CN115160197A - Preparation method of carbocisteine bulk drug - Google Patents
Preparation method of carbocisteine bulk drug Download PDFInfo
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- CN115160197A CN115160197A CN202110353601.0A CN202110353601A CN115160197A CN 115160197 A CN115160197 A CN 115160197A CN 202110353601 A CN202110353601 A CN 202110353601A CN 115160197 A CN115160197 A CN 115160197A
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- carbocisteine
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- sodium hydroxide
- hydroxide solution
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- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 title claims abstract description 141
- 229960004399 carbocisteine Drugs 0.000 title claims abstract description 135
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 229940079593 drug Drugs 0.000 title claims abstract description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 174
- 238000003756 stirring Methods 0.000 claims abstract description 85
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000012043 crude product Substances 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000047 product Substances 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 claims description 5
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 16
- 230000008025 crystallization Effects 0.000 abstract description 15
- 239000000428 dust Substances 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000007873 sieving Methods 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 description 47
- 230000001276 controlling effect Effects 0.000 description 38
- 239000002245 particle Substances 0.000 description 30
- 239000002994 raw material Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 238000009826 distribution Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 6
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 6
- 230000002349 favourable effect Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 229940106681 chloroacetic acid Drugs 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- LJPYJRMMPVFEKR-UHFFFAOYSA-N prop-2-ynylurea Chemical compound NC(=O)NCC#C LJPYJRMMPVFEKR-UHFFFAOYSA-N 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- JJVXHDTWVIPRBZ-VKHMYHEASA-N (2r)-2-[carboxy(methyl)amino]-3-sulfanylpropanoic acid Chemical compound OC(=O)N(C)[C@@H](CS)C(O)=O JJVXHDTWVIPRBZ-VKHMYHEASA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- GBFLZEXEOZUWRN-UHFFFAOYSA-N carbocisteine Chemical compound OC(=O)C(N)CSCC(O)=O GBFLZEXEOZUWRN-UHFFFAOYSA-N 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 239000011362 coarse particle Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000004478 non-suppurative otitis media Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a preparation method of carbocisteine bulk drug, which comprises the steps of adding water into a carbocisteine crude product, dropwise adding concentrated hydrochloric acid under controlled temperature, controlling dropwise adding, stirring speed and reaction time, then dropwise adding sodium hydroxide solution, controlling the parameters in the same way, carrying out crystallization in a platform period, then continuously controlling the parameters to dropwise add the sodium hydroxide solution for further crystallization, wherein the obtained carbocisteine bulk drug meets the requirements of subsequent preparation processes in the aspects of granularity, density, fluidity and the like, the granularity range of the prepared carbocisteine bulk drug is D90 less than or equal to 95 mu m and can be directly used for granulating subsequent preparations without crushing through simple sieving, so that the working procedures are saved, and the dust is reduced.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of carbocisteine bulk drug.
Technical Field
Carbocisteine (Carbocisteine) is a expectorant and antitussive, and can be used for treating cough and expectoration caused by chronic bronchitis, bronchial asthma, etc., and can be used for treating infantile non-suppurative otitis media to prevent deafness, and has chemical name of S- (Carboxymethyl) cysteine (S-Carboxymethyl-L-cysteine) and molecular formula of C 5 H 9 NO 4 And S. The molecular weight is 179.19, and the carbocisteine structural formula is as follows:
the dissolution rate and degree of the medicine dissolved in the solvent can be expressed by the dissolution rate, the tablet is a common preparation formulation in oral preparations, and the dissolution rate is closely related to raw materials, auxiliary materials, prescription composition, particle size distribution, particle hardness, process conditions and the like. In the production of the raw material medicine, the granularity is an indispensable index, and the raw material medicine with the target granularity form is obtained by adopting a pretreatment (such as crushing and the like) mode in the prior art so as to meet the requirement of a preparation.
Chinese patent CN201911414274.4 at 2020.05.12 discloses a preparation method of S-carboxymethyl-L-cysteine (carbocisteine), which comprises adding excessive dilute hydrochloric acid into a crude product of S-carboxymethyl-L-cysteine obtained after preparation, adding seed crystals of S-carboxymethyl-L-cysteine with high density after dissolution, and dropwise adding an alkali solution (II) to adjust to isoelectric point so as to induce crystallization, thereby obtaining coarse particles and high density S-carboxymethyl-L-cysteine.
Chinese patent CN201610488728.2 at 2016.11.09 discloses a process for preparing carbocisteine, which adopts L-cysteine hydrochloride monohydrate and solid chloroacetic acid as raw materials, has high content of chloroacetic acid in the solid chloroacetic acid, can effectively improve preparation efficiency and quality, and can effectively improve the concentration of reaction substrates in a solution by controlling temperature in a dissolving system of the L-cysteine hydrochloride monohydrate and the solid chloroacetic acid, thereby ensuring production efficiency and yield.
Chinese patent No. CN201210085042.0 to 2013.05.15 discloses a method for producing carboxymethyl cysteine (carbocisteine), which uses cysteine hydrochloride monohydrate as a main raw material and chloroacetic acid, liquid ammonia, activated carbon and refined hydrochloric acid as auxiliary materials, and prepares a finished product by the procedures of acid addition reaction, decoloration, filtration, centrifugal separation, drying and the like.
As mentioned above, during the preparation process of carbocisteine preparation (such as tablet), the carbocisteine raw material drug is firstly crushed and sieved, but after being crushed, the hygroscopicity is obviously increased, the static electricity is strong, and the aggregation is easy, so that the raw material drug powder has poor flowability, and is not beneficial to long-term storage, and the crushing process has partial product loss or pollution, which causes waste, and a large amount of dust is easy to cause during the crushing process, and is not beneficial to the production in a preparation workshop. In the existing carbocisteine preparation methods, the particle size of carbocisteine raw materials is less researched, and although a preparation method of carbocisteine is disclosed in Chinese patent CN201911414274.4, carbocisteine crystal grains with larger particle size and higher density can be prepared, the particle size is close to 0.85mm, the carbocisteine crystal grains are still required to be subjected to crushing treatment and cannot be directly used for preparing carbocisteine preparations (such as tablets), and the method needs to be heated to 55-60 ℃, and high-density carbocisteine crystal seeds are also required to be added to adjust to isoelectric points, and the method is refrigerated overnight, relatively complex in conditions and has certain limitation on large-scale workshop production.
In summary, in the prior art, there is no disclosure of a method for preparing carbocisteine crude drug with appropriate particle size, which has mild conditions and simple operation and can be directly used for preparation. Therefore, a preparation method of the carbocisteine raw material medicine is needed, the raw material medicine suitable for subsequent preparation granulation can be directly prepared, the carbocisteine raw material medicine prepared by the preparation method meets the granularity requirement of a tablet preparation, further crushing is not needed, and the subsequent preparation process is saved.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a preparation method of carbocisteine bulk drug with proper particle size, the method has mild condition, convenient operation and high yield, the particle size range of the prepared carbocisteine bulk drug is more than or equal to 50 mu m and less than or equal to D90 and less than or equal to 95 mu m, the powder property is suitable for preparation, the bulk drug can be directly used for the granulation of subsequent preparations without crushing by simple sieving, and the effects of saving working procedures, reducing dust and the like are achieved.
Specifically, the scheme prepares the carbocisteine raw material in a target powder form by a two-step crystallization method, namely: adding water into the carbocisteine crude product, dropwise adding concentrated hydrochloric acid under the condition of controlling the temperature, controlling the dropwise adding, stirring speed and reaction time, then dropwise adding a sodium hydroxide solution, controlling the parameters in the same way, crystallizing in a plateau phase, and then continuously controlling the parameters to dropwise add the sodium hydroxide solution for further crystallizing to obtain the bulk drug suitable for preparation production.
The beneficial effects of the invention are realized by the following method:
a preparation method of carbocisteine bulk drug comprises the following steps:
a) Adding the carbocisteine crude product into water, controlling the temperature to be 35-50 ℃, dropwise adding concentrated hydrochloric acid at the speed of 0.3-0.7L/min, stirring for 20-40min at the speed of 50-100 rpm until the pH is =0.5-1.0, dissolving the solid, and preparing a carbocisteine solution with the concentration range of 0.15-0.25 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution at the speed of 0.1-0.5L/min until the pH is =2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 25-35min;
d) Continuously dropwise adding sodium hydroxide solution, adjusting pH to 2.8-3.0 at 10-15 deg.C, stirring at 40-80 rpm for 20-30min, filtering, washing with water, and drying to obtain refined carbocisteine.
In the step c), the temperature and the stirring time are one of the keys for realizing the technical effect. The inventor finds that if the step c) is omitted in the preparation process, the grain size, the density and the fluidity of the obtained crystals are greatly influenced, and particularly, the obtained carbocisteine crystals have small grain size, are viscous, are easy to extrude and agglomerate and have poor fluidity, so that a plateau period is set in the process of dropwise adding the sodium hydroxide solution, and the growth of the crystals is facilitated. Preferably, when the platform period is set to be 15-25 ℃, the stirring speed is 60-90 r/min, and the stirring time is 25-35min, the obtained crystal particle size, density and fluidity meet the requirements, and no stickiness occurs, analysis shows that in the technical scheme, 25-35min is the favorable time for the growth of the carbocisteine crystal, when the time is longer, the density and fluidity of the generated crystal are obviously reduced, when the time is shorter, the crystal growth time is insufficient, the particle size of the generated crystal is not uniform, the crystallization speed is controlled by adjusting the time, the product properties can be effectively improved, and the product quality is improved. More preferably, when the stirring time is 30min, the evaluation of the factors such as particle size, density and fluidity is optimal.
In addition, the combination of gradient pH regulation and gradient cooling method can ensure the stable precipitation and growth of carbocisteine crystal nucleus and the uniformity of the carbocisteine fine product. The proper stirring speed is favorable for ensuring the slow precipitation of the crystals so as to improve the density of the crystals, and the formed crystals are also favorable for being attached to the formed crystals so as to obtain a fine product with proper granularity.
In the step a), the speed of dripping the concentrated hydrochloric acid, the stirring time and the stirring speed are one of the keys for realizing the technical effect. The proper dripping speed can effectively reduce the generation of chloride impurities difficult to remove, and simultaneously control the local temperature of the reaction system not to suddenly rise, and the proper stirring time and the stirring speed are favorable for the growth of crystal forms and ensure the uniformity of the grain diameter of subsequent fine products. Preferably, in the step a), the crude carbocisteine is added into water, the temperature is controlled to be 35-50 ℃, concentrated hydrochloric acid is dripped, the dripping speed is 0.4-0.6L/min, and the stirring is carried out for 30min, wherein the stirring speed is 60-80 r/min. More preferably, the temperature is controlled to be 40-45 ℃, and concentrated hydrochloric acid is dripped at the dripping speed of 0.5L/min.
In the step b), the speed of dripping the sodium hydroxide solution and the pH value are one of the keys for realizing the technical effect. When the sodium hydroxide solution is dripped, the dripping speed of the sodium hydroxide solution is reduced, so that the alkalinity of the solution is controlled not to be locally too large, crystals are precipitated after the crystals reach a crystallization point and are not arranged in time, and particles are loose. The proper pH environment in the plateau phase can prevent the generation of the phenomenon of sudden precipitation and can ensure that carbocisteine crystals can grow to a certain extent. When the pH is less than 2.0, less crystals are precipitated, the crystallization efficiency is reduced, the obtained crystal forms are formed in an aggregation form, the viscosity and the fluidity are poor, and when the pH is more than 2.5, a large amount of crystals are precipitated without growing, and the crystal form is poor. Preferably, in step b), the sodium hydroxide solution is added dropwise at a rate of 0.2 to 0.4L/min to a pH =2.0 to 2.5, and the addition of the sodium hydroxide solution is stopped. More preferably, in the step b), the sodium hydroxide solution is dropwise added at a speed of 0.3L/min.
In the step d), the crystallization temperature, the pH value, the stirring speed and the stirring time are one of important factors for realizing the technical effect. After the carbocisteine crystal is subjected to the initial growth in the stage of the step c), the carbocisteine crystal has certain target crystal form conditions, and the proper crystallization conditions can promote the carbocisteine crystal to be further separated out, remove impurities in the carbocisteine crystal and improve the purity. When the crystallization temperature is more than 15 ℃, the crystal morphology is easy to form into blocks, the uniformity is poor, and when the crystallization temperature is less than 10 ℃, the related inorganic salt residue risk is increased. The proper pH value is beneficial to removing impurities, simultaneously ensures the precipitation amount of carbocisteine and improves the yield. The proper stirring speed and stirring time can disperse larger crystallization particles in the plateau phase, improve the crystal form density, ensure that the finally obtained carbocisteine granularity is in the required range, reduce the residue of the solvent and improve the product purity. The best crystallization effect can be achieved only when the above parameter conditions are integrally combined. Preferably, in the step d), the sodium hydroxide solution is continuously added dropwise, the pH is adjusted to be 2.8-3.0 at 10-15 ℃, the stirring speed is 40-80 r/min, and the stirring time is 20-30min. More preferably, in step d), the stirring speed is between 50 and 70 revolutions per minute.
In the invention, the sodium hydroxide solution added in step b) and step d) may be sodium hydroxide solutions with different concentrations, preferably, the sodium hydroxide is a sodium hydroxide solution with a mass concentration of 40-60%; most preferably, the sodium hydroxide is a 50% sodium hydroxide solution by mass.
In the step a), the concentration of the carbocisteine solution is one of important factors for realizing the technical effect. Although the yield can be improved to a certain extent by increasing the concentration, the density of the obtained product tends to be reduced in the crystallization process due to the excessively high concentration, and the obtained product does not meet the requirements of subsequent preparations; and the crystal with too low concentration has slow nucleation and growth and low yield. The inventors have found that the formation of crystals is favoured when the concentration of the carbocisteine solution is between 0.15 and 0.25g/mL, preferably 0.20 g/mL.
The carbocisteine can be prepared in a reaction kettle with an anchor type stirring paddle, a paddle type stirring paddle, a turbine type stirring paddle, a propelling type stirring paddle and a frame type stirring paddle, preferably the reaction kettle with the anchor type stirring paddle, can obtain large shearing force along the wall surface when rotating at low speed by using anchor type stirring, can prevent sedimentation and wall surface adhesion, and ensures that materials are mixed more uniformly.
The scheme has a certain refining effect, so that the adopted carbocisteine crude product has no special requirement, a finished product with higher purity sold in the market can be used, a self-made crude product can be used in consideration of industrial production, and carbocisteine with the purity of more than or equal to 95.0 percent is preferably used. Specifically, in the industrial production, the carbocisteine crude product in the technical scheme can be prepared by the following preparation steps, and the carbocisteine crude product obtained by using the method has high yield and high purity, and is more suitable for subsequent crystallization refining:
dissolving L-cysteine hydrochloride with water, controlling the temperature to be 10-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 40-60%, adjusting the pH =8.5-9.0, controlling the temperature to be 20-25 ℃, dropwise adding a sodium chloroacetate solution, controlling the molar ratio of the L-cysteine hydrochloride to the sodium chloroacetate to be 1.
The carbocisteine crystal prepared by the method meets the process requirements of subsequent preparations. Specifically, the carbocisteine crystal achieves the preset purpose, namely the particle size range is that D90 is more than or equal to 50 mu m and less than or equal to 95 mu m, the fluidity is improved, and the electrostatic phenomenon is reduced. The fluidity is represented by the powder repose angle, and the powder fluidity is measured by adopting a conventional detection method in the field such as a fixed funnel method; the static phenomenon can be embodied by bulk density, the bulk density is detected by adopting a measuring cylinder method, and the tap density is detected by adopting a measuring cylinder knocking method.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. the prepared carbocisteine bulk drug has the particle size range of 50 mu m-95 mu m, can be directly used for granulating subsequent preparations through simple sieving without crushing, achieves the effects of saving working procedures and reducing dust, ensures proper dissolution time by using the carbocisteine tablets prepared from the carbocisteine bulk drug, and is more favorable for absorption in human bodies.
2. The carbocisteine refined product obtained by the preparation method has higher fluidity and density, can meet the requirements of subsequent high-requirement preparation processes, has high purity, and is suitable for industrial production.
Drawings
FIG. 1 SEM photograph of carbocisteine obtained in example 2.
Figure 2 particle size distribution of carbocisteine obtained in example 2.
Figure 3 particle size distribution of carbocisteine obtained in comparative example 1.
Figure 4 particle size distribution plot of carbocisteine obtained in comparative example 2.
Figure 5 particle size distribution plot of carbocisteine obtained in comparative example 3.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
In the following examples, the reaction equipment may be selected from 2000L (anchor stirred) closed-type reactor or GR-20CE-20L speed-adjustable glass reactor, depending on the reaction conditions.
Example 1
Preparation of crude carbocisteine
Solution preparation: dissolving 117.0kg of chloroacetic acid in 328.0L of water, adding 104.0kg of sodium bicarbonate, and stirring for dissolving for later use;
condensation reaction: dissolving 279.0kg of L-cysteine hydrochloride in 558.0L of water, controlling the temperature to be 10-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, adjusting the pH to be 8.5-9.0, controlling the temperature to be 20-25 ℃, dropwise adding a sodium chloroacetate solution, controlling the pH to be 7.5-8.0, reacting for 3 hours at the temperature of 20-25 ℃, adding activated carbon after the reaction is finished, stirring and decoloring, filtering, controlling the temperature of the filtrate to be 20-25 ℃, adding concentrated hydrochloric acid to adjust the pH to be 2.5-3.0, and separating out 213.0kg of carbocisteine crude product with the purity of 95.8%.
Example 2
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 7.77L of water into 2.22kg of carbocisteine crude product, controlling the temperature to be 40-45 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.5L/min, stirring for 30min at the stirring speed of 60-80 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing into 0.20g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, wherein the dropwise adding speed is 0.3L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 30min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 50%, adjusting the pH value to be =2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 50-70 r/min for 25min, filtering, washing and drying to obtain 1.98kg of a fine carbocisteine product with the yield of 89.1%, wherein the SEM picture of the obtained product is shown in figure 1, and the fine carbocisteine product can be seen to be granular, has good fluidity and uniform particle size distribution. The D90 of the product is more than or equal to 50 microns and less than or equal to 95 microns, and the particle size distribution is shown in figure 2.
Example 3
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 10.95L of water into 2.18kg of carbocisteine crude product, controlling the temperature to be 35-40 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.3L/min, stirring for 20min at the stirring speed of 50-60 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing into 0.15g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 40%, wherein the dropwise adding speed is 0.1L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 25min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 40%, adjusting the pH value to be =2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 40-50 r/min for 20min, filtering, washing and drying to obtain 1.89kg of refined carbocisteine product, wherein the yield is 86.5%, and the refined carbocisteine product is granular from the appearance.
Example 4
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 6.25L of water into 2.19kg of carbocisteine crude product, controlling the temperature to be 45-50 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.7L/min, stirring for 40min at the stirring speed of 80-100 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing into 0.25g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 60%, wherein the dropwise adding speed is 0.5L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 35min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 60%, adjusting the pH value to be 2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 70-80 r/min for 30min, filtering, washing with water and drying to obtain 1.87kg of a refined carbocisteine product, wherein the yield is 85.5%, and the refined carbocisteine product is granular from the appearance.
Example 5
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, 2.14kg of carbocisteine crude product is added with 8.55L of water, the temperature is controlled to be 35-40 ℃, concentrated hydrochloric acid is dripped, the dripping speed is 0.5L/min, the stirring is carried out for 25min, the stirring speed is 60-80 r/min until the pH is =0.5-1.0, and the solid is dissolved to prepare 0.22g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, wherein the dropwise adding speed is 0.2L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 30min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 50%, adjusting the pH value to be 2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 50-70 r/min for 25min, filtering, washing with water and drying to obtain 1.87kg of a refined carbocisteine product with the yield of 87.2%, wherein the refined carbocisteine product is granular from the appearance.
Example 6
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 9.65L of water into 2.14kg of carbocisteine crude product, controlling the temperature to be 45-50 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.6L/min, stirring for 35min at the stirring speed of 60-80 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing into 0.18g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, wherein the dropwise adding speed is 0.4L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 30min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 50%, adjusting the pH value to be 2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 50-70 r/min for 30min, filtering, washing with water and drying to obtain 1.86kg of a refined carbocisteine product with the yield of 86.7%, wherein the refined carbocisteine product is granular from the appearance.
Comparative example 1
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 11.50L of water into 2.11kg of carbocisteine crude product, controlling the temperature to be 55-60 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.8L/min, stirring for 45min at the stirring speed of 110-130 r/min until the pH is =1.1-1.5, and preparing 0.13g/mL of carbocisteine solution;
b) Controlling the temperature to be 40-45 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 30%, wherein the dropwise adding speed is 0.6L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.6-3.0;
c) Controlling the temperature to 26-30 ℃, stirring at the speed of 100-110 rpm, and stirring for 40min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 30%, adjusting the pH to be 3.1-3.5 at the temperature of 16-20 ℃, stirring at the speed of 90-110 r/min for 35min, filtering, washing and drying to obtain 1.73kg of refined carbocisteine product with the yield of 81.9%, wherein the carbocisteine is flaky and is easy to agglomerate and loosen. The D90 of the product is more than or equal to 30 mu m and less than or equal to 65 mu m, and the particle size distribution is shown in figure 3.
Comparative example 2
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, 2.00kg of carbocisteine crude product is added with 5.00L of water, the temperature is controlled between 25 and 30 ℃, concentrated hydrochloric acid is dripped, the dripping speed is 0.2L/min, the stirring is carried out for 18min, the stirring speed is 30 to 40 r/min until the pH is =0.3 to 0.4, and the solid is dissolved to prepare 0.28g/mL of carbocisteine solution;
b) Controlling the temperature to be 15-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 65%, wherein the dropwise adding speed is 0.08L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 1.5-1.9;
c) Controlling the temperature to 5-14 ℃, stirring at the speed of 40-55 r/min, and stirring for 20min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 65%, adjusting the pH value to be =2.0-2.4 at the temperature of 5-9 ℃, stirring at the speed of 20-30 r/min for 15min, filtering, washing and drying to obtain 1.59kg of refined carbocisteine, wherein the yield is 79.4%, and the carbocisteine is flaky, easy to agglomerate and coarse in appearance. The D90 of the product is more than or equal to 100 mu m and less than or equal to 170 mu m, and the particle size distribution is shown in figure 4.
Comparative example 3
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, adding 7.77L of water into 2.22kg of carbocisteine crude product, controlling the temperature to be 40-45 ℃, dropwise adding concentrated hydrochloric acid at the dropping speed of 0.5L/min, stirring for 30min at the stirring speed of 60-80 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing 0.20g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, wherein the dropwise adding speed is 0.3L/min, the pH value is regulated to be =2.8-3.0, the stirring speed is 50-70 r/min, stirring is carried out for 25min, filtering, washing and drying are carried out, 2.02kg of fine carbocisteine product is obtained, the yield is 91.2%, and the carbocisteine is in a blocky shape, is rough in appearance and poor in fluidity. The D90 of the product is more than or equal to 10 mu m and less than or equal to D90 and less than or equal to 50 mu m, and the particle size distribution is shown in figure 5.
Example 7 Industrial Scale-Up production of crude Carbocisteine
a) After the carbocisteine crude product is prepared according to the method of the embodiment 1, 222kg of carbocisteine crude product is filtered, 777L of water is added, the temperature is controlled to be 40-45 ℃, concentrated hydrochloric acid is dripped, the dripping speed is 0.5L/min, the stirring is carried out for 30min, the stirring speed is 60-80 r/min until the pH is =0.5-1.0, and the solid is dissolved to prepare 0.20g/mL of carbocisteine solution;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, wherein the dropwise adding speed is 0.3L/min, and stopping dropwise adding the sodium hydroxide solution until the pH is = 2.0-2.5;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 30min;
d) Continuously dropwise adding a sodium hydroxide solution with the mass concentration of 50%, adjusting the pH value to be 2.8-3.0 at the temperature of 10-15 ℃, stirring at the speed of 50-70 r/min for 25min, filtering, washing with water and drying to obtain 194.0kg of a refined carbocisteine product, wherein the yield is 87.4%, and the refined carbocisteine product is granular from the appearance.
Example 8
The examination of the fine carbocisteine preparations of examples 2 to 7, comparative examples 1 to 3 gave the results shown in the following table:
from the above data, it can be seen that the temperature of the preparation method described in comparative example 1 is relatively high, and the dropping speed of concentrated hydrochloric acid is too fast, so that the local temperature is too high, the carbocisteine part is decomposed, and when the sodium hydroxide solution is dropped, the dropping speed of the sodium hydroxide solution is too fast, the alkaline part of the solution is too large and directly reaches the crystallization point, so that the crystals are precipitated after being not arranged in time, and the particles are loose. Meanwhile, the stirring speed is too high, and the particle size of the generated crystal is smaller. Therefore, the carbocisteine obtained by the preparation method of comparative example 1 has low yield and purity, and small particle size, which is not favorable for the requirement of subsequent preparations.
On the contrary, in comparative example 2, the temperature is low, the dropping speed of concentrated hydrochloric acid is slow, the acidity is low, the risk of chloride residue is increased, and the subsequent precipitation amount of the carbocisteine refined product is reduced due to insufficient alkalinity when the sodium hydroxide solution is dropped. Meanwhile, the stirring speed is too slow, and the generated crystals have large particle size and low density, so that the requirements of subsequent preparations are not facilitated.
In comparative example 3, the yield of the obtained carbocisteine crystals is improved due to the omission of the plateau phase, but the phenomena of small particle size, viscosity, easy extrusion and agglomeration and poor fluidity exist, and the obtained carbocisteine crystals cannot meet the requirement of directly being used for granulating subsequent preparations. The inventors have found that an excessively high yield is accompanied by deterioration in crystal morphology, and therefore, it is important to balance the crystal morphology, yield and purity as a whole.
It can be seen from the examples 2 and 6 that the setting of the plateau phase is beneficial to the growth of the required crystal form, and the combination of the gradient pH adjustment method and the gradient cooling method can ensure the stable precipitation growth of the carbocisteine crystal nucleus, ensure the uniformity of the obtained carbocisteine fine product, concentrate the particle size in the required range, and ensure that D90 is more than or equal to 50 μm and less than or equal to 95 μm, and the powder has better flowability, thereby facilitating the preparation of the subsequent preparation. In example 2, various parameters including reaction temperature, reaction time, dropping speed, acid-base environment and the like are most preferable, and the overall combination of the above conditions enables the obtained crystal form, yield and purity to be comprehensively optimized.
It can be seen from example 7 that the present solution has a certain feasibility in industrial scale-up production, and the obtained refined carbocisteine product has the advantages of the refined product obtained under pilot plant conditions, no matter in crystal form, or in yield and purity.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of carbocisteine bulk drug comprises the following steps:
a) Adding the carbocisteine crude product into water, controlling the temperature to be 35-50 ℃, dropwise adding concentrated hydrochloric acid at the speed of 0.3-0.7L/min, stirring for 20-40min at the speed of 50-100 r/min until the pH is =0.5-1.0, dissolving the solid, and preparing a carbocisteine solution with the concentration range of 0.15-0.25 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution at the speed of 0.1-0.5L/min until the pH is =2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at the speed of 60-90 r/min, and stirring for 25-35min;
d) Continuously dropwise adding sodium hydroxide solution, adjusting pH to 2.8-3.0 at 10-15 deg.C, stirring at 40-80 rpm for 20-30min, filtering, washing with water, and drying to obtain refined carbocisteine.
2. The preparation method of carbocisteine bulk drug according to claim 1, wherein in step c), the stirring time is 30min.
3. The method for preparing a carbocisteine bulk drug according to claim 1, wherein in step a), a carbocisteine solution is prepared at a concentration in the range of 0.20 g/mL.
4. The preparation method of carbocisteine bulk drug according to claim 1, wherein in step a), concentrated hydrochloric acid is added dropwise at a rate of 0.4-0.6L/min, and the mixture is stirred for 30min at a rate of 60-80 rpm.
5. The preparation method of carbocisteine bulk drug according to claim 1 or 4, wherein in the step a), the temperature is controlled at 40-45 ℃, concentrated hydrochloric acid is dripped, and the dripping speed is 0.5L/min.
6. The preparation method of carbocisteine bulk drug according to claim 1, wherein in the step b), the sodium hydroxide solution with the mass concentration of 40-60% is dripped at the speed of 0.2-0.4L/min until the pH is =2.0-2.5, and the dripping of the sodium hydroxide solution is stopped.
7. The preparation method of carbocisteine bulk drug according to claim 1 or 6, characterized in that in step b), sodium oxide solution with mass concentration of 40-60% is dripped at a dripping speed of 0.3L/min.
8. The preparation method of carbocisteine bulk drug according to claim 1, wherein in step d), sodium hydroxide solution with mass concentration of 40-60% is continuously added dropwise, and stirring speed is 50-70 r/min.
9. The method for preparing a carbocisteine bulk drug according to claim 1, wherein the method further comprises the step of preparing a crude carbocisteine product:
dissolving L-cysteine hydrochloride with water, controlling the temperature to be 10-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 40-60%, adjusting the pH =8.5-9.0, controlling the temperature to be 20-25 ℃, dropwise adding a sodium chloroacetate solution, controlling the molar ratio of the L-cysteine hydrochloride to the sodium chloroacetate to be 1.
10. A carbocisteine pharmaceutical composition, characterized in that said pharmaceutical composition comprises a refined carbocisteine prepared according to the method of any one of claims 1-8.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105012254A (en) * | 2015-06-10 | 2015-11-04 | 临汾奇林药业有限公司 | Production process for carbocisteine buccal tablet |
| CN105418471A (en) * | 2015-12-24 | 2016-03-23 | 宜昌三峡制药有限公司 | Synthetic method of carbocisteine |
| CN109053508A (en) * | 2018-09-19 | 2018-12-21 | 山西云鹏制药有限公司 | A kind of preparation method of carbocisteine |
| CN111138326A (en) * | 2019-12-31 | 2020-05-12 | 宁波市远发生物工程有限公司 | Preparation method of S-carboxymethyl-L-cysteine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012254A (en) * | 2015-06-10 | 2015-11-04 | 临汾奇林药业有限公司 | Production process for carbocisteine buccal tablet |
| CN105418471A (en) * | 2015-12-24 | 2016-03-23 | 宜昌三峡制药有限公司 | Synthetic method of carbocisteine |
| CN109053508A (en) * | 2018-09-19 | 2018-12-21 | 山西云鹏制药有限公司 | A kind of preparation method of carbocisteine |
| CN111138326A (en) * | 2019-12-31 | 2020-05-12 | 宁波市远发生物工程有限公司 | Preparation method of S-carboxymethyl-L-cysteine |
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