CN102382007B - Doxycycline hydrochloride compound and preparation method thereof - Google Patents
Doxycycline hydrochloride compound and preparation method thereof Download PDFInfo
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- CN102382007B CN102382007B CN 201110281296 CN201110281296A CN102382007B CN 102382007 B CN102382007 B CN 102382007B CN 201110281296 CN201110281296 CN 201110281296 CN 201110281296 A CN201110281296 A CN 201110281296A CN 102382007 B CN102382007 B CN 102382007B
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- doxycycline hyclate
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Abstract
The invention relates to a doxycycline hydrochloride compound which has a purity of greater than 95% and a structural formula shown in the specification, and also relates to a preparation method of the high purity doxycycline hydrochloride compound. The preparation method comprises the following steps: 1, dissolving a raw material doxycycline hydrochloride in water, processing by a dilute acid, heating in the processing process, cooling, and filtering out the precipitated precipitate to obtain a water-contained filtrate; 2, adding a solvent which is insoluble in water to an aqueous solution (the water-contained filtrate) obtained in step 1 to extract, and removing the organic phase containing impurities to obtain an aqueous solution containing doxycycline hydrochloride; and 3, adding a poor solvent of doxycycline hydrochloride to the aqueous solution obtained in step 2, gradiently cooling to recrystallize, and centrifuging, washing and drying the precipitated crystal to obtain the purified doxycycline hydrochloride. The method of the invention, which allows the high purity doxycycline hydrochloride compound to be obtained and is in favor of improving the quality of preparation products and reducing toxic side effects, is suitable for the industrialized production.
Description
Technical field
The present invention relates to a kind of highly purified Doxycycline Hyclate compound and method for making thereof, belong to medical technical field.
Background technology
Doxycycline Hyclate (Doxycycline hydrochloride), chemical name are 6-methyl-4-(dimethylamino)-3,5,10,12,12a-penta hydroxy group-1,11-dioxo-Isosorbide-5-Nitrae, 4a, 5,5a, 6,11,12a-octahydro-2-tetracene carboxamide hydrochloride, molecular formula C
22H
24N
2O
8HCl, molecular weight: 480.90, structural formula:
Doxycycline Hyclate is the semi-synthetic tetracycline antibiotics of a kind of wide spectrum, effective to gram-positive microorganism, Gram-negative bacteria and chlamydozoan, clinical treatment for respiratory tract infection, biliary tract infection, tonsillitis, poradenolymphitis, phlegmon, senile chronic bronchitis, mycoplasma pneumonia, syphilis, gonorrhoea, typhus fever, cholera, typhinia, pernicious malaria and leptospiral prevention.
At present, the preparation of Doxycycline Hyclate is take 11a-chloro-6-methyne terramycin tosilate as starting raw material, generate a-6-deoxidation soil enzyme element sulfosalicylate through hydro-reduction, salify, generate a-6-doxycycline alkali through alkalization again, turn at last salt and generate Doxycycline Hyclate.
About the refining crystallization of Doxycycline Hyclate, adopt dehydrated alcohol suspendible free alkali to add the hydrochloric acid refining crystallization always.Shandong medicine thing had been reported improving one's methods of crystallization process of Doxycycline Hydrochloride in 2004, and hydrochloric acid is replaced carrying out the refining of Doxycycline Hyclate with Hydrochlorine-Ethanol.Yet the purity of the Doxycycline Hyclate that this kind method makes is still not high.
Summary of the invention
In order to overcome the defective of above-mentioned prior art, particularly overcome the low defective of Doxycycline Hyclate purity of prior art preparation, the invention provides a kind of method for making of highly purified Doxycycline Hyclate compound.
Process for purification provided by the invention for Doxycycline Hyclate be the present known prepared Doxycycline Hyclate crude product of synthetic method or Doxycycline Hyclate bulk drug commercially available or import, below be referred to as the raw material Doxycycline Hyclate that the present invention adopts.
The inventor by comprising the process for purification of following treatment step, can increase substantially the purity of raw material Doxycycline Hyclate through with keen determination research discovery:
Step 1), the raw material Doxycycline Hyclate is soluble in water, use diluted acid, preferably process with hydrochloric acid, the optional heating in treating processes, then the sedimentation and filtration of separating out is fallen in cooling, obtains to contain filter liquor;
Step 2), add and the immiscible solvent of water in the above-mentioned aqueous solution, one or more that are preferably in ethyl acetate, hexanaphthene and the chloroform extract, and then separate the organic phase that contains impurity, obtain to contain the aqueous solution of Doxycycline Hyclate;
Step 3), add the poor solvent of Doxycycline Hyclate in this aqueous solution, be preferably ethanol or acetone, and gradient reduces temperature, carry out recrystallization, with the crystal centrifuge washing of separating out, drying obtains the Doxycycline Hyclate of purifying.
The following specifically describes the present invention.
Step 1)
The raw material Doxycycline Hyclate is soluble in water, use diluted acid, preferably process with hydrochloric acid, the optional heating in treating processes, then the sedimentation and filtration of separating out is fallen in cooling, acquisition contain filter liquor.
This processes the diluted acid that uses 0.005-0.1M, preferred 0.01-0.08M, and more preferably 0.02-0.05M preferably adopts the hydrochloric acid in this concentration range.
This processing is chosen wantonly under heating and is carried out, and preferred temperature is 30-60 ℃, more preferably 40-50 ℃.Excess Temperature causes the unnecessary decomposition of organic substance or polyreaction easily, thereby causes the active constituents of medicine content, and color and luster is strengthened, and polymeric impurities content raises.
The time of this processing is generally several minutes to a few hours, and being preferably is 0.5 hour to 2 hours, more preferably 1 hour.After above-mentioned processing, have a small amount of Precipitation, along with temperature reduces, the precipitation capacity of separating out increases to some extent.
Generally speaking, when obtaining Doxycycline Hyclate, often introduce a small amount of ester class impurity.Under acidic conditions, help residual Ester hydrolysis, can effectively reduce impurity like this, can also promote in addition other insoluble impurities Precipitation.Preferably adopting hydrochloric acid and do not use other acid, is for fear of introducing unnecessary anionic impurity, for follow-up removal brings unnecessary trouble.
Step 2)
Add and the immiscible solvent of water in the above-mentioned aqueous solution, one or more that are preferably in ethyl acetate, hexanaphthene and the chloroform extract, and then separate the organic phase that contains impurity, obtain to contain the aqueous solution of Doxycycline Hyclate.
Described organic solvent ethyl acetate, hexanaphthene or chloroform also can use any two or three mixed solvent that forms in them.
The consumption of organic solvent is the 20-40% of the aqueous solution, can repeatedly extract, and preferably carries out 2 to 3 extractions, for abundant extraction, preferably stirs, and then removes the organic phase that contains impurity by separatory.
Why employing extracts, be based on following reason: generally speaking, also contain the solvent of introducing in the preparation process, various raw material and intermediate product in the raw material Doxycycline Hyclate, owing to drawing the moist moisture of bringing into, bacterial endotoxin, and various inorganics and heavy metal etc.These materials exist with the impurity form, affect the purity of raw material Doxycycline Hyclate.We notice that these substances content are very low, still be dissolved in the Doxycycline Hyclate aqueous solution with trace, but the solvability of these materials in organic solvent is larger, and extraction process are more common and the good separation method of effect.
Step 3)
The poor solvent that adds Doxycycline Hyclate in this aqueous solution is preferably a kind of in ethanol and the acetone or mixed solvent that their form, and the control temperature carries out recrystallization, and with the crystal centrifuge washing of separating out, drying obtains the Doxycycline Hyclate of purifying.
We study discovery, for Doxycycline Hyclate, adopt backflow recrystallization in the solvent commonly used or are suspended in the method for return stirring in the solvent, perhaps are difficult to crystallization, and perhaps double team has impurity in the precipitate.And directly process the purity that the Doxycycline Hyclate crude product can not reach expection with optimum-poor solvent liberation method.
Surprisingly, through above-mentioned steps 1 of the present invention) and 2) process after, when with above-mentioned solvent system Doxycycline Hyclate being carried out recrystallization, the crystal of acquisition based on very high purity.Its reason may be step 1 of the present invention) and 2) removed the impurity material that recrystallization is had disadvantageous effect.
When carrying out recrystallization, first at elevated temperatures, as not being higher than under 60 ℃ the temperature, with step 2) the Doxycycline Hyclate aqueous solution that obtains concentrates, thus water content is reduced, be 1: 1～4 according to aqueous solution volume with the solvent volume ratio then, preferred 1: 1～3, more preferably 1: 1～2 add solvent, and said solvent can be ethanol or acetone, perhaps the mixed solvent of ethanol and acetone equal-volume formation.Then carry out gradient cooling, the temperature that namely never is higher than 60 ℃ begins, and cools the temperature to 40～45 ℃ in 1 hour, then cools the temperature to 30～35 ℃ in 1 to 4 hour, in 2 to 10 hours, cool the temperature to room temperature at last, in this process, have crystal slowly to separate out.The optional Doxycycline Hyclate crystal seed that drops in temperature-fall period.After placing 5-12 hour, crystallization is complete.
Carry out drying after the crystallization, can adopt air to dry or dry, preferred 40-60 ℃ of oven for drying mode carried out drying.
The present invention has fundamentally changed the lower present situation of domestic and international Doxycycline Hyclate material purity; solved the difficult problem that rough Doxycycline Hyclate and Doxycycline Hyclate bulk drug face; improved because a series of clinical adverse of particulate matter or the more initiation of polymeric impurities composition; improve the formulation products quality, reduced toxic side effect.That the inventive method also has is easy, be easy to control and the characteristics of suitability for industrialized production.
In view of the powder flowbility of Doxycycline Hyclate, intrinsic dissolution rate, stability and preparation operability huge on the impact of the performance of its activity and the preparation prepared, and the Doxycycline Hyclate that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement.
Therefore, be fit to be mixed with treatment for to respiratory tract infection, biliary tract infection, tonsillitis, poradenolymphitis, phlegmon, senile chronic bronchitis, mycoplasma pneumonia, syphilis, gonorrhoea, typhus fever, cholera, typhinia, the pharmaceutical composition of pernicious malaria and leptospiral prevention fully according to the refining Doxycycline Hyclate of the inventive method.Described pharmaceutical composition comprises according to the inventive method refining Doxycycline Hyclate and pharmaceutically acceptable vehicle.Preferably, described pharmaceutical composition can be tablet, capsule, dry suspensoid or capsule and pill.
Embodiment
Further explain and describe by the following examples content of the present invention.But the embodiment that provides should not be understood to protection domain of the present invention is construed as limiting.
HPLC detects the purity of Doxycycline Hyclate
Chromatographic condition and system suitability
Be weighting agent (the pH value scope of application should greater than 9) with octadecylsilane chemically bonded silica; With acetate buffer [0.25mol/L ammonium acetate-0.1mol/L Calcium Disodium Versenate-triethylamine (100: 10: 1).Regulate pH value to 8.8 with Glacial acetic acid or ammoniacal liquor]-acetonitrile (85: 15) is moving phase; Column temperature is 35 ℃; The detection wavelength is 280nm.It is an amount of to take by weighing terramycin reference substance, metacycline reference substance, β-Vibravenos reference substance and how western strop reference substance.Adding 0.01mol/L. dissolve with hydrochloric acid solution well dilution makes and contains approximately respectively terramycin, metacycline, β-Vibravenos 0.1mg and molten tucking in of mixing of how western strop 0.2mg among every 1ml, get 20 μ l injection liquid chromatographies, the record color atlas, the resolution at Vibravenos peak and β-Vibravenos peak should should meet the requirements greater than 4.0. Vibravenos peak and rear adjacent towering resolution.
Detection method
Get sample of the present invention, the solution that contains Vibravenos 0.2mg among every 1ml is made in the dissolve with hydrochloric acid solution and the dilution that add 0.01mol, as need testing solution: precision is measured in right amount, with the 0.01mol/L hydrochloric acid soln quantitatively dilution make the solution that contains how western strop 4 μ g among every 1ml, in contrast solution.Get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be about 20% of full range.Precision is measured need testing solution and each 20 μ l of contrast solution.The injection liquid chromatography records color atlas to 2 times of principal constituent peak retention time respectively.If any impurity peaks, metacycline and β-Vibravenos peak area must not distinguish greater than contrast solution main peak area (2.0%) in the need testing solution color atlas.Other single impurity peak area must not be greater than 0.5 times (1.0%) of contrast solution main peak area.Each impurity peak area sum must not be greater than 2 times (4.0%) of contrast solution main peak area.
Embodiment 1
It is soluble in water to get 10g content and be 65% the Doxycycline Hyclate crude product according to the traditional method preparation, processes with the hydrochloric acid soln of 0.05M, and treatment temp is 45-50 ℃, treatment time is 1 hour, then be cooled to room temperature, Precipitation is arranged, obtain to contain filter liquor after filtering.
Add hexanaphthene extraction 2 times in the above-mentioned aqueous solution, each solvent for use volume accounts for 20% of described aqueous solution volume, after fully stirring, leaves standstill, and then separates organic phase, obtains to contain the water of Doxycycline Hyclate.
The Doxycycline Hyclate aqueous solution that obtains is increased to 60 ℃ to be concentrated, then in this aqueous solution, add ethanol at 1: 3 according to water and ethanol volume ratio, in 1 hour, cool the temperature to 40～43 ℃, then in 2 hours, cool the temperature to 30～33 ℃, in 5 hours, cool the temperature to room temperature at last, carry out recrystallization, crystallize out was placed 5 hours until no longer include crystal and separate out, centrifugal, 40 ℃ of oven dry get refining Doxycycline Hyclate 5.9g, and it is 95.6% that HPLC records purity.
Comparing embodiment 1
According to the method for describing in the medicine thing of Shandong the Doxycycline Hyclate that adopts among the embodiment 1 is made with extra care, the purity that records Doxycycline Hyclate is 80.1%.
Embodiment 2
Get 10g content and be 85.7% Doxycycline Hyclate bulk drug (Changzhou Pharmaceutical Factory Co., Ltd, H32021676), aqueous hydrochloric acid with 0.1M is processed, treatment temp is 45-50 ℃, treatment time is 0.5 hour, then be cooled to room temperature, Precipitation is arranged, obtain to contain filter liquor after filtering.
Add ethyl acetate extraction 3 times in the above-mentioned aqueous solution, each solvent for use volume accounts for 30% of described aqueous solution volume, after fully stirring, leaves standstill, and then separates organic phase, obtains to contain the water of Doxycycline Hyclate.
The Doxycycline Hyclate aqueous solution that obtains is increased to 58 ℃ to be concentrated, then in this aqueous solution, add acetone at 1: 4 according to water and acetone volume ratio, in 1 hour, cool the temperature to 42～45 ℃, then in 3 hours, cool the temperature to 31～34 ℃, in 6 hours, cool the temperature to room temperature at last, carry out recrystallization, crystallize out was placed 12 hours until no longer include crystal and separate out, centrifugal, 60 ℃ of oven dry get refining Doxycycline Hyclate 8.3g, and it is 96.7% that HPLC records purity.
Embodiment 3
(Shijiazhuang Hua Shushan closes pharmaceutcal corporation, Ltd to get 10g content and be 87.1% Doxycycline Hyclate bulk drug, H20043611), aqueous hydrochloric acid with 0.08M is processed, treatment temp is about 40 ℃, treatment time is 1.5 hours, then be cooled to room temperature, Precipitation is arranged, obtain to contain filter liquor after filtering.
Add chloroform extraction 2 times in the above-mentioned aqueous solution, each solvent for use volume accounts for 30% of described aqueous solution volume, after fully stirring, leaves standstill, and then separates organic phase, obtains to contain the water of Doxycycline Hyclate.
The Doxycycline Hyclate aqueous solution that obtains is increased to 55 ℃ to be concentrated, then in this aqueous solution, added ethanol and the isopyknic mixed solvent of acetone than 1: 2 according to the aqueous solution and solvent volume, in 1 hour, cool the temperature to 40～42 ℃, then in 1 hour, cool the temperature to 31～33 ℃, in 4 hours, cool the temperature to room temperature at last, carry out recrystallization, crystallize out, placed 5 hours until no longer include crystal and separate out, centrifugal, 50 ℃ of oven dry get refining Doxycycline Hyclate 8.6g, and it is 97.2%% that HPLC records purity.
Embodiment 4
Get the expired content of 10g and be Doxycycline Hyclate bulk drug (Shanghai Wuzhou Pharmaceutical Industry Co., Ltd. of 71.1%, H31020100), aqueous hydrochloric acid with 0.01M is processed, treatment temp is 40 ℃, treatment time is 1 hour, then be cooled to room temperature, Precipitation is arranged, obtain to contain filter liquor after filtering.
Add hexanaphthene extraction 3 times in the above-mentioned aqueous solution, each solvent for use volume accounts for 30% of described aqueous solution volume, after fully stirring, leaves standstill, and then separates organic phase, obtains to contain the water of Doxycycline Hyclate.
The Doxycycline Hyclate aqueous solution that obtains is increased to 55 ℃ to be concentrated, then in this aqueous solution, added ethanol and the isopyknic mixed solvent of acetone than 1: 3 according to the aqueous solution and solvent volume, slowly be cooled to room temperature, carry out recrystallization, crystallize out was placed 12 hours until no longer include crystal and separate out, centrifugal, 60 ℃ of oven dry get refining Doxycycline Hyclate 6.8g, and it is 95.9% that HPLC records purity.
According to the above embodiments the present invention is described in detail.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (9)
1. the method for making of a Doxycycline Hyclate compound is characterized in that may further comprise the steps:
Step 1), the raw material Doxycycline Hyclate is soluble in water, process with diluted acid, the optional heating in treating processes, then the sedimentation and filtration of separating out is fallen in cooling, obtains to contain filter liquor;
Step 2), adds with the immiscible solvent of water in the above-mentioned aqueous solution and extract, then separate the organic phase that contains impurity, obtain to contain the aqueous solution of Doxycycline Hyclate;
Step 3) adds the poor solvent of Doxycycline Hyclate in this aqueous solution, and gradient reduces temperature, carries out recrystallization, and with the crystal centrifuge washing of separating out, drying obtains the Doxycycline Hyclate of purifying.
2. the method for making of Doxycycline Hyclate compound according to claim 1 is characterized in that,
In step 1), described acid is hydrochloric acid,
In step 2) in, described solvent is one or more in ethyl acetate, hexanaphthene and the chloroform,
In step 3), described solvent is the mixed solvent of ethanol or acetone or their formation.
3. the method for making of each described Doxycycline Hyclate compound according to claim 1 and 2 is characterized in that, uses the diluted acid of 0.005-0.1M in the step 1).
4. the method for making of Doxycycline Hyclate compound according to claim 3 is characterized in that, uses the hydrochloric acid of 0.005-0.1M in the step 1).
5. the method for making of Doxycycline Hyclate compound according to claim 1 is characterized in that, treatment temp described in the step 1) is 30-60 ℃, and the treatment time is 0.5 hour to 2 hours.
6. the method for making of Doxycycline Hyclate compound according to claim 1 is characterized in that step 2) in, the consumption of organic solvent is the 20-40% of the aqueous solution when extracting at every turn, extraction times is 2 to 3 times.
7. the method for making of Doxycycline Hyclate compound according to claim 1, it is characterized in that, in the step 3), be 1 ~ 4 adding solvent according to aqueous solution volume and solvent volume ratio, described solvent is ethanol or acetone, perhaps the mixed solvent of ethanol and acetone equal-volume formation.
8. the method for making of Doxycycline Hyclate compound according to claim 1, it is characterized in that, in the step 3), in the gradient cooling process, the temperature that never is higher than 60 ℃ begins, in 1 hour, cool the temperature to 40 ~ 45 ℃, then in 1 to 4 hour, cool the temperature to 30 ~ 35 ℃, in 2 to 10 hours, cool the temperature to room temperature at last.
9. the compound method for making of Doxycycline Hyclate according to claim 1 is characterized in that, in the step 3), drops into the Doxycycline Hyclate crystal seed in the temperature-fall period, adopts 40-60 ℃ of oven for drying mode to carry out drying to crystallization.
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| CN106543025A (en) * | 2015-09-21 | 2017-03-29 | 瑞普（天津）生物药业有限公司 | A kind of preparation method of high-purity hydrochloric acid doxycycline |
| CN107445855B (en) * | 2017-08-07 | 2018-12-14 | 绍兴市逸晨医疗科技有限公司 | A kind of preparation method of Doxycycline Hyclate impurity C |
| CN107703228B (en) * | 2017-10-18 | 2020-03-27 | 北京市药品检验所 | Method for determining tetracycline antibiotic residue in bovine lung surfactant extract |
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| CN101555215B (en) * | 2009-05-12 | 2010-06-09 | 海口奇力制药股份有限公司 | Preparation technology of doxycycline hydrochloride for injection |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101555215B (en) * | 2009-05-12 | 2010-06-09 | 海口奇力制药股份有限公司 | Preparation technology of doxycycline hydrochloride for injection |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
Non-Patent Citations (6)
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| spectroscopic and Thermodynamic Study of Charge Transfer Interaction of Doxycycline ydrochloride with Riboflavin in Aqueous Ethanol Media of Varying Compolsitions;Saha等;《J. Phys. Chem. B》;20041113;第108卷(第49期);18988 * |
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