control product 1 | 80.4 |
| Preparations. Control product 2 | 80.7 |
| Preparations. Control product 3 | 79.7 |
| Preparations. Control product 4 | 98.0 |
| Preparations. Control product 5 | 81.2 |
| Preparations. Control product 6 | 80.4 |
| Preparations. Control product 7 | 78.9 |
| Preparations. Control product 8 | 83.1 |
| Preparations. Control product 9 | 80.8 |
It can be seen that use cefadroxil benzyl compound produced by the present invention compared with commercial product from above-mentioned test result and show
There is capsule made from technology that there is preferable dissolution rate.
Experimental example 7：The test of preparation influence factor
Hot test takes trial target and reference substance, and opening is set in sealing clean container, places 10 days, presses at a temperature of 60 DEG C of degree
Stability high spot reviews project is detected.
High humidity test takes trial target and reference substance, and opening sets in constant-humidity clean container (relative humidity 90% ± 5%) placement
It 10 days, is detected by stability high spot reviews project.
Highlight test takes trial target and reference substance, and opening is set in lighting box, placed 10 days under the conditions of 4500LX, by stabilization
Property high spot reviews project is detected.
7 preparation influence factor test result of table
It is above-mentioned the experimental results showed that：Products of Cefadroxil Capsules prepared by invention formulation embodiment 1,3 is respectively through illumination, height
Indices are substantially unchanged after wet, hot test, and impurity content is low, compared with other samples, to strong light, high humility, height
The stability of temperature is obviously improved.
Above-mentioned experimental example 6-7 has also been carried out to the Products of Cefadroxil Capsules of the other example of formulations of the present invention, has been obtained
As a result similar.
Claims (6)
1. a kind of anti-infectives cefadroxil crystal-form compound, which is characterized in that the cefadroxil crystal form chemical combination
Shown in the structural formula of object such as formula (I), which is measured with powder x-ray diffraction measuring method, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern of expression as shown in Figure 1,
2. a kind of preparation method of anti-infectives cefadroxil crystal-form compound described in claim 1, which is characterized in that
This method comprises the following steps：
Cefadroxil bulk pharmaceutical chemicals are taken, is added in the mixed solvent A of the water of certain temperature, methanol, dimethylformamide, obtains molten
Liquid；Then apply stationary magnetic field in the horizontal direction of the liquid level of acquired solution, and to solution under conditions of the stationary magnetic field
The middle mixed solvent B that acetone, ethyl acetate, ether is added dropwise；After being added dropwise to complete, 3-5 hours are stood, filtering, filter cake is washed with ethyl alcohol
It washs, is dried in vacuo 2-4 hours, obtain the cefadroxil crystals compound；The wherein water, methanol, dimethyl formyl
The volume of the mixed solvent A of amine is 6-8 times of cefadroxil weight, and water, methanol and dimethylformamide volume ratio are 1：1:
2.5；The magnetic field strength is 0.8T-1.5T；The acetone, ethyl acetate, ether mixed solvent B volume be cefadroxil
8-10 times of benzyl weight；The volume ratio of the acetone, ethyl acetate and ether is 2:3:5.
3. preparation method according to claim 2, which is characterized in that the temperature is 35-45 DEG C.
4. a kind of Products of Cefadroxil Capsules, which is characterized in that it is brilliant that the capsule contains cefadroxil described in claim 1
Type compound.
5. Products of Cefadroxil Capsules according to claim 4, which is characterized in that contain 100% cefadroxil.
6. the preparation method of Products of Cefadroxil Capsules according to claim 4, which is characterized in that the preparation method includes such as
Lower step：
（1）Cefadroxil crystal-form compound described in claim 1 is crossed into 60 meshes, observation has foreign after sieving；
（2）It is filled, is dispensed with capsule, controlled content uniformity and disintegration time, must meet the quality standard.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031085A (en) * | 1987-08-03 | 1989-02-15 | 里法尔公司 | The method for preparing crystalline cefadroxil monoltyrate |
| CN101448842A (en) * | 2006-05-19 | 2009-06-03 | 帝斯曼知识产权资产管理有限公司 | Process for the crystallisation of cefadroxil |
| CN102134250A (en) * | 2011-01-19 | 2011-07-27 | 天津大学 | Crystallization method of cefadroxil monohydrate and crystals |
| CN102268019A (en) * | 2011-07-15 | 2011-12-07 | 海南美大制药有限公司 | Cefadroxil compound and preparation method thereof |
| CN103360412A (en) * | 2013-06-08 | 2013-10-23 | 苏州中联化学制药有限公司 | A kind of synthetic method of S 578 |
| CN104447795A (en) * | 2014-11-28 | 2015-03-25 | 珠海金鸿药业股份有限公司 | Cefadroxil compound and pharmaceutical composition comprising same |
| CN105534937A (en) * | 2015-12-30 | 2016-05-04 | 石药集团欧意药业有限公司 | Cefadroxil tablet and preparation method thereof |
| CN105640895A (en) * | 2016-01-15 | 2016-06-08 | 石药集团欧意药业有限公司 | Cefadroxil granular preparation and preparation method thereof |
| US20160263224A1 (en) * | 2015-03-09 | 2016-09-15 | Theaprin Pharmaceuticals Inc. | Platform drug delivery system utilizing crystal engineering and theanine dissolution |
-
2016
- 2016-11-08 CN CN201610977283.4A patent/CN106588953B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031085A (en) * | 1987-08-03 | 1989-02-15 | 里法尔公司 | The method for preparing crystalline cefadroxil monoltyrate |
| CN101448842A (en) * | 2006-05-19 | 2009-06-03 | 帝斯曼知识产权资产管理有限公司 | Process for the crystallisation of cefadroxil |
| CN102134250A (en) * | 2011-01-19 | 2011-07-27 | 天津大学 | Crystallization method of cefadroxil monohydrate and crystals |
| CN102268019A (en) * | 2011-07-15 | 2011-12-07 | 海南美大制药有限公司 | Cefadroxil compound and preparation method thereof |
| CN103360412A (en) * | 2013-06-08 | 2013-10-23 | 苏州中联化学制药有限公司 | A kind of synthetic method of S 578 |
| CN104447795A (en) * | 2014-11-28 | 2015-03-25 | 珠海金鸿药业股份有限公司 | Cefadroxil compound and pharmaceutical composition comprising same |
| US20160263224A1 (en) * | 2015-03-09 | 2016-09-15 | Theaprin Pharmaceuticals Inc. | Platform drug delivery system utilizing crystal engineering and theanine dissolution |
| CN105534937A (en) * | 2015-12-30 | 2016-05-04 | 石药集团欧意药业有限公司 | Cefadroxil tablet and preparation method thereof |
| CN105640895A (en) * | 2016-01-15 | 2016-06-08 | 石药集团欧意药业有限公司 | Cefadroxil granular preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 头孢羟氨苄单水合物反应结晶工艺优化;龚俊波等;《中国抗生素杂志》;20120430;第37卷(第4期);实验部分及结果与讨论部分 * |
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