CN102516096A - Hydrochloric acid ambroxol compound and novel preparation method thereof - Google Patents
Hydrochloric acid ambroxol compound and novel preparation method thereof Download PDFInfo
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- CN102516096A CN102516096A CN2011103877365A CN201110387736A CN102516096A CN 102516096 A CN102516096 A CN 102516096A CN 2011103877365 A CN2011103877365 A CN 2011103877365A CN 201110387736 A CN201110387736 A CN 201110387736A CN 102516096 A CN102516096 A CN 102516096A
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Abstract
The invention relates to a hydrochloric acid ambroxol compound and a novel preparation method thereof, which include the following steps: 1, dissolving coarse hydrochloric acid ambroxol with certain amount into solvent, adding active carbon for adsorption, filtering, collecting filtering liquid and conducting decompressing and concentration; 2 conducting separation purification on concentration liquid through a preparation type chromatographic column, collecting eluent and conducting decompressing and concentration; and 3 conducting negative pressure crystallization on hydrochloric acid ambroxol concentration liquid obtained in the step2, first conducting concentration under negative pressure and rising temperature, then reducing temperature, adding hydrochloric acid ambroxol seed crystal, maintaining the temperature till the ideal crystal is obtained if fine crystal occurs, separating the precipitated crystal by filtering or centrifugation and conducting washing and drying on the crystal to finally obtain purified hydrochloric acid ambroxol. The hydrochloric acid ambroxol prepared in the method is high in purity, even in crystal, complete in crystal shape, good in flowing performance and large in processing quantity. The reaction can be conducted continuously, so that the method is especially suitable for industrial production. Simultaneously, the hydrochloric acid ambroxol compound and the method improve product quality and reduce toxic side effect.
Description
Technical field
The present invention relates to a kind of Ambroxol HCl compound and method for making thereof, belong to medical technical field.
Background technology
Ambroxol HCl (Ornidazole), white to little yellow crystalline powder; Almost tasteless, chemical name: trans-4-[(the amino 3.5-dibromo-benzyl of 2-) amino] cyclohexanol hydrochloridumi, molecular formula: C
13H
18Br
2N
2OHCl, molecular weight: 414.57, structural formula is:
Ambroxol HCl has the characteristic that mucus is got rid of promoter action and dissolving secretory product, and it can promote the eliminating of the inner thick secretions of respiratory tract and reduce mucous delay, thereby significantly promotes expectoration, improves breath state.During the treatment of these article of application, the mucous secretion of patient can return to normal condition.Cough and amount of expectoration usually significantly reduce, the surfactant on the respiratory mucosa thereby can bring into play its normal defencive function.
The method of prior art, step is various, is not suitable for industrial production; Perhaps yield is lower, has expended a large amount of raw materials, causes the high enterprise of cost.
In addition, deposit improper or shelf-time when long at compound, can cause active constituents of medicine content to reduce, color and luster is strengthened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Prior art does not disclose special purification process to this, therefore be necessary underproof like this product or bullion are further carried out purifying, is refined into highly purified compound with high yield.This area presses for the compound method that works out a kind of low cost, high yield, is applicable to the Ambroxol HCl of big production, to overcome above-mentioned shortcoming.
The technical issues that need to address of the present invention are the deficiencies that overcome prior art, and a kind of purification process of Ambroxol HCl compound is provided, and this method is simple, and product purity is high, and yield is high, is easy to suitability for industrialized production.
Summary of the invention
In order to overcome the defective of above-mentioned prior art, improve Ambroxol HCl purity, reduce the residual of toxic solvents; The invention provides a kind of purification process of Ambroxol HCl compound; Preparing method of the present invention can improve the formulation products quality, reduces toxic side effect, is suitable for industrialized production.
Aspect separation and purification; Know in the specificity owing to compound aspect the high yield compound of acquisition high purity with those skilled in the art know that and face all difficulties; All these just can be expected by the theory of existing general separation and purification absolutely not solution need overcome many difficult problems.
Generally speaking, conventional separation method has, and for example comprises the cooling of reaction mixture, then through filtering the crystalline method of collecting; Comprise adding thermal crystalline, and use solvent wash that distillation is except that desolvating and cooling off the crystalline method that obtains then; Solvent extration; Dilution method; Recrystallization method; Column chromatography; Methods such as preparation thin-layer chromatography.
The applicant is on the basis of a large amount of existing documents; Experiment through a large amount of screenings; Find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter possibly exist varied associativity and unpredictability.The inventor is through long-term conscientious research, and after Combination application specific method and parameters optimization, accident has been found a kind of purification process of Ambroxol HCl compound, has obtained the highly purified product of high yield astoundingly.
The Ambroxol HCl that process for purification provided by the invention was directed against is prepared Ambroxol HCl bullion of present known compound method or commercially available Ambroxol HCl bulk drug, below is referred to as the Ambroxol HCl bullion that the present invention adopts.
The inventor through comprising the preparation method of following treatment step, can increase substantially the purity of raw material Ambroxol HCl through discovering:
(1) with a certain amount of Ambroxol HCl dissolving crude product in solvent, add charcoal absorption, filter, collect filtrating, concentrating under reduced pressure;
(2) above-mentioned liquid concentrator is carried out separation and purification with the preparative scale chromatography post, collect elutriant, concentrating under reduced pressure;
(3) the Ambroxol HCl liquid concentrator that above-mentioned steps 2 is obtained carries out the negative pressure crystallization,, under the temperature of negative pressure and rising, concentrates earlier for this reason; Reduce temperature then, add the Ambroxol HCl crystal seed, when tiny crystal grain occurring; Keep temperature until obtaining the ideal crystal, afterwards with the crystal of separating out through filtering or centrifugal the separation washing; Drying finally obtains the purified Ambroxol HCl.
The following specifically describes the present invention.
Step 1, in solvent, charcoal absorption is filtered with a certain amount of Ambroxol HCl dissolving crude product, collects filtrating, and concentrating under reduced pressure obtains the Ambroxol HCl of elementary purification.
Said solvent is selected from the lower alcohol or the non-alcohols polar solvent that can make the Ambroxol HCl homogenizing, is selected from one or more the mixture in methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile, tetramethylene sulfone, hydroxy-propionic acid, the terepthaloyl moietie, is preferably methyl alcohol.
In one aspect of the invention, the separation and the purification process of medicine comprise adsorption method, as using gac.The present invention confirms that gac can be used for the preparation method of Ambroxol HCl, and the amount of wherein said adding gac is the 0.2-0.5% (g/ml) of overall solution volume.
Above-mentioned described preparation method is dissolved in order to make Ambroxol HCl better, chooses wantonly through heating it to be dissolved in the said solvent.The temperature of whip attachment can also can be carried out for room temperature at elevated temperatures, and the time of whip attachment is 15-25 minute.
The possible reason of effect that step 1 of the present invention adopts charcoal absorption why can reach purification is: the larger molecular organicses such as coloring matter of gac molecule in can adsorbent solution.
Step 2 is carried out separation and purification with the preparative scale chromatography post, collects elutriant, and concentrating under reduced pressure obtains the Ambroxol HCl that secondary is purified.
Generally speaking, contain the solvent of introducing in the preparation process, various raw material, intermediate product in the Ambroxol HCl, owing to drawing the moist moisture of bringing into; Bacterial endotoxin; And various inorganicss and heavy metal etc., these materials exist with the form of impurity, have influenced the purity of Ambroxol HCl.The present invention uses the separation and purification function of preparative scale chromatography post, and the part of the Ambroxol HCl in the solution is partly separated with impurity, reaches the purpose of purification Ambroxol HCl.
The applicant is through long-term conscientious big quantity research; In the separation and purification process; Screened various filler chromatographic columns such as silica gel, aluminum oxide or macroporous resin, for example the particle diameter of silica gel is 45-250 μ m, the silica gel of aperture for
; Aluminum oxide or neutral alumina particle diameter are aluminum oxide or the neutral alumina of 18-200 μ m, and the macroporous resin model is macroporous resins such as AmberliteXAD-6, AmberliteXAD-7, AmberliteXAD-8, Diaion HP2MG, GDX-501, HPD400, HPD450, HPD750, AmberliteXAD-9, AmberliteXAD-10, GDX-401, GDX-601, AB-8.
The unexpected application macroporous resin of finding of the inventor does not have clear improvement to product gas purity; Silica gel is also undesirable; And special-purpose neutral alumina not only can fully adsorb composition impurity and other pigment in the upper prop thing, also these article purifying is had original windfall effect, and operation is simpler and easy.
In one aspect of the invention, said stationary phase is that particle diameter is 18-200 μ m, and the aperture is 50-200 μ m for pore neutral alumina or the particle diameter of about 6nm, and the aperture is 6nm, the column chromatography special neutral aluminum oxide of pH 7.0 or pH 7.5.
In one aspect of the invention, neutral alumina can for example be that the ICN allumina N preferable particle size of supplier ICN is 18-63 μ m, and the aperture is the pore neutral alumina of 6nm; PH 7.5; Preferable particle size is 18-32 μ m, and the aperture is the pore neutral alumina of 6nm, and pH 7.5.Perhaps, neutral alumina for example is a supplier Baker column chromatography special neutral aluminum oxide, and particle diameter is 50-200 μ m, and the aperture is 6nm, pH 7.0 or pH 7.5.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of chromatographic column filler: 10-200, the preferred mass ratio is 1: 15-100.The consumption of moving phase is as long as satisfy the complete basically wash-out of medicine; Flow point Fractional Collections behind the wash-out; The content of the flow point Chinese traditional medicine of different sections is different, in order to obtain highly purified medicine (for example purity is greater than 99.5%), needs medicament contg is merged greater than 85% flow point; Preferably medicament contg is incorporated in one aspect of the present invention greater than 90% flow point, the required purity that obtains in the methods of the invention depends on the amount of impurity and the operating environment of chromatographic column to a certain extent.The selection of organic solvent and consumption must be controlled in moving phase, make can not come out the impurity wash-out prematurely.
Generally speaking, the column diameter of the used chromatographic column of the present invention is about 0.1 to about 20cm, is preferably 3cm at least.The chromatogram column length scope is preferably about 10 centimetres to about 100 centimetres in this method, and more preferably length range is about 20 centimetres to about 30 centimetres, and most preferred length is 25 centimetres.
Preparing method of the present invention; Wherein the moving phase used of chromatographic column is 1: 1～2 acetonitrile and the mixed solvent of water or the mixed solvent of methyl alcohol and water as volume ratio; Preferred its volume ratio is 1: 1.2～1.8, more preferably 1: 1.3～1.6, most preferably be 1: 1.5; Fixed phase stuffing is selected from neutral alumina, and flow velocity 0.2-2ml/min, column temperature are room temperature, wavelength 248nm.
Preparing method of the present invention, wherein the temperature of concentrating under reduced pressure is 50 ℃.
Step 3, the Ambroxol HCl liquid concentrator that above-mentioned steps 2 is obtained carries out the negative pressure crystallization, for this reason; Under the temperature of negative pressure and rising, concentrate earlier, reduce temperature then, add the Ambroxol HCl crystal seed; When tiny crystal grain occurring, keep temperature until obtaining the ideal crystal, afterwards with the crystal of separating out through filtering or centrifugal the separation; Washing, drying finally obtains the purified Ambroxol HCl.
According to the present invention, the negative pressure crystallization of Ambroxol HCl solution is carried out in the preferred crystallizer in crystallisation vessel.Below be that example is described its concrete operations with the crystallizer:
1), Ambroxol HCl solution is partly or entirely added in the crystallizer, then crystallizer is vacuumized, realize negative pressure; For example make vacuum tightness reach-0.05 to-0.25MPa, preferred-0.08 to-0.20Mpa, more preferably-0.10 to-0.15Mpa; Then through the heating unit on the crystallizer; For example, make temperature reach 72-82 ℃, carry out evaporation concentration through steam through opening the hot steam valve;
2), when being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-60%, lower the temperature, for example through closing the heating steam valve; Temperature natural is descended, when for example reducing to 52-62 ℃, close and vacuumize valve; Open and add the crystal seed valve; Preprepared Ambroxol HCl crystal seed is sucked crystallizer rapidly, close and add the crystal seed valve, open then and vacuumize valve and accomplish and add crystal seed work;
When 3), on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up in the boiling concentration process gradually, and supersaturated solution on every side is fewer and feweri; Can invent the Ambroxol HCl solution that above-mentioned steps 2 obtains by suitable supplementary copy this moment in crystallizer; Temperature is controlled at 52-62 ℃, if continue feed supplement, crystallization can continue to carry out; In order to make crystallization more complete, through the chuck on the crystallization apparatus, utilize circulating water temperature to come attemperation or cooling, make the Ambroxol HCl solution in the crystallization apparatus further carry out the supersaturation crystallization, and help crystal growth;
4), observe crystal grain and whether reach requirement, general the about 6-12 of crystallization hour, the preferred crystal of the suitable crystal grain of acquisition after 8-10 hour.Open baiting valve the material of advantages of good crystallization is infeeded in the tripping device this moment, for example strainer or whizzer, and through filtering or centrifugal the separation, washing, drying finally obtains the purified Ambroxol HCl.
Preparing method of the present invention, wherein said Ambroxol HCl crystallization can use solid drier dry, and said solid drier is selected from a kind of in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous calciumsulphate and the activated alumina, preferred Calcium Chloride Powder Anhydrous.
The whole crystallisation process time spent of the present invention is also short than the conventional crystallization mode time spent, and prepared Ambroxol HCl uniform crystal particles, complete in crystal formation; And better mobile, compared with prior art, this present invention process for refining is simple and easy to do; Mild condition, cost is low, and product purity is high.Especially treatment capacity is big, and can carry out continuously, therefore is particularly suitable for carrying out suitability for industrialized production.
In view of the powder flowbility of Ambroxol HCl, intrinsic dissolution rate, Pickering property and preparation operability huge to the influence of its active performance and the preparation prepared; And the Ambroxol HCl that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement; Therefore improve the quality product of preparation, reduced toxic side effect.
According to the inventive method purified Ambroxol HCl, it can promote the eliminating of the inner thick secretions of respiratory tract and reduce mucous delay, thereby significantly promotes expectoration, improves breath state.During the treatment of these article of application, the mucous secretion of patient can return to normal condition.Cough and amount of expectoration usually significantly reduce, the surfactant on the respiratory mucosa thereby can bring into play its normal defencive function.
The present invention has fundamentally changed the lower present situation of domestic and international Ambroxol HCl material purity, has solved the difficult problem that rough Ambroxol HCl and Ambroxol HCl bulk drug face, and has improved because a series of clinical adverse of the more initiation of impurity.
In addition, the inventive method purity is high, obtains purity and is not less than 99.5%.Its method for detecting purity is known in the art, but High performance liquid chromatography, for example Ambroxol HCl Injection by HPLC assay method.
Embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
The HPLC method for detecting purity
These article of getting are with moving phase dissolving and process the solution that contains 1mg among every 1ml, as need testing solution; Precision is measured 1ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as contrast solution; Other gets the about 5mg of these article, adds methyl alcohol 0.2ml dissolving, adds formaldehyde solution (1 → 100) 40 μ l again, shakes up; Put 60 ℃ of heating 5 minutes, nitrogen dries up, residue water 5ml dissolving; Add moving phase again and be diluted to 20ml, get 20 μ l and inject liquid chromatograph, measure according to efficient phase of wave chromatography (appendix V D); Using octadecylsilane chemically bonded silica to be weighting agent, is moving phase with 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50), and the detection wavelength is 248nm.The separating size of Ambroxol HCl and impurity B (relative retention time is about 0.8) should be greater than 4.0.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, making principal constituent chromatographic peak peak height is the 20%-25% of full range; Precision is measured each 20 μ l of need testing solution and contrast solution again, injects liquid chromatograph respectively, 2 times of record color atlas to principal constituent peak RT.In the need testing solution color atlas, if any impurity peaks, each impurity peak area with must not be greater than 1/3 of contrast solution main peak area.
Making with extra care of embodiment 1 Ambroxol HCl
The Ambroxol HCl bullion (its HPLC purity is 92.52%) that 10g is made according to art methods is dissolved in the 80ml methyl alcohol, stirs, and it is dissolved fully, adds the gac of 0.3g then, whip attachment 20 minutes, and filtering decarbonization is collected filtrating; Add the 10g aluminum oxide again after concentrating and stir, be added to preparative scale chromatography post upper end after flinging to solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 1: 1.5 the acetonitrile and the mixed solvent of water as volume ratio, and flow velocity 0.2ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure.
The Ambroxol HCl solution that is obtained is added in the crystallizer, then crystallizer is vacuumized, vacuum tightness is reached-0.10Mpa, open the hot steam valve on the crystallizer then, make temperature reach 75-78 ℃, carry out evaporation concentration through steam;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 55-60%; Close the heating steam valve, when making temperature reduce to 55-60 ℃, close and vacuumize valve; Open and add the crystal seed valve; Preprepared Ambroxol HCl crystal seed is sucked crystallizer, close and add the crystal seed valve, open then and vacuumize valve;
When on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up gradually, and supersaturated solution on every side reduces; Can replenish a part of Ambroxol HCl solution this moment in crystallizer, temperature is controlled at 55-60 ℃; Can utilize circulating water temperature to lower the temperature through the chuck on the crystallization apparatus then, make further crystallization of Ambroxol HCl solution and growth;
Crystallization obtains the crystal of suitable crystal grain after about 8 hours.Open baiting valve this moment and the material of advantages of good crystallization is infeeded strainer separate, the less water washing, Calcium Chloride Powder Anhydrous is dry, Ambroxol HCl 9.03g, its HPLC purity is 99.63%, mp. is 77.5 ℃.
IR(KBr)：v?1627(NH
2)，1469，1063，819cm
-1；
1H-NMR (CDCl
3): δ 7.50 (s, 1H, C
4-H), 7.15 (5,1H, C
6-H), 5.35 (s, 2H, Ar-NH
2), 3.85 (s, 2H, Ar-CH
2), 3.65 (m, 1H, C
1-H), 2.50 (m, 1H, C
4-H), 2.05 (d, 4H, C
2-H and C
6-H), 1.55 (s, 2H, OH, NH), 1.30 (m, 4H, C
3-H and C
5-H);
MS：m/z378(M
+)，279，264，114。
Making with extra care of comparative example's 1 Ambroxol HCl
10g Ambroxol HCl bullion (its HPLC purity is 92.52%) is dissolved in the 80ml methyl alcohol, stirs, it is dissolved fully, add the gac of 0.3g then, whip attachment 20 minutes, filtering decarbonization is collected filtrating; Add 10g silica gel again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 1: 1.5 the acetonitrile and the mixed solvent of water as volume ratio, and flow velocity 0.2ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are that the AmberliteXAD-6 type macroporous resin model of 6nm does; Column temperature is a room temperature; Wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets Ambroxol HCl 8.53g, and its purity is 98.63%, and mp. is 77-78 ℃.
Making with extra care of embodiment 2 Ambroxol HCls
With 10g Ambroxol HCl bulk drug (pharmaceutical factory: SHANDONG LUOXIN PHARMACY STOCK Co., LTD., lot number: 20091102; HPLC purity is 92.76%) under heating, be dissolved in the 100ml ethanol, stir, it is dissolved fully, add the gac of 0.2g then, whip attachment 15 minutes, filtering decarbonization is collected filtrating; Add the 10g aluminum oxide again after concentrating and stir, be added to preparative scale chromatography post upper end after flinging to solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is the mixed solvent of 1: 1.2 first alcohol and water as volume ratio, and flow velocity 2ml/min, fixed phase stuffing are particle diameter 50-200 μ m; The Baker column chromatography special neutral aluminum oxide of aperture 6nm, column temperature is a room temperature, wavelength 248nm; Collect elutriant, 50 ℃ of concentrating under reduced pressure.
In the most of adding of the Ambroxol HCl solution that is obtained crystallizer, then crystallizer is vacuumized, vacuum tightness is reached-0.13Mpa, open the hot steam valve on the crystallizer then, make temperature reach 73-76 ℃ through steam, carry out evaporation concentration;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 53-57%; Close the heating steam valve, make temperature natural drop to 54-58 ℃, close and vacuumize valve; Open and add the crystal seed valve; Preprepared Ambroxol HCl crystal seed is sucked crystallizer rapidly, close and add the crystal seed valve, open then and vacuumize valve and accomplish and add crystal seed work;
When on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up in the boiling concentration process gradually, and supersaturated solution on every side is fewer and feweri; In crystallizer, replenish remaining Ambroxol HCl solution this moment; Temperature is controlled at 54-58 ℃, continues feed supplement, and crystallization continues to carry out; Through the chuck on the crystallization apparatus, utilize circulating water temperature to adjust the temperature to 42-45 ℃, make the Ambroxol HCl solution in the crystallization apparatus further carry out the supersaturation crystallization;
Crystallization obtains the crystal of suitable crystal grain after about 10 hours.Opening baiting valve, that the material of advantages of good crystallization is infeeded whizzer 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, Ambroxol HCl 9.27g, its HPLC purity is 99.7%, mp. is 78 ℃.
Making with extra care of embodiment 3 Ambroxol HCls
With 10g Ambroxol HCl bulk drug (pharmaceutical factory: SHANDONG LUOXIN PHARMACY STOCK Co., LTD., lot number: 20091102; HPLC purity is 92.76%) under heating, be dissolved in the 120ml terepthaloyl moietie, stir, it is dissolved fully, add the gac of 0.4g then, whip attachment 15 minutes, filtering decarbonization is collected filtrating; Add the 15g aluminum oxide again after concentrating and stir, be added to preparative scale chromatography post upper end after flinging to solvent, then filtrating is carried out separation and purification; Wherein the moving phase used of chromatographic column is the mixed solvent of 1: 1.8 first alcohol and water as volume ratio, and flow velocity 1ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure.
60% of Ambroxol HCl liquor capacity is added in the crystallizer, then the crystallizer suction is reached more preferably-0.13Mpa, through opening the hot steam valve on the crystallizer, make temperature reach 72-77 ℃ then, carry out evaporation concentration through steam;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-55%,, temperature natural is descended through closing the heating steam valve; When for example reducing to 51-54 ℃; Close and vacuumize valve, open and add the crystal seed valve, preprepared Ambroxol HCl crystal seed is sucked crystallizer; Close and add the crystal seed valve, open then and vacuumize valve and accomplish and add crystal seed work;
When on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up in the boiling concentration process gradually, and supersaturated solution on every side is fewer and feweri; In crystallizer, suitably replenish remaining Ambroxol HCl solution this moment; Temperature is controlled at 51-54 ℃, continues feed supplement, and crystallization continues to carry out; Through the chuck on the crystallization apparatus, utilize circulating water temperature to come attemperation 40-44 ℃ then, make further supersaturation crystallization of Ambroxol HCl solution and slowly growth in the crystallization apparatus;
Crystallization obtains the crystal of suitable crystal grain after about 12 hours.Open baiting valve the material of advantages of good crystallization is infeeded strainer this moment, separates through filtration, and Calcium Chloride Powder Anhydrous is dry, Ambroxol HCl 9.36g, its HPLC purity is 99.78%, mp. is 77.5 ℃.
Making with extra care of embodiment 4 Ambroxol HCls
With the expired Ambroxol HCl raw material of 10g (pharmaceutical factory: SHANDONG LUOXIN PHARMACY STOCK Co., LTD.'s lot number: 20040902; HPLC purity is 89.02%) be dissolved in the 100ml methyl alcohol, stir, it is dissolved fully, add the gac of 0.3g then, whip attachment 20 minutes, filtering decarbonization is collected filtrating; Add the 15g aluminum oxide again after concentrating and stir, be added to preparative scale chromatography post upper end after flinging to solvent, then filtrating is carried out separation and purification; Wherein the moving phase used of chromatographic column is 1: 1.3 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 1.5ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure.
70% of Ambroxol HCl liquor capacity is added in the crystallizer, then the crystallizer suction is reached more preferably-0.08Mpa, through opening the hot steam valve on the crystallizer, make temperature reach 75-78 ℃ then, carry out evaporation concentration through steam;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 56-59%,, temperature natural is descended through closing the heating steam valve; When for example reducing to 55-59 ℃; Close and vacuumize valve, open and add the crystal seed valve, preprepared Ambroxol HCl crystal seed is sucked crystallizer; Close and add the crystal seed valve, open then and vacuumize valve;
When on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up in the boiling concentration process gradually, and supersaturated solution on every side is fewer and feweri; In crystallizer, suitably replenish remaining Ambroxol HCl solution this moment; Temperature is controlled at 55-59 ℃, continues feed supplement, and crystallization continues to carry out; Through the chuck on the crystallization apparatus, utilize circulating water temperature to come attemperation 42-45 ℃ then, make further supersaturation crystallization of Ambroxol HCl solution and slowly growth in the crystallization apparatus;
Crystallization obtains the crystal of suitable crystal grain after about 10 hours.Open baiting valve the material of advantages of good crystallization is infeeded strainer this moment, separate through filtration, less water washing 3 times, Calcium Chloride Powder Anhydrous is dry, Ambroxol HCl 8.90g, its HPLC purity 99.65%, mp. is 77.7 ℃.
Making with extra care of comparative example's 2 Ambroxol HCls
With the expired Ambroxol HCl raw material of 10g (pharmaceutical factory: SHANDONG LUOXIN PHARMACY STOCK Co., LTD.'s lot number: 20040902; HPLC purity is 89.02%) be dissolved in the 120ml ethanol, stir, it is dissolved fully, add the gac of 0.3g then, whip attachment 20 minutes is filtered decarburization, collects filtrating; Concentrated back adds pure water, stirs, and crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets Ambroxol HCl 7.42g, its HPLC purity 95.28%.
The foregoing description and Comparative Examples have proved absolutely the meliority of particular combination method of the present invention from different aspects, especially comprise the chromatographic condition and the optimum parameters of preparative scale chromatography post, have brought beyond thought effect, are in theory can't rational expectation.Bound by theory not; What possibly be various purification process to different impurities in the medicine removes the effect difference; The purification process of the present invention's combination has collaborative centrifugation to the impurity in the medicine; Process for purification provided by the invention has the characteristics and the obvious improvement of essence, and the beyond thought technique effect of obtaining has obtained the highly purified product of high yield.
According to the above embodiments the present invention has been made detailed description, and the present invention confirms that through relevant with it comparative example the present invention has obtained unexpected excellent effect.What need explanation is 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 is within protection scope of the present invention.
Claims (10)
1. the highly purified Ambroxol HCl compound of a structure as follows is characterized in that method for making may further comprise the steps:
Step 1 in solvent, adds charcoal absorption with a certain amount of Ambroxol HCl dissolving crude product, filters, and collects filtrating, concentrating under reduced pressure;
Step 2 is carried out separation and purification with above-mentioned liquid concentrator with the preparative scale chromatography post, collects elutriant, concentrating under reduced pressure;
Step 3, the Ambroxol HCl liquid concentrator that above-mentioned steps 2 is obtained carries out the negative pressure crystallization, for this reason; Under the temperature of negative pressure and rising, concentrate earlier, reduce temperature then, add the Ambroxol HCl crystal seed; When tiny crystal grain occurring, keep temperature until obtaining the ideal crystal, afterwards with the crystal of separating out through filtering or centrifugal the separation; Washing, drying finally obtains the purified Ambroxol HCl.
2. the process for purification of an Ambroxol HCl is characterized in that may further comprise the steps:
Step 1 in solvent, adds charcoal absorption with a certain amount of Ambroxol HCl dissolving crude product, filters, and collects filtrating, concentrating under reduced pressure;
Step 2 is carried out separation and purification with above-mentioned liquid concentrator with the preparative scale chromatography post, collects elutriant, concentrating under reduced pressure;
Step 3, the Ambroxol HCl liquid concentrator that above-mentioned steps 2 is obtained carries out the negative pressure crystallization, for this reason; Under the temperature of negative pressure and rising, concentrate earlier, reduce temperature then, add the Ambroxol HCl crystal seed; When tiny crystal grain occurring, keep temperature until obtaining the ideal crystal, afterwards with the crystal of separating out through filtering or centrifugal the separation; Washing, drying finally obtains the purified Ambroxol HCl.
3. according to the process for purification of the Ambroxol HCl of claim 1 or 2; It is characterized in that; In the step 1, described solvent is one or more the mixture in methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile, tetramethylene sulfone, hydroxy-propionic acid, the terepthaloyl moietie, is preferably methyl alcohol.
4. according to the process for purification of the Ambroxol HCl of one of claim 1-3, it is characterized in that in the step 1, the amount that adds gac is the 0.2-0.5% (g/ml) of overall solution volume.
5. according to the process for purification of the Ambroxol HCl of one of claim 1-4; It is characterized in that; In the step 2, said stationary phase is that particle diameter is 18-200 μ m, and the aperture is 50-200 μ m for pore neutral alumina or the particle diameter of about 6nm; The aperture is 6nm, the column chromatography special neutral aluminum oxide of pH 7.0 or pH 7.5.
6. according to the process for purification of the Ambroxol HCl of one of claim 1-5, it is characterized in that, in the step 2; Neutral alumina can for example be that the ICN allumina N preferable particle size of supplier ICN is 18-63 μ m; The aperture is the pore neutral alumina of 6nm, and pH 7.5, and preferable particle size is 18-32 μ m; The aperture is the pore neutral alumina of 6nm, and pH 7.5.Perhaps, neutral alumina for example is a supplier Baker column chromatography special neutral aluminum oxide, and particle diameter is 50-200 μ m, and the aperture is 6nm, pH 7.0 or pH 7.5.
7. according to the process for purification of the Ambroxol HCl of one of claim 1-6; It is characterized in that; In the step 2, the moving phase that chromatographic column is used is 1: 1～2 acetonitrile and the mixed solvent of water or the mixed solvent of methyl alcohol and water as volume ratio, and preferably its volume ratio is 1: 1.2～1.8; More preferably 1: 1.3～1.6, most preferably be 1: 1.5.
8. according to the process for purification of the Ambroxol HCl of one of claim 1-7, it is characterized in that in the step 3, the negative pressure crystallization of Ambroxol HCl solution is carried out in the preferred crystallizer in crystallisation vessel.
9. according to the process for purification of the Ambroxol HCl of one of claim 1-8, it is characterized in that in the step 3, the negative pressure crystallization concrete operations in crystallizer are following:
1), partly or entirely add Ambroxol HCl solution in the crystallizer; Then crystallizer is vacuumized, realize negative pressure, for example make vacuum tightness reach-0.05 to-0.25MPa; Then through the heating unit on the crystallizer; For example, make temperature reach 72-82 ℃, carry out evaporation concentration through steam through opening the hot steam valve;
2), when being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-60%, lower the temperature, for example through closing the heating steam valve; Temperature natural is descended, when for example reducing to 52-62 ℃, close and vacuumize valve; Open and add the crystal seed valve; Preprepared Ambroxol HCl crystal seed is sucked crystallizer rapidly, close and add the crystal seed valve, open then and vacuumize valve and accomplish and add crystal seed work;
When 3), on observing visor, being covered with tiny crystal grain; The slow steam valve of opening makes that material is in the boiling enrichment stage in the jar, and crystal grain is grown up in the boiling concentration process gradually, and supersaturated solution on every side is fewer and feweri; Can invent the Ambroxol HCl solution that above-mentioned steps 2 obtains by suitable supplementary copy this moment in crystallizer; Temperature is controlled at 52-62 ℃, and is more complete in order to make crystallization, through the chuck on the crystallization apparatus; Utilize circulating water temperature to come attemperation or cooling, make the Ambroxol HCl solution in the crystallization apparatus further carry out supersaturation crystallization and growth;
4), the about 6-12 of crystallization hour, the preferred crystal that obtains suitable crystal grain after 8-10 hour.Open baiting valve the material of advantages of good crystallization is infeeded in the tripping device this moment, for example strainer or whizzer, and through filtering or centrifugal the separation, washing, drying finally obtains the purified Ambroxol HCl.
10. according to the process for purification of the Ambroxol HCl of claim 9, it is characterized in that, step 3 step by step 1) in, vacuum tightness reaches-0.08 to-0.20Mpa, more preferably-0.10 to-0.15Mpa.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN103073439A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Synthesis method of ambroxol hydrochloride compound |
| CN103073438A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride compound refining method |
| CN104788327A (en) * | 2015-05-15 | 2015-07-22 | 苗怡文 | Ambroxol hydrochloride compound for treating respiratory system disease and preparation method of ambroxol hydrochloride compound |
| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104829467A (en) * | 2015-04-14 | 2015-08-12 | 天津梅花生物医药科技有限公司 | Ambroxol hydrochloride dihydrate compound |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| DE2207460A1 (en) * | 1972-02-17 | 1973-08-23 | Thomae Gmbh Dr K | NEW LUNG THERAPEUTIC |
| ES2002438A6 (en) * | 1986-12-01 | 1988-08-01 | Servicios Y Suministros Farmac | Cyclohexyl-benzylamine deriv. prepn. |
| CN101337897A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for preparing ambroxol, analogue thereof or salts thereof |
| CN102153482A (en) * | 2011-02-28 | 2011-08-17 | 天津市铭泰医药科技有限公司 | Method for refining injection-level ambroxol hydrochloride, product and injection thereof |
-
2011
- 2011-11-28 CN CN 201110387736 patent/CN102516096B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| DE2207460A1 (en) * | 1972-02-17 | 1973-08-23 | Thomae Gmbh Dr K | NEW LUNG THERAPEUTIC |
| ES2002438A6 (en) * | 1986-12-01 | 1988-08-01 | Servicios Y Suministros Farmac | Cyclohexyl-benzylamine deriv. prepn. |
| CN101337897A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for preparing ambroxol, analogue thereof or salts thereof |
| CN102153482A (en) * | 2011-02-28 | 2011-08-17 | 天津市铭泰医药科技有限公司 | Method for refining injection-level ambroxol hydrochloride, product and injection thereof |
Non-Patent Citations (3)
| Title |
|---|
| 于书海，等: "盐酸氨溴索的合成", 《中国医药工业杂志》, vol. 27, no. 10, 31 December 1996 (1996-12-31), pages 435 - 437 * |
| 李付刚，张敏恒: "含溴医药的制备方法与生产现状（一）", 《精细与专用化学品》, vol. 14, no. 6, 21 March 2006 (2006-03-21), pages 1 - 6 * |
| 雷光清，等: "祛痰新药氨溴索的合成方法研究", 《中国药物化学杂志》, vol. 10, no. 3, 30 September 2000 (2000-09-30), pages 205 - 206 * |
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| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
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