CN102516096B - Refining method of hydrochloric acid ambroxol compound - Google Patents
Refining method of hydrochloric acid ambroxol compound Download PDFInfo
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- CN102516096B CN102516096B CN 201110387736 CN201110387736A CN102516096B CN 102516096 B CN102516096 B CN 102516096B CN 201110387736 CN201110387736 CN 201110387736 CN 201110387736 A CN201110387736 A CN 201110387736A CN 102516096 B CN102516096 B CN 102516096B
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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 is to little yellow crystalline powder; Almost tasteless, chemical name: the amino amino 3.5-dibromo-benzyl of trans-4-[(2-)] 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 the delay of minimizing mucus, thereby significantly promotes expectoration, improves breath state.When using this product treatment, the secretion of patient's mucus 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 crude product are further carried out purifying, is refined into highly purified compound with high yield.This area presses for the synthetic 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 to overcome the deficiencies in the prior art, and a kind of purification process of Ambroxol HCl compound is provided, and this method is simple, the product purity height, and the yield height 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, preparation 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, collects the method for crystallization then after filtration; Comprise adding thermal crystalline, and use solvent wash, distill the method that desolventizing and cooling obtain crystallization 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 by 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 may 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.
Process for purification provided by the invention at Ambroxol HCl be the present known prepared Ambroxol HCl crude product of synthetic method or commercially available Ambroxol HCl bulk drug, below be referred to as the Ambroxol HCl crude product that the present invention adopts.
The inventor by 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 filtrate, concentrating under reduced pressure;
(2) above-mentioned concentrated solution is carried out separation and purification with the preparative scale chromatography post, collect elutriant, concentrating under reduced pressure;
(3) the Ambroxol HCl concentrated solution 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 desirable crystal, afterwards with the crystal of separating out by filtering or centrifugal the separation washing, drying, the refining Ambroxol HCl of final acquisition.
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 filtrate, and concentrating under reduced pressure obtains the Ambroxol HCl of elementary purification.
Described solvent is selected from 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 ethylene glycol, is preferably methyl alcohol.
In one aspect of the invention, 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.
Preparation method described above is dissolved better in order to make Ambroxol HCl, chooses wantonly by heating it to be dissolved in the described solvent.The temperature of whip attachment can also can be carried out at elevated temperatures for room temperature, 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 in the separation and purification process, has screened various filler chromatographic columns such as silica gel, aluminum oxide or macroporous resin through long-term conscientious big quantity research, and for example the particle diameter of silica gel is that 45-250 μ m, aperture are
Silica gel; 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 AmberliteXAD-6, AmberliteXAD-7, AmberliteXAD-8, Diaion HP2MG, GDX-501, HPD400, HPD450, HPD750, AmberliteXAD-9, AmberliteXAD-10, GDX-401, macroporous resins such as GDX-601, AB-8.
The unexpected application macroporous resin of finding of the inventor does not have clear improvement to the purity of product, 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 this product purifying is had original windfall effect, and operation is simpler and easy.
In one aspect of the invention, described 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 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 medicine wash-out fully basically, flow point Fractional Collections behind the wash-out, the content difference of the flow point Chinese traditional medicine of different sections, in order to obtain highly purified medicine (for example purity is greater than 99.5%), need 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.
Preparation 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.
Preparation method of the present invention, wherein the temperature of concentrating under reduced pressure is 50 ℃.
Step 3, the Ambroxol HCl concentrated solution that above-mentioned steps 2 is obtained carries out the negative pressure crystallization,, concentrates under the temperature of negative pressure and rising earlier for this reason, reduce temperature then, add the Ambroxol HCl crystal seed, when tiny crystal grain occurring, keep temperature until obtaining desirable crystal, afterwards with the crystal of separating out by filtering or centrifugal the separation, washing, drying, the refining Ambroxol HCl of final acquisition.
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), 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, preferred-0.08 to-0.20Mpa, more preferably-0.10 to-0.15Mpa, then by the heating unit on the crystallizer, for example by opening the hot steam valve, make temperature reach 72-82 ℃ by steam, carry out evaporation concentration;
When 2), being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-60%, lower the temperature, for example by closing the heating steam valve, temperature is descended naturally, when for example being down to 52-62 ℃, closing 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 finish 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, crystal grain is grown up in the boiling concentration process gradually, supersaturated solution on every side is fewer and feweri, this moment can be to the Ambroxol HCl solution of suitable supplementary copy invention above-mentioned steps 2 acquisitions in the crystallizer, temperature control is at 52-62 ℃, if continue feed supplement, crystallization can continue to carry out; In order to make crystallization more complete, by the chuck on the crystallization apparatus, utilize circulating water temperature to regulate temperature or cooling, make the Ambroxol HCl solution in the crystallization apparatus further carry out the supersaturation crystallization, and be conducive to 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 this moment in the material infeed tripping device of baiting valve with advantages of good crystallization, for example strainer or whizzer by filtering or centrifugal the separation, wash, and drying finally obtains the Ambroxol HCl made from extra care.
Preparation method of the present invention, wherein said Ambroxol HCl crystallization can be used the solid drier drying, and described 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, the product purity height.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 and preparation operability huge to the influence of the performance of its activity 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 refining Ambroxol HCl of the inventive method, it can promote the eliminating of the inner thick secretions of respiratory tract and the delay of minimizing mucus, thereby significantly promotes expectoration, improves breath state.When using this product treatment, the secretion of patient's mucus 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 height obtains purity and is not less than 99.5%.Its method for detecting purity is known in the art, can use high performance liquid chromatography, for example Ambroxol HCl Injection by HPLC assay method.
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment that provides should not be understood that protection domain of the present invention is construed as limiting.
The HPLC method for detecting purity
Get this product, with moving phase dissolving and make 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, in contrast solution; Other gets the about 5mg of this product, adds methyl alcohol 0.2ml dissolving, adds formaldehyde solution (1 → 100) 40 μ l again, shake up, put 60 ℃ of heating 5 minutes, nitrogen dries up, residue water 5ml dissolving, add moving phase again and be diluted to 20ml, getting 20 μ l and inject liquid chromatograph, measure according to efficient phase of wave chromatography (appendix V D), is weighting agent with octadecylsilane chemically bonded silica, (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50) is moving phase with the 0.01mol/L ammonium dibasic phosphate solution, and the detection wavelength is 248nm.The resolution 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 need testing solution and each 20 μ l of contrast solution again, injects liquid chromatograph respectively, and the record color atlas is to 2 times of principal constituent peak retention time.In the need testing solution color atlas, if any impurity peaks, each impurity peak area and 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 crude product (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 filtrate; Adding the 10g aluminum oxide again after concentrating stirs, be added to preparative scale chromatography post upper end after flinging to solvent, with the preparative scale chromatography post filtrate is carried out separation and purification then, wherein the moving phase used of chromatographic column is 1: 1.5 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 room temperature, wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure.
The Ambroxol HCl solution that obtains 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 ℃ by steam, carry out evaporation concentration;
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 be down 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 by the chuck on the crystallization apparatus then, make the 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 fed strainer separate, the less water washing, the Calcium Chloride Powder Anhydrous drying gets Ambroxol HCl 9.03g, and its HPLC purity is that 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 crude product (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 filtrate; Adding 10g silica gel again after concentrating stirs, be added on the chromatographic column of preparation after flinging to solvent, with the preparative scale chromatography post filtrate is carried out separation and purification then, wherein the moving phase used of chromatographic column is 1: 1.5 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 is, column temperature is room temperature, wavelength 248nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In concentrated solution, add pure water, stir, crystallization, 500rpm is centrifugal, and the Calcium Chloride Powder Anhydrous drying gets Ambroxol HCl 8.53g, and its purity is that 98.63%, 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 filtrate; Adding the 10g aluminum oxide again after concentrating stirs, be added to preparative scale chromatography post upper end after flinging to solvent, with the preparative scale chromatography post filtrate 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, flow velocity 2ml/min, fixed phase stuffing is particle diameter 50-200 μ m, the Baker column chromatography special neutral aluminum oxide of aperture 6nm, column temperature is room temperature, wavelength 248nm, collect elutriant, 50 ℃ of concentrating under reduced pressure.
In the most of adding of the Ambroxol HCl solution crystallizer that obtains, then crystallizer is vacuumized, vacuum tightness is reached-0.13Mpa, open the hot steam valve on the crystallizer then, make temperature reach 73-76 ℃ by 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 drop to 54-58 ℃ naturally, 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 finish 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, crystal grain is grown up in the boiling concentration process gradually, supersaturated solution on every side is fewer and feweri, replenish remaining Ambroxol HCl solution this moment in crystallizer, temperature control continues feed supplement at 54-58 ℃, and crystallization continues to carry out; By 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.It is centrifugal with the material infeed whizzer 500rpm of advantages of good crystallization to open baiting valve, and the Calcium Chloride Powder Anhydrous drying gets Ambroxol HCl 9.27g, and its HPLC purity is that 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 ethylene glycol, stir, it is dissolved fully, add the gac of 0.4g then, whip attachment 15 minutes, filtering decarbonization is collected filtrate; Adding the 15g aluminum oxide again after concentrating stirs, be added to preparative scale chromatography post upper end after flinging to solvent, then filtrate 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 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, by opening the hot steam valve on the crystallizer, make temperature reach 72-77 ℃ by steam then, carry out evaporation concentration;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-55%, by closing the heating steam valve, temperature is descended naturally, when for example being down 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 finish 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, crystal grain is grown up in the boiling concentration process gradually, supersaturated solution on every side is fewer and feweri, suitably replenish remaining Ambroxol HCl solution this moment in crystallizer, temperature control continues feed supplement at 51-54 ℃, and crystallization continues to carry out; By the chuck on the crystallization apparatus, utilize circulating water temperature to regulate temperature 40-44 ℃ then, make the 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 this moment with the material infeed strainer of advantages of good crystallization, separate by filtration, the Calcium Chloride Powder Anhydrous drying gets Ambroxol HCl 9.36g, and its HPLC purity is that 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 filtrate; Adding the 15g aluminum oxide again after concentrating stirs, be added to preparative scale chromatography post upper end after flinging to solvent, then filtrate is carried out separation and purification, wherein the moving phase used of chromatographic column is 1: 1.3 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 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, by opening the hot steam valve on the crystallizer, make temperature reach 75-78 ℃ by steam then, carry out evaporation concentration;
When being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 56-59%, by closing the heating steam valve, temperature is descended naturally, when for example being down 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, crystal grain is grown up in the boiling concentration process gradually, supersaturated solution on every side is fewer and feweri, suitably replenish remaining Ambroxol HCl solution this moment in crystallizer, temperature control continues feed supplement at 55-59 ℃, and crystallization continues to carry out; By the chuck on the crystallization apparatus, utilize circulating water temperature to regulate temperature 42-45 ℃ then, make the 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 this moment with the material infeed strainer of advantages of good crystallization, separate by filtration, less water washing 3 times, the Calcium Chloride Powder Anhydrous drying gets 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 filtrate; Concentrate the back and add pure water, stir, crystallization, 500rpm is centrifugal, and the Calcium Chloride Powder Anhydrous drying gets Ambroxol HCl 7.42g, its HPLC purity 95.28%.
Above-described embodiment and Comparative Examples have proved absolutely the superiority of particular combination method of the present invention from different aspects, especially comprise 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 may 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 characteristics and the obvious improvement of essence, 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 by associated comparative example the present invention has obtained unexpected excellent effect.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 is within protection scope of the present invention.
Claims (9)
1. 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 filtrate, concentrating under reduced pressure;
Step 2 is carried out separation and purification with above-mentioned concentrated solution with the preparative scale chromatography post, collects elutriant, concentrating under reduced pressure;
Step 3, the Ambroxol HCl concentrated solution that above-mentioned steps 2 is obtained carries out the negative pressure crystallization,, concentrates under the temperature of negative pressure and rising earlier for this reason, reduce temperature then, add the Ambroxol HCl crystal seed, when tiny crystal grain occurring, keep temperature until obtaining desirable crystal, afterwards with the crystal of separating out by filtering or centrifugal the separation, washing, drying, the refining Ambroxol HCl of final acquisition;
In the step 2, stationary phase is that particle diameter is 18-200 μ m, and the aperture is that pore neutral alumina or the particle diameter of 6nm is 50-200 μ m, and the aperture is 6nm, the column chromatography special neutral aluminum oxide of pH7.0 or pH7.5;
In the step 2, the moving phase that chromatographic column is used is acetonitrile and the mixed solvent of water or the mixed solvent of methyl alcohol and water of volume ratio as 1:1～2.
2. according to the process for purification of the Ambroxol HCl of claim 1, 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 ethylene glycol.
3. according to the process for purification of the Ambroxol HCl of claim 2, it is characterized in that in the step 1, described solvent is methyl alcohol.
4. according to the process for purification of the Ambroxol HCl of claim 1, 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 claim 1, it is characterized in that in the step 2, neutral alumina is the ICN allumina N of supplier ICN, perhaps is supplier Baker column chromatography special neutral aluminum oxide.
6. according to the process for purification of the Ambroxol HCl of claim 1, it is characterized in that in the step 3, the negative pressure crystallization of Ambroxol HCl solution is carried out in crystallisation vessel.
7. according to the process for purification of the Ambroxol HCl of claim 6, it is characterized in that in the step 3, the negative pressure crystallization of Ambroxol HCl solution is carried out in crystallizer.
8. according to the process for purification of the Ambroxol HCl of claim 7, it is characterized in that in the step 3, the negative pressure crystallization concrete operations in crystallizer are as follows:
1), Ambroxol HCl solution is partly added in the crystallizer, then crystallizer is vacuumized, realize that negative pressure reaches-0.05 to-0.25MPa, make temperature reach 72-82 ℃ by the heating unit on the crystallizer then, carry out evaporation concentration;
When 2), being evaporated to the mass percent concentration of Ambroxol HCl in solution and reaching 50-60%, lower the temperature, when making temperature drop to 52-62 ℃ naturally, 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 finish 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, crystal grain is grown up in the boiling concentration process gradually, supersaturated solution on every side is fewer and feweri, suitably replenish the Ambroxol HCl solution that above-mentioned steps 2 obtains this moment in crystallizer, temperature control is at 52-62 ℃, in order to make crystallization more complete, by the chuck on the crystallization apparatus, utilize circulating water temperature to regulate temperature or cooling, make the Ambroxol HCl solution in the crystallization apparatus further carry out supersaturation crystallization and growth;
4), obtain the crystal of suitable crystal grain behind the crystallization 6-12 hour, open baiting valve this moment the material of advantages of good crystallization fed in the tripping device, separate, washing, drying finally obtains refining Ambroxol HCl.
9. the process for purification of Ambroxol HCl according to Claim 8 is characterized in that, step 3 step by step 1) in, vacuum tightness reaches-0.08 to-0.20MPa.
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| CN102964257B (en) * | 2012-11-24 | 2014-08-06 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN103073439B (en) * | 2013-02-05 | 2013-10-16 | 山东罗欣药业股份有限公司 | Synthesis method of ambroxol hydrochloride compound |
| CN103073438B (en) * | 2013-02-05 | 2013-08-14 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride compound refining method |
| 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 |
| CN104803860B (en) * | 2015-05-12 | 2017-08-08 | 山东罗欣药业集团股份有限公司 | A kind of ambroxol compound and its pharmaceutical composition |
| CN106242983A (en) * | 2015-05-15 | 2016-12-21 | 苗怡文 | A kind of method of the ambroxol compound crystal preparing treatment respiratory system disease |
| CN106265615A (en) * | 2015-05-15 | 2017-01-04 | 苗怡文 | A kind of ambroxol compound crystal of the pharmaceutical composition for preparing treatment respiratory system disease |
| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
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