CN115160197B - Preparation method of carbocisteine bulk drug - Google Patents
Preparation method of carbocisteine bulk drug Download PDFInfo
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- CN115160197B CN115160197B CN202110353601.0A CN202110353601A CN115160197B CN 115160197 B CN115160197 B CN 115160197B CN 202110353601 A CN202110353601 A CN 202110353601A CN 115160197 B CN115160197 B CN 115160197B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title claims abstract description 25
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 title claims description 114
- 229960004399 carbocisteine Drugs 0.000 title claims description 109
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 177
- 238000003756 stirring Methods 0.000 claims abstract description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims description 57
- 230000001276 controlling effect Effects 0.000 claims description 44
- 238000001914 filtration Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- 230000001105 regulatory effect Effects 0.000 claims description 10
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000008186 active pharmaceutical agent Substances 0.000 claims 7
- 229940088679 drug related substance Drugs 0.000 claims 7
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 abstract description 29
- 238000002425 crystallisation Methods 0.000 abstract description 16
- 230000008025 crystallization Effects 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 10
- 238000004090 dissolution Methods 0.000 abstract description 7
- 239000000428 dust Substances 0.000 abstract description 4
- 230000002349 favourable effect Effects 0.000 abstract description 4
- 238000007873 sieving Methods 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 description 44
- 239000002245 particle Substances 0.000 description 29
- 230000000052 comparative effect Effects 0.000 description 11
- 238000009826 distribution Methods 0.000 description 11
- 230000009286 beneficial effect Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229940106681 chloroacetic acid Drugs 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010979 pH adjustment Methods 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
- 206010011224 Cough 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
- 239000002253 acid Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation 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
- 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
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 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
- 239000000203 mixture Substances 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
- 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
Classifications
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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
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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
- A61P11/14—Antitussive agents
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- 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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- Engineering & Computer Science (AREA)
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Abstract
The invention discloses a preparation method of a carboxymethyl settane bulk drug, which comprises the steps of adding water into a carboxymethyl settane crude product, dropwise adding concentrated hydrochloric acid under the control of temperature, controlling the dropwise adding speed, stirring speed and reaction time, dropwise adding sodium hydroxide solution, controlling the parameters in the same way, performing crystallization in a stage, continuously controlling the above parameters, dropwise adding sodium hydroxide solution, performing further crystallization, and the like, wherein the granularity, the density, the fluidity and the like of the obtained carboxymethyl settane bulk drug meet the requirements of the subsequent preparation process, the granularity range of the prepared carboxymethyl settane bulk drug is 50 mu m or less and D90 or less is 95 mu m, the carboxymethyl settane bulk drug can be directly used for granulating the subsequent preparation through simple sieving without crushing, the effects of saving procedures and reducing dust are achieved, and the proper dissolution time is ensured, so that the carboxymethyl settane tablet prepared by using the carboxymethyl settane bulk drug is more favorable for the absorption in human body.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a carboxymethyl settane bulk drug.
Technical Field
Carbocisteine (Carbocysteine) is used for treating cough and expectoration caused by chronic bronchitis and bronchial asthma, and can be used for treating infantile non-suppurative otitis media, and has chemical name of S- (Carboxymethyl) cysteine (S-Carboxymethyl-L-cysteine) and molecular formula of C 5 H 9 NO 4 S, S. The molecular weight is 179.19, and the structural formula of the carbocisteine is:
the dissolution rate and degree of the medicine in the solvent can be expressed by dissolution rate, and the tablet is a common dosage form in oral preparations, wherein 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 bulk drugs, the granularity is an indispensable index, and the prior art mostly adopts pretreatment (such as crushing and the like) to obtain bulk drugs with target granularity forms so as to meet the preparation requirements.
Chinese patent CN201911414274.4 to 2020.05.12 discloses a preparation method of S-carboxymethyl-L-cysteine (carboxymethyl-stam), which comprises adding excessive diluted hydrochloric acid into a crude S-carboxymethyl-L-cysteine product obtained after preparation, adding seed crystals of high-density S-carboxymethyl-L-cysteine after dissolution, and adding dropwise an alkali solution (II) to adjust isoelectric point to induce crystallization, thereby obtaining coarse-particle, high-density S-carboxymethyl-L-cysteine.
Chinese patent CN201610488728.2 in 2016.11.09 discloses a process for preparing carboxymethyl span, which uses L-cysteine hydrochloride monohydrate and solid chloroacetic acid as raw materials, wherein the chloroacetic acid in the solid chloroacetic acid has high effective content, which can effectively improve the preparation efficiency and quality, and meanwhile, in the dissolution system of L-cysteine hydrochloride monohydrate and solid chloroacetic acid, the concentration of the reaction substrate in the solution can be effectively improved by controlling the temperature, so that the production efficiency and yield are ensured.
Chinese patent CN201210085042.0 to 2013.05.15 discloses a method for producing carboxymethyl cysteine (carboxymethyl settane), which uses cysteine hydrochloride monohydrate as main raw material, chloroacetic acid, liquid ammonia, active carbon, refined hydrochloric acid as auxiliary materials, and prepares the finished product through the procedures of acid adding reaction, decolorizing and filtering, centrifugal separation, drying and the like.
As described above, in the preparation process of the carbocisteine preparation (such as tablet), the carbocisteine raw material medicine is firstly subjected to crushing and sieving pretreatment, but after crushing, hygroscopicity is obviously increased, static electricity is strong, aggregation is easy, fluidity of raw material medicine powder is poor, long-term storage is not facilitated, part of products are lost or polluted in the crushing process, waste is caused, and a large amount of dust is easy to cause in the crushing process, so that the carbocisteine preparation is not beneficial to production in a preparation workshop. In the existing preparation method of the carbocisteine, the research on the granularity of carbocisteine raw materials is less, but although China patent CN201911414274.4 discloses a preparation method of the carbocisteine, carbocisteine crystal grains with larger grain diameter and higher density can be prepared, but the grain diameter is close to 0.85mm, the carbocisteine crystal grains still need to be crushed and treated, and cannot be directly used for preparing carbocisteine preparations (such as tablets), the method needs to be heated to 55-60 ℃, and high-density carbocisteine crystal seeds need to be added for regulating to isoelectric points, the conditions are relatively complex, and the method has certain limitation on large-scale workshop production.
In summary, the prior art does not disclose a method for effectively preparing the carbocisteine bulk drug with proper particle size, which is used for preparation directly, with mild conditions and simple operation. Therefore, a preparation method of the carbocisteine bulk drug is needed, the bulk drug suitable for granulating subsequent preparations can be directly prepared, the carbocisteine bulk drug prepared by the preparation method meets the granularity requirement of a tablet preparation, further crushing is not needed, and the subsequent preparation procedures are saved.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of a carboxymethyl settane bulk drug with proper particle size, which has the advantages of mild condition, convenient operation and high yield, wherein the particle size range of the prepared carboxymethyl settane bulk drug is 50 mu m or less and D90 or less and 95 mu m, the powder property is suitable for preparation, and the bulk drug supports the granulation of the subsequent preparation just by simple sieving without crushing, thereby achieving the effects of saving procedures, reducing dust and the like.
Specifically, the preparation method of the carboxymethyl settane raw material in the form of target powder by a two-step crystallization method comprises the following steps: adding water into the crude carbocisteine product, dropwise adding concentrated hydrochloric acid at a controlled temperature, controlling the dropwise adding speed, stirring speed and reaction time, dropwise adding sodium hydroxide solution, controlling the parameters in the same way, crystallizing in a flat stage, and continuously controlling the parameters to dropwise adding sodium hydroxide solution for further crystallizing to obtain the bulk drug applicable to preparation production.
The beneficial effects of the invention are realized by the following method:
the preparation method of the carbocisteine bulk drug comprises the following steps:
a) Adding the crude carbocisteine product into water, controlling the temperature to be 35-50 ℃, dropwise adding concentrated hydrochloric acid, stirring for 20-40min at the speed of 0.3-0.7L/min and the stirring speed of 50-100 r/min until the pH value is=0.5-1.0, and dissolving the solid to prepare carbocisteine solution with the concentration range of 0.15-0.25 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding sodium hydroxide solution, wherein the dropwise adding speed is 0.1-0.5L/min, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 25-35min;
d) Continuously dripping sodium hydroxide solution, adjusting pH to be less than 2.8-3.0 at 10-15 ℃, stirring at 40-80 r/min for 20-30min, filtering, washing with water, and drying to obtain refined carbocisteine.
In step c), the temperature and the stirring time are one of the keys to achieve the technical effect. The inventor finds that if step c) is omitted in the preparation process, the particle size, density and fluidity of the obtained crystals are greatly influenced, and in particular, the obtained carbocisteine crystals have smaller particle size, are sticky, are easy to extrude and agglomerate and have poorer fluidity, so that the platform period is set in the process of dropwise adding sodium hydroxide solution, and are beneficial to the growth of crystals. Preferably, when the platform period is set to 15-25 ℃, the stirring speed is 60-90 r/min, and the stirring time is 25-35min, the grain size, density and fluidity of the obtained crystals meet the requirements, and viscosity is not generated, and analysis shows that in the technical scheme, 25-35min is the favorable time for the growth of carboxymethyl settane crystals, when the time is longer, the density and fluidity of the generated crystals are obviously reduced, when the time is shorter, the growth time of the crystals is insufficient, the grain size of the generated crystals is uneven, the crystallization speed is controlled by adjusting the time, the product properties can be effectively improved, and the quality of the products is improved. More preferably, when the stirring time is 30 minutes, the comprehensive particle diameter, density, fluidity and other factors are evaluated optimally.
In addition, the combination of the gradient pH adjustment and the gradient cooling method can ensure the stable precipitation and growth of the carbocisteine crystal nucleus and ensure the uniformity of the obtained carbocisteine refined product. The proper stirring speed is beneficial to ensuring the slow precipitation of crystals, thereby improving the density of the crystals, and also beneficial to adhering the formed crystals to the formed crystals, thereby obtaining the fine product with proper granularity.
In the step a), the speed of dropwise adding concentrated hydrochloric acid, the stirring time and the stirring speed are one of the keys for realizing the technical effect. The proper dropping speed can effectively reduce the generation of chloride impurities which are difficult to remove, and meanwhile, the local temperature of the reaction system is controlled not to rise suddenly, and the proper stirring time and stirring speed are beneficial to the growth of crystal forms and ensure the uniformity of the subsequent fine particle size. Preferably, in the step a), the crude carbocisteine product is added into water, the temperature is controlled to be 35-50 ℃, concentrated hydrochloric acid is added dropwise, the dropping speed is 0.4-0.6L/min, and the stirring is carried out for 30min, and the stirring speed is 60-80 r/min. More preferably, the temperature is controlled to be 40-45 ℃, concentrated hydrochloric acid is added dropwise, and the dropping speed is 0.5L/min.
In the step b), the speed and the pH value of the sodium hydroxide solution are one of the keys for realizing the technical effect. When the sodium hydroxide solution is added dropwise, the dropping speed of the sodium hydroxide solution is reduced, so that the alkalinity of the solution is controlled not to be locally overlarge, crystals are precipitated after reaching a crystallization point, and particles are loose. The proper pH environment in the stage can prevent the occurrence of the phenomenon of dialysis and can enable the carbocisteine crystal to grow to a certain extent. When the pH is less than 2.0, the crystallization efficiency is reduced, and the obtained crystal form is formed in an aggregated form, so that the crystal form is viscous and poor in fluidity, and when the pH is more than 2.5, a large amount of crystals are not grown, i.e., are precipitated, and the crystal form is poor. Preferably, in step b), sodium hydroxide solution is added dropwise at a rate of 0.2 to 0.4L/min to ph=2.0 to 2.5, and the addition of sodium hydroxide solution is stopped. More preferably, in the step b), a sodium hydroxide solution is added dropwise at a rate of 0.3L/min.
In the step d), crystallization temperature, pH value, stirring speed and stirring time are one of important factors for realizing technical effects. After the carbocisteine crystal is subjected to preliminary growth in the stage c), certain target crystal form conditions are provided, the carbocisteine crystal can be further separated out under the proper crystallization conditions, impurities in the carbocisteine crystal can be removed, and the purity is improved. When the crystallization temperature is more than 15 ℃, the crystal morphology is easy to form into a block shape, 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 favorable for removing impurities, and simultaneously ensures the precipitation amount of the carbocisteine and improves the yield. The stirring speed and stirring time are proper, larger crystallization particles in the stage of the platform can be dispersed, the crystal form density is improved, the granularity of finally obtained carbocisteine is ensured to be in a required range, the residue of a solvent can be reduced, and the purity of a product is improved. Only when the above parameter conditions are integrally combined, the optimal crystallization effect can be achieved. Preferably, in step d), the dropwise addition of sodium hydroxide solution is continued, the ph=2.8-3.0 is adjusted at 10-15 ℃, the stirring speed is 40-80 rpm, and the stirring time is 20-30min. More preferably, in step d), the stirring speed is 50-70 rpm.
In the present invention, in the step b) and the step d), the sodium hydroxide solution added dropwise 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 concentration.
In said step a), the concentration of the carbocisteine solution is one of the important factors for achieving the technical effect. Although the yield can be improved to a certain extent by improving 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 requirement of subsequent preparations; and the nucleation and growth of the crystal are slow at too low concentration, and the yield is low. The inventors found that the formation of crystals is favored when the concentration of carbocisteine solution is 0.15 to 0.25g/mL, preferably 0.20 g/mL.
The carbocisteine can be prepared in a reaction kettle with anchor type, paddle type, turbine type, propelling type and frame type stirring paddles, preferably the reaction kettle with the anchor type stirring paddles, can obtain large shearing force along the wall surface during low-speed rotation by using the anchor type stirring, can prevent sedimentation and wall surface adhesion, and ensures that materials are mixed more uniformly.
Because the scheme has a certain refining effect, the method has no special requirement on the adopted crude carbocisteine, can use a finished product with higher purity on the market, can also consider industrial production to use a self-made crude product, and is preferably more than or equal to 95.0 percent of carbocisteine. Specifically, in industrial production, the crude carbocisteine product in the technical scheme can be prepared by the following preparation steps, and the carbocisteine crude product obtained by the method has high yield and high purity, and is more suitable for subsequent crystallization and refining:
dissolving L-cysteine hydrochloride in water, controlling the temperature to be 10-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 40-60%, regulating the pH value to be 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 1:0.5-0.8, controlling the pH value to be 7.5-8.0, reacting for 3 hours at 20-25 ℃, adding active carbon after the reaction is finished, stirring and filtering, regulating the temperature of filtrate to be 20-25 ℃, adding concentrated hydrochloric acid, regulating the pH value to be 2.5-3.0, and separating out a carbocisteine crude product.
The carbocisteine crystal prepared by the method meets the process requirements of subsequent preparations. Specifically, the carbocisteine crystal achieves the preset aim, namely the particle size range is 50 μm or less and D90 is or less than 95 μm, the fluidity is improved, and the electrostatic phenomenon is reduced. The fluidity is represented by the angle of repose of the powder, and the fluidity of the powder is measured by adopting a conventional detection method in the field, such as a fixed funnel method; the static phenomenon can be represented by bulk density, the bulk density is detected by a measuring cylinder method, and the tap density is detected by a measuring cylinder knocking method.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. the preparation method of the carbocisteine bulk drug with proper particle size is provided, the particle size range of the prepared carbocisteine bulk drug is 50 μm or less and D90 is or less than 95 μm, the carbocisteine bulk drug can be directly used for granulating subsequent preparations without crushing through simple sieving, the effects of saving working procedures and reducing dust are achieved, and the carbocisteine tablet prepared by using the carbocisteine bulk drug ensures proper dissolution time, thereby being more beneficial to absorption in human bodies.
2. The preparation method of the carbocisteine bulk drug with proper particle size is provided, the carbocisteine refined product obtained by the preparation method has higher fluidity and density, can meet the requirement of the subsequent preparation process with high requirement, has high purity, and is suitable for industrial production.
Drawings
FIG. 1 SEM photograph of carbocisteine obtained in example 2.
FIG. 2 distribution of the particle size distribution of carbocisteine obtained in example 2.
FIG. 3 shows the particle size distribution of carbocisteine obtained in comparative example 1.
FIG. 4 shows the particle size distribution of carbocisteine obtained in comparative example 2.
FIG. 5 shows the particle size distribution of carbocisteine obtained in comparative example 3.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
In the following examples, the reaction apparatus may be selected from a closed reaction vessel 2000L (anchor stirring) or a speed-regulated glass reaction vessel GR-20CE-20L, depending on the reaction conditions.
Example 1
Preparation of crude carbocisteine
Preparing a solution: 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: 279.0kg of L-cysteine hydrochloride is dissolved in 558.0L of water, the temperature is controlled to be 10-20 ℃, 50% sodium hydroxide solution is dripped, the pH value is regulated to be 8.5-9.0, the temperature is controlled to be 20-25 ℃, sodium chloroacetate solution is dripped, the pH value is regulated to be 7.5-8.0, the reaction is carried out for 3 hours at the temperature of 20-25 ℃, active carbon is added after the reaction is finished, stirring and decoloration are carried out, filtration is carried out, the temperature of filtrate is controlled to be 20-25 ℃, concentrated hydrochloric acid is added to regulate the pH value to be 2.5-3.0, 213.0kg of crude carbocisteine is separated out, and the purity is 95.8%.
Example 2
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 7.77L of water into 2.22kg of the crude carbocisteine product, controlling the temperature to be 40-45 ℃, dropwise adding concentrated hydrochloric acid at the dropwise speed of 0.5L/min, stirring for 30min at the stirring speed of 60-80 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.20 g/mL;
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, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 30min;
d) Continuously dripping 50% sodium hydroxide solution, adjusting pH=2.8-3.0 at 10-15deg.C, stirring at 50-70 r/min, stirring for 25min, filtering, washing with water, and drying to obtain 1.98kg carboxymethyl refined product with 89.1% yield, wherein SEM photograph of the obtained product shows that carboxymethyl refined product is granular, has good fluidity, and uniform particle size distribution. The D90 of the product is 50 μm or less and D90 is or less than 95 μm, and the particle size distribution is shown in figure 2.
Example 3
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 10.95L of water into 2.18kg of the crude carbocisteine product, controlling the temperature to be 35-40 ℃, dropwise adding concentrated hydrochloric acid, stirring for 20min at the speed of 0.3L/min and 50-60 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.15 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding sodium hydroxide solution with the mass concentration of 40%, wherein the dropwise adding speed is 0.1L/min, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 25min;
d) Continuously dripping 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 stirring speed of 40-50 r/min, stirring for 20min, filtering, washing with water and drying to obtain 1.89kg of carboxymethyl settane refined product, wherein the yield is 86.5%, and the carboxymethyl settane refined product is granular from the appearance.
Example 4
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 6.25L of water into 2.19kg of the crude carbocisteine product, controlling the temperature to be 45-50 ℃, dropwise adding concentrated hydrochloric acid, stirring for 40min at the speed of 0.7L/min and the stirring speed of 80-100 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.25 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding sodium hydroxide solution with the mass concentration of 60%, wherein the dropwise adding speed is 0.5L/min, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 35min;
d) Continuously dripping 60% sodium hydroxide solution, adjusting pH to be 2.8-3.0 at 10-15deg.C, stirring at 70-80 r/min, stirring for 30min, filtering, washing with water, and drying to obtain 1.87kg carboxymethyl settane essence with yield of 85.5% and granular carboxymethyl settane essence.
Example 5
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 8.55L of water into 2.14kg of the crude carbocisteine product, controlling the temperature to be 35-40 ℃, dropwise adding concentrated hydrochloric acid, stirring for 25min at the speed of 0.5L/min and at the stirring speed of 60-80 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.22 g/mL;
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, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 30min;
d) Continuously dripping 50% sodium hydroxide solution, adjusting pH to be 2.8-3.0 at 10-15deg.C, stirring at 50-70 r/min for 25min, filtering, washing with water, and drying to obtain 1.87kg carboxymethyl refined product with yield of 87.2% and granular carboxymethyl refined product.
Example 6
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 9.65L of water into 2.14kg of the crude carbocisteine product, controlling the temperature to be 45-50 ℃, dropwise adding concentrated hydrochloric acid, stirring for 35min at the speed of 0.6L/min and 60-80 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.18 g/mL;
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, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 30min;
d) Continuously dripping 50% sodium hydroxide solution, adjusting pH to be 2.8-3.0 at 10-15deg.C, stirring at 50-70 r/min, stirring for 30min, filtering, washing with water, and drying to obtain 1.86kg carboxymethyl settane fine product with 86.7% yield, and making carboxymethyl settane fine product into granule.
Comparative example 1
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 11.50L of water into 2.11kg of the crude carbocisteine product, controlling the temperature to be 55-60 ℃, dropwise adding concentrated hydrochloric acid, stirring for 45min at the speed of 0.8L/min and the stirring speed of 110-130 r/min until the pH=1.1-1.5, and preparing into a carbocisteine solution of 0.13 g/mL;
b) Controlling the temperature to be 40-45 ℃, dropwise adding sodium hydroxide solution with the mass concentration of 30%, wherein the dropwise adding speed is 0.6L/min, until the pH value is=2.6-3.0, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 26-30 ℃, stirring at a stirring speed of 100-110 rpm, and stirring for 40min;
d) Continuously dripping 30% sodium hydroxide solution, adjusting pH to be=3.1-3.5 at 16-20deg.C, stirring at 90-110 r/min, stirring for 35min, filtering, washing with water, and drying to obtain 1.73kg carboxymethyl settane refined product with yield of 81.9%, wherein the carboxymethyl settane is flaky and easy to agglomerate and loosen. The D90 of the product is 30 μm or less and D90 is or less than 65 μm, and the particle size distribution is shown in figure 3.
Comparative example 2
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 5.00L of water into 2.00kg of the crude carbocisteine product, controlling the temperature to be 25-30 ℃, dropwise adding concentrated hydrochloric acid, stirring for 18min at the speed of 0.2L/min and at the stirring speed of 30-40 r/min until the pH=0.3-0.4, and dissolving the solid to prepare a carbocisteine solution of 0.28 g/mL;
b) Controlling the temperature to 15-20 ℃, dropwise adding sodium hydroxide solution with the mass concentration of 65%, wherein the dropwise adding speed is 0.08L/min, until the pH value is=1.5-1.9, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 5-14 ℃, stirring at 40-55 rpm, and stirring for 20min;
d) Continuously dripping 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 stirring speed of 20-30 r/min, stirring for 15min, filtering, washing with water and drying to obtain 1.59kg of refined carbocisteine product, wherein the yield is 79.4%, and the carbocisteine product is flaky, easy to agglomerate and rough in appearance. The D90 of the product is not less than 100 mu m and not more than 170 mu m, and the particle size distribution is shown in figure 4.
Comparative example 3
a) After the crude carbocisteine product is prepared according to the method of the example 1, adding 7.77L of water into 2.22kg of the crude carbocisteine product, controlling the temperature to be 40-45 ℃, dropwise adding concentrated hydrochloric acid at the dropwise speed of 0.5L/min, stirring for 30min at the stirring speed of 60-80 r/min until the pH=0.5-1.0, and dissolving the solid to prepare a carbocisteine solution of 0.20 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 50%, controlling the dropwise adding speed to be 0.3L/min, adjusting the pH value to be 2.8-3.0, stirring at the stirring speed of 50-70 r/min, stirring for 25min, filtering, washing with water and drying to obtain 2.02kg of refined carbocisteine, wherein the yield is 91.2%, and the carbocisteine is in a blocky shape, has rough appearance and poor fluidity. The D90 of the product is more than or equal to 10 mu m and less than or equal to 50 mu m, and the particle size distribution is shown in figure 5.
Example 7 commercial scale-up production of crude carbocisteine
a) After the crude carbocisteine product is prepared according to the method of the example 1, 222kg of the crude carbocisteine product is filtered, 777L of water is added, the temperature is controlled at 40-45 ℃, concentrated hydrochloric acid is added dropwise, the dropping speed is 0.5L/min, stirring is carried out for 30min, the stirring speed is 60-80 r/min, the pH=0.5-1.0, and the solid is dissolved to prepare 0.20g/mL 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, until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 30min;
d) Continuously dripping 50% sodium hydroxide solution, adjusting pH to be 2.8-3.0 at 10-15deg.C, stirring at 50-70 r/min for 25min, filtering, washing with water, and drying to obtain 194.0kg carboxymethyl refined product with yield of 87.4% and granular form.
Example 8
The carboxymethyl settane fine products of examples 2 to 7, comparative examples 1 to 3 were examined to obtain the results of the following tables:
from the above table data, the preparation method described in comparative example 1 has a higher temperature and a too high dropping speed of concentrated hydrochloric acid, so that the local temperature is too high, and the carboxymethyl settane is partially decomposed, while when the sodium hydroxide solution is dropped, the dropping speed of the sodium hydroxide solution is too high, the alkaline local part of the solution is too large to directly reach the crystallization point, so that crystals are precipitated without being arranged, and particles are loose. Meanwhile, the stirring speed is too high, and the particle size of the produced crystals is smaller. Therefore, the carbocisteine obtained by the preparation method described in comparative example 1 has low yield and purity, and small particle size, and is unfavorable for the requirements of subsequent preparations.
In contrast, in comparative example 2, the temperature was low, the dropping speed of concentrated hydrochloric acid was low, the acidity was low, there was a risk of increasing the residue such as chloride, and the alkalinity was insufficient when sodium hydroxide solution was dropped, resulting in a decrease in the amount of refined carbocisteine precipitated subsequently. Meanwhile, the stirring speed is too slow, and the produced crystals have larger particle size and lower density, which is not beneficial to the requirements of subsequent preparations.
In comparative example 3, the carbocisteine crystals obtained, although having an improved yield, have the phenomena of small particle size, tackiness, easy extrusion and agglomeration and poor fluidity, and cannot meet the requirement of being directly used for granulating subsequent preparations due to the omission of the plateau phase. The inventors found that, at the same time of excessively high yield, deterioration in crystal morphology generally occurs, and therefore, it is important to balance the overall crystal morphology, yield and purity.
As can be seen from examples 2 and 6, the setting of the plateau phase is favorable for the growth of the required crystal form, and the combination of the gradient pH adjustment and the gradient cooling method can ensure the stable precipitation growth of the crystal nucleus of the carbocisteine, ensure the uniformity of the obtained carbocisteine fine product, concentrate the particle size in the required range, ensure that the D90 is less than or equal to 50 mu m and less than or equal to 95 mu m, ensure better powder flowability and facilitate the preparation of the subsequent preparation. The various parameters in example 2, including reaction temperature, reaction time, dropping speed, acid-base environment, etc., are all most preferable, and the overall combination of the above conditions makes the obtained crystal morphology, yield and purity, and the combination thereof optimal.
As can be seen from example 7, the present solution also has a certain feasibility in industrial scale-up production, and the obtained carbocisteine fine product has advantages compared with the fine product obtained under pilot plant conditions, whether in crystal form or in yield and purity.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
1. The preparation method of the carbocisteine bulk drug comprises the following steps:
a) Adding the crude carbocisteine product into water, controlling the temperature to be 35-50 ℃, dropwise adding concentrated hydrochloric acid, stirring for 20-40min at the speed of 0.3-0.7L/min until the pH value is=0.5-1.0 and the solid is dissolved, and preparing carbocisteine solution with the concentration range of 0.15-0.25 g/mL;
b) Controlling the temperature to be 25-35 ℃, dropwise adding sodium hydroxide solution with the mass concentration of 40-60% at the dropwise speed of 0.1-0.5L/min until the pH value is=2.0-2.5, and stopping dropwise adding the sodium hydroxide solution;
c) Controlling the temperature to 15-25 ℃, stirring at 60-90 r/min, and stirring for 25-35min;
d) Continuously dripping 40-60% sodium hydroxide solution, adjusting pH to be 2.8-3.0 at 10-15deg.C, stirring at 40-80 rpm for 20-30min, filtering, washing with water, and drying to obtain refined carbocisteine.
2. The method for preparing a carbocisteine drug substance according to claim 1, wherein in step c), the stirring time is 30min.
3. The method for preparing a carbocisteine drug substance according to claim 1, wherein in step a), a carbocisteine solution with a concentration range of 0.20g/mL is prepared.
4. The method for preparing a carbocisteine drug substance according to claim 1, wherein in the step a), concentrated hydrochloric acid is added dropwise, the dropping speed is 0.4-0.6L/min, stirring is carried out for 30min, and the stirring speed is 60-80 rpm.
5. The method for preparing a carbocisteine drug substance according to claim 1 or 4, wherein in step a), concentrated hydrochloric acid is added dropwise at a temperature of 40-45 ℃ at a dropping speed of 0.5L/min.
6. The method for preparing a carbocisteine drug substance according to claim 1, wherein in step b), a sodium hydroxide solution with a mass concentration of 40-60% is added dropwise, the dropping speed is 0.2-0.4L/min, the ph=2.0-2.5, and the dropping of the sodium hydroxide solution is stopped.
7. The method for preparing a carbocisteine drug substance according to claim 1 or 6, wherein in step b), a sodium hydroxide solution with a mass concentration of 40-60% is added dropwise, and the dropping speed is 0.3L/min.
8. The method for preparing a carbocisteine drug substance according to claim 1, wherein in step d), a sodium hydroxide solution with a mass concentration of 40-60% is continuously added dropwise, and the stirring speed is 50-70 rpm.
9. The method for preparing a crude carbocisteine product according to claim 1, further comprising the steps of:
dissolving L-cysteine hydrochloride in water, controlling the temperature to be 10-20 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 40-60%, regulating the pH value to be 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 1:0.5-0.8, controlling the pH value to be 7.5-8.0, reacting for 3 hours at 20-25 ℃, adding active carbon after the reaction is finished, stirring and filtering, regulating the temperature of filtrate to be 20-25 ℃, adding concentrated hydrochloric acid, regulating the pH value to be 2.5-3.0, and separating out a carbocisteine crude product.
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