CN105769873A - Cefaclor preparation and preparation method thereof - Google Patents
Cefaclor preparation and preparation method thereof Download PDFInfo
- Publication number
- CN105769873A CN105769873A CN201610154698.1A CN201610154698A CN105769873A CN 105769873 A CN105769873 A CN 105769873A CN 201610154698 A CN201610154698 A CN 201610154698A CN 105769873 A CN105769873 A CN 105769873A
- Authority
- CN
- China
- Prior art keywords
- cefaclor
- preparation
- reaction
- solution
- dichloromethane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a cefaclor preparation and a preparation method thereof. The preparation method comprises: preparing cefaclor crystal, pretreating a main material and auxiliary materials, weighing, mixing, forming, and packaging; wherein the preparation of the cefaclor crystal includes subjecting 7-ACCA and potassium (R)-[(3-ethoxy-1-methyl-3-oxoprop-1-enyl)amino]phenylacetate to silylation, acylation, condensation, acid hydrolysis, extraction and cleaning, decoloring, and crystallization; the preparation comprises the cefaclor crystal as the main material and auxiliary materials, the cefaclor crystal is </=33 degrees in angle of repose, 0.50-0.60 g/m in bulk density, 0.70-0.80 g/ml in compactness and 40-60 Mum in D10 of particle size distribution, 120-140 Mum in D50 and 210-230 Mum in D90. The conversion rate of cefaclor in chemical synthesis is increased, reaction conditions are simplified, the crystal form and particle size distribution of the cefaclor crystal are improved, and the quality of finished cefaclor crystal is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of Cefaclor preparation and preparation method thereof.
Background technology
Cefaclor (Cefaclor), chemical name: (6R, 7R)-7-[(R)-2-amino-2-phenylacetylamino]-3-
Chloro-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid monohydrate.Chemical structural formula is as follows
Shown in,
Cefaclor is that white is to micro-yellow powder or crystalline powder；Micro-smelly.Slightly soluble in water, methyl alcohol,
In ethanol, chloroform or dichloromethane the most insoluble.
Cefaclor is beta-lactam antibiotic, cephalosporins medicine, for white to micro-yellow powder or knot
Crystalline substance powder；Micro-smelly.It is second generation cephalosporin, have concurrently first generation cephalosporin to gram positive bacteria and
The feature that second generation cephalosporin is strong to gram-negative bacteria effect.To the S. aureus L-forms of Penicillin-resistant and influenza addicted to
Blood bacillus, first, beta hemolytic streptococcus, pneumococcus, Escherichia coli all have preferable antibacterial activity.
At present, the preparation method of Cefaclor mainly has chemical synthesis and catalyzed by biological enzyme.
Catalyzed by biological enzyme is a kind of method of conventional industrialized production Cefaclor, the method be typically with
7-ACCA and D-PG, under the catalytic action of corresponding catalyzing enzyme, generate Cefaclor, but the method
Use condition the harshest, process control is the strictest, causes production process loaded down with trivial details, such as: the work of enzyme
Property is affected by each side factors such as temperature, and a little change of external environment all can cause product yield and product
Purity declines.The impurity that catalyzed by biological enzyme produces simultaneously is more, and product process for separating and purifying process is complicated,
The problems such as product crystalline quality difference.
Existing chemical synthesis includes kinds of processes path, but generally have that conversion ratio is low, poor product quality,
Reaction condition complexity, complex operation step, organic solvent residual is serious, purifying crystal processes complicated, production
High in cost of production problem.The Cefaclor bulk drug that said method prepares is in the preparation process of preparation, right
The preparation condition of preparation requires more harsh, and the product quality of preparation can not be guaranteed and promote.Therefore,
Existing chemical synthesis process must be improved, in order to industrialized production.
Summary of the invention
The technical issues that need to address of the present invention are to provide a kind of Cefaclor preparation and preparation method thereof, to carry
Rise the product quality of Cefaclor preparation, improve conversion present in existing Cefaclor bulk drug building-up process
Rate is low, poor product quality, reaction condition complicated, purifying crystal processes the shortcomings such as complicated.
For solving above-mentioned technical problem, the technical solution used in the present invention is:
Cefaclor preparation, described preparation comprises cefaclor crystals major ingredient and auxiliary material, described Cefaclor
Angle of repose≤33 degree of crystal, bulk density 0.50～0.60g/ml, tight ness rating 0.70～0.80g/ml, size distribution
In D10 be 40～60um, D50 is 120～140um, and D90 is 210～230um.
Further improvement is that of technical solution of the present invention: the type of described Cefaclor preparation is Cefaclor
Capsule, Cefaclor tablet, Cefaclor dry suspensoid agent.
The invention also discloses the preparation method of Cefaclor preparation, described preparation method includes that Cefaclor is brilliant
The pretreatment of the preparation of body, major ingredient and auxiliary material, weighing, mix, be molded, pack, described Cefaclor is brilliant
The preparation of body is with 7-ACCA, dane potassium salts as raw material, via Silanization reaction, acylation reaction, condensation reaction,
Acidolysis reaction, abstraction impurity removal, decolouring and crystallisation step, prepare cefaclor crystals.
Further improvement is that of technical solution of the present invention: the preparation method of described cefaclor crystals is specifically wrapped
Include following processing step,
(1) Silanization reaction: joined by 7-ACCA in dichloromethane, when solution temperature is 25～30 DEG C
Dissolving obtains 7-ACCA solution, adds silylating reagent in 7-ACCA solution, and reaction temperature is 40～46 DEG C
Shi Jinhang Silanization reaction, is cooled to-15 DEG C after completion of the reaction；
(2) prepare mixed acid anhydride: joined by dane potassium salts in dichloromethane, be cooled to-40～-70 DEG C obtain Deng
Potassium salt soln, first adds ethyl chloroformate in dane potassium salts solution, is then slowly added into 1-METHYLPYRROLIDONE,
Reaction temperature is-30～stirring reaction 30～60min when-55 DEG C, adds diluent and controls temperature and be
-35～-55 DEG C, continue stirring and be reacted to terminal；
(3) condensation reaction: the mixed acid anhydride in step (2) continues to be cooled to-60～-95 DEG C, by step
(1) the Silanization reaction product in proceeds in mixed acid anhydride, stir and be to slowly warm up to-20～-45 DEG C contract
Close reaction；
(4) acidolysis reaction: the condensation reaction products in step (3) is joined certain density hydrochloric acid molten
In liquid, controlling temperature is-25～10 DEG C, and controlling pH is 0.3～0.5, and stirring carries out acidolysis reaction；
(5) abstraction impurity removal: after being stood by the acidolysis reaction product in step (4), split-phase, and if carrying out
Dry extraction, obtains the thick solution of Cefaclor salt；
(6) decolouring: add activated carbon, ethylenediamine tetra-acetic acid, pyrosulfurous acid in the thick solution of Cefaclor salt
Sodium, continues stirring, stands, separates to obtain filtrate and filter residue, with the hydrochloric acid solution washing filter that pH is 0.7～1.0
Slag, merges into destainer by cleaning solution and filtrate；
(7) crystallization: the temperature controlling destainer is 20～35 DEG C, with the ammoniacal liquor tune that volume fraction is 10～25%
Crystalline substance, controlling temperature is 10～35 DEG C, and growing the grain is centrifugal, and water washs 3 times, and 40～50 DEG C are dried, obtain cephalo
Clo crystal.
Further improvement is that of technical solution of the present invention: the quality of 7-ACCA solution in described step (1)
Percentage concentration is 10～30%, and silylating reagent is trim,ethylchlorosilane, HMDS and N, O-double three
The comprehensive silicon Alkylators of first silica-based acetamide composition, wherein, trim,ethylchlorosilane and the quality of 7-ACCA
Ratio is 31: 100～50: 100, and HMDS is 18: 100～47: 100 with the mass ratio of 7-ACCA,
The double trimethylsilyl acetamide of N, O-is 4: 1000～10: 1000 with the mass ratio of 7-ACCA.
Further improvement is that of technical solution of the present invention: the quality hundred of dane potassium salts solution in described step (2)
Point concentration is 5～30%, and ethyl chloroformate is 12: 29 with the mass ratio of dane potassium salts, described N-crassitude
Ketone be concentration expressed in percentage by volume be the DMF solution of 0.5～1.5%, described diluent is DMF solvent and diluent
It is 15～100～75～100 with the volume ratio of dane potassium salts solution.
Further improvement is that of technical solution of the present invention: the volume basis of hydrochloric acid solution in described step (4)
Concentration is 5～10%, condensation reaction products and hydrochloric acid solution volume ratio be 1.5: 1～2.5: 1.
Further improvement is that of technical solution of the present invention: concretely comprising the following steps of described step (5), by acidolysis
Product stand after split-phase, obtain an aqueous phase and a dichloromethane phase, to a dichloromethane mutually in
Adding water, stirring, stand, split-phase obtains secondary aqueous phase and secondary dichloromethane phase, merges aqueous phase with
Secondary aqueous phase also adds dichloromethane, stirring, stands, and split-phase obtains three aqueous phases and three dichloromethane phases,
In three aqueous phases, add hydrochloric acid solution and add dichloromethane, stirring, stand, split-phase obtains four aqueous phases
With four dichloromethane phases, adding dichloromethane, stirring, stand in four aqueous phases, split-phase obtains five times
Five aqueous phases are carried out vacuum outgas, obtain Cefaclor salting liquid by aqueous phase and five dichloromethane phases.
Further improvement is that of technical solution of the present invention: activated carbon and Cefaclor salt in described step (6)
The mass ratio of solution is 3: 100～6: 100, and ethylenediamine tetra-acetic acid with the mass ratio of Cefaclor salting liquid is
2: 1000～4: 1000, sodium pyrosulfite is 1: 100～2: 100 with the mass ratio of Cefaclor salting liquid.
The technological process that in the present invention prepared by cefaclor crystals is:
The Silanization reaction of step (1), is using the 7-ACCA (7-amino-3-chloro-3-cephem as parent nucleus
-4-carboxylate) react with the comprehensive silicon Alkylators silica-based containing trimethyl, with on 7-ACCA parent nucleus
Carboxyl is protected, and the most also introduces trimethyl in the amino on 7-ACCA parent nucleus silica-based, improves amino
Reactivity.
Step prepares mixed acid anhydride in (2), is using dane potassium salts (L-Phenylglycine ethyl Deng as side chain
Sylvite) react generation acid anhydrides, to improve the reactivity of carboxylate radical on dane potassium salts with ethyl chloroformate.
Condensation reaction in step (3), is to utilize acid anhydrides to react with the amino on 7-ACCA parent nucleus,
To introduce corresponding side chain on 7-ACCA parent nucleus.
Acidolysis reaction in step (4), is by the carboxy protective group on parent nucleus and other base on side chain
Group dissociates, to prepare Cefaclor.
Using abstraction impurity removal in step (5)～(7), decolour, crystallize, to prepare, purity is higher, crystal formation
Preferably cefaclor crystals.
Owing to have employed technique scheme, the technological progress acquired by the present invention is:
In the Cefaclor preparation of the present invention, Cefaclor bulk drug has following parameter attribute: have more
Suitable angle of repose, angle of repose≤33 degree, the frictional force between particle is less, mobility is preferable, it is possible to preferably
Ground meets the need for liquidity in Cefaclor formulation manufacturing processes, it is possible to adapt to operation prepared by several formulations
Condition requirement.There is more suitably bulk density and tight ness rating, bulk density 0.50～0.60g/ml, tight ness rating
0.70～0.80g/ml, it is possible to meet the demand of different preparation type.The Cefaclor bulk drug of the present invention also has
The most suitable size distribution, the size distribution index using Malvern particles distribution instrument to measure is as follows: D10
Being 40～60um, D50 is 120～140um, and D90 is 210～230um.The crystalline substance of the Cefaclor of the present invention
Type is mainly type III, is medicinal crystal-form Cefaclor monohydrate, and the dissolution of raw material of this crystal formation is good, body
Interior organism-absorbing availability is high, therefore in order to ensure the stability of preparation, the content of this crystal formation uses X-ray to spread out
Penetrating method detection, consistent with standard diagram, content is more than 90%.The preparation type of the present invention includes Cefaclor
Capsule, Cefaclor tablet, Cefaclor dry suspensoid agent.
The present invention ensures the characterisitic parameter of Cefaclor bulk drug by the following method, and the present invention is by enemy
The improvement of spore clo preparation method, selecting 7-ACCA and dane potassium salts is primary raw material, via Silanization reaction,
Acylation reaction, condensation reaction, acidolysis reaction obtain Cefaclor salt, improve chemical method the synthesis of cefaclor
Conversion ratio, simplify reaction condition, and by abstraction impurity removal, decolouring and crystallisation step, improve head
The crystal formation of spore clo crystal and size distribution, improve the product quality of cefaclor crystals.
Cefaclor preparation method of the present invention during Silanization reaction, add by trim,ethylchlorosilane, six
Methyl disilazane and N, the comprehensive silicon Alkylators of O-double trimethylsilyl acetamide composition so that silanization is anti-
The reactivity answered is high, selectivity is good, reaction yield is high, can protect carboxyl on 7-ACCA parent nucleus
Protect, it is to avoid the reaction between 7-ACCA core molecule, generation can also be reacted containing N-Si with amino simultaneously
The group of key, improves the reactivity of amino, and meanwhile, the double trimethylsilyl acetamide of N, O-can also remove instead
Answer the water in system, reduce the generation of side reaction.The reaction rate of the Silanization reaction of the present invention is fast, conversion
Rate is high, accessory substance is few, and product can carry out next step condensation reaction without carrying out separation.
Cefaclor preparation method of the present invention dane potassium salts is prepared as after corresponding mixed acid anhydride again with 7-ACCA
Parent nucleus reacts, and carboxylate radical is converted into acid anhydrides, drastically increases reactivity, prepares mixing simultaneously
The reaction rate of acid anhydrides is fast, conversion ratio is high, accessory substance is few, and product can carry out next step without carrying out separation
Condensation reaction.
In the condensation reaction of Cefaclor preparation method of the present invention, it is to utilize acid anhydrides to contain on 7-ACCA parent nucleus
The group having N-Si key reacts, and introduces corresponding side chain, the reaction of this reaction on 7-ACCA parent nucleus
Speed is fast, conversion ratio is high, accessory substance is few.Product, through acidolysis reaction, i.e. can get Cefaclor salt
Solution, accessory substance and other impurity can be completely removed by easy separating step.
During the abstraction impurity removal of Cefaclor preparation method of the present invention, by extracting operation several times, it is ensured that
In aqueous phase, the yield of product and purity, effectively removes the accessory substance in product and other impurity.De-
In look step, impurity absorption that activated carbon can be dissolved in aqueous phase is removed, and ethylenediamine tetra-acetic acid can be by
Metal ion in aqueous phase removes, and the product that sodium pyrosulfite is prevented from aqueous phase is oxidized rotten.Finally
Pass through crystallisation step, it is possible to obtain the cefaclor crystals that quality is higher, can use directly as bulk drug.
Accompanying drawing explanation
Fig. 1 is the micro-enlarged drawing of the cefaclor crystals of the present invention；
Fig. 2 is the micro-enlarged drawing of the cefaclor crystals of existing chemical synthesis；
Fig. 3 is the particle size distribution figure of the cefaclor crystals before and after the present invention；
Fig. 4 is the X ray diffracting spectrum of the Cefaclor of the present invention.
Detailed description of the invention
The invention discloses a kind of Cefaclor preparation, preparation comprises cefaclor crystals major ingredient and auxiliary material,
Wherein angle of repose≤33 degree of cefaclor crystals, bulk density 0.50～0.60g/ml, tight ness rating
0.70～0.80g/ml, the D10 in size distribution are 40～60um, and D50 is 120～140um, and D90 is
210～230um.The type of Cefaclor preparation is Cefaclor Capsules, Cefaclor tablet, Cefaclor
Dry suspensoid agent.
The invention discloses the preparation method of Cefaclor preparation, including preparation, the major ingredient of cefaclor crystals
And the pretreatment of auxiliary material, weigh, mix, be molded, pack, the preparation of cefaclor crystals be with 7-ACCA,
Dane potassium salts is raw material, via Silanization reaction, acylation reaction, condensation reaction, acidolysis reaction, abstraction impurity removal,
Decolouring and crystallisation step, prepare cefaclor crystals.
In the present invention, the preparation method of cefaclor crystals specifically includes following processing step,
(1) Silanization reaction: joined by 7-ACCA in dichloromethane, solution temperature is molten when being 25～30 DEG C
Solution obtains 7-ACCA solution, adds silylating reagent, when reaction temperature is 40～46 DEG C in 7-ACCA solution
Carry out Silanization reaction, be cooled to-15 DEG C after completion of the reaction.
In step (1), the mass percentage concentration of 7-ACCA solution is 10～30%, and silylating reagent is trimethyl
Chlorosilane, HMDS and N, the comprehensive silicon Alkylators of O-double trimethylsilyl acetamide composition, its
In, the mass ratio of trim,ethylchlorosilane and 7-ACCA is 31: 100～50: 100, HMDS with
The mass ratio of 7-ACCA is 18: 100～47: 100, the double trimethylsilyl acetamide of N, O-and the mass ratio of 7-ACCA
It is 4: 1000～10: 1000.
(2) prepare mixed acid anhydride: joined by dane potassium salts in dichloromethane, be cooled to-40～-70 DEG C obtain Deng
Potassium salt soln, first adds ethyl chloroformate in dane potassium salts solution, is then slowly added into 1-METHYLPYRROLIDONE,
Reaction temperature is-30～stirring reaction 30～60min when-55 DEG C, adds diluent and controls temperature and be
-35～-55 DEG C, continue stirring and be reacted to terminal.
In described step (2), the mass percentage concentration of dane potassium salts solution is 5～30%, ethyl chloroformate and Deng's potassium
The mass ratio of salt is 12: 29, described 1-METHYLPYRROLIDONE be concentration expressed in percentage by volume be the DMF of 0.5～1.5%
Solution, described diluent is DMF solvent and diluent and the volume ratio of dane potassium salts solution is
15～100～75～100.
(3) condensation reaction: the mixed acid anhydride in step (2) continues to be cooled to-60～-95 DEG C, by step
(1) the Silanization reaction product in proceeds in mixed acid anhydride, stir and be to slowly warm up to-20～-45 DEG C contract
Close reaction.
(4) acidolysis reaction: the condensation reaction products in step (3) is joined certain density hydrochloric acid molten
In liquid, controlling temperature is-25～10 DEG C, and controlling pH is 0.3～0.5, and stirring carries out acidolysis reaction.
In step (4), the concentration expressed in percentage by volume of hydrochloric acid solution is 5～10%, condensation reaction products with hydrochloric acid molten
Liquid volume ratio is 1.5: 1～2.5: 1.
(5) abstraction impurity removal: after being stood by the acidolysis reaction product in step (4), split-phase, and if carrying out
Dry extraction, obtains the thick solution of Cefaclor salt.
Concretely comprising the following steps of step (5), split-phase after acidolysis reaction product is stood, obtain an aqueous phase and
Secondary dichloromethane phase, to the dichloromethane middle water that adds, a stirring mutually, stands, and split-phase obtains secondary aqueous phase
With secondary dichloromethane phase, merge an aqueous phase and secondary aqueous phase and add dichloromethane, stirring, stand,
Split-phase obtains three aqueous phases and three dichloromethane phases, adds hydrochloric acid solution and add dichloro in three aqueous phases
Methane, stirring, stand, split-phase obtains four aqueous phases and four dichloromethane phases, adds in four aqueous phases
Dichloromethane, stirring, stand, split-phase obtains five aqueous phases and five dichloromethane phases, enters five aqueous phases
Row vacuum outgas, obtains Cefaclor salting liquid.
(6) decolouring: add activated carbon, ethylenediamine tetra-acetic acid, pyrosulfurous acid in the thick solution of Cefaclor salt
Sodium, continues stirring, stands, separates to obtain filtrate and filter residue, washs filter residue with the hydrochloric acid solution that pH is 0.7～1.0,
Cleaning solution and filtrate are merged into destainer.
In step (6), activated carbon is 3: 100～6: 100 with the mass ratio of Cefaclor salting liquid, ethylenediamine tetrem
Acid is 2: 1000～4: 1000 with the mass ratio of Cefaclor salting liquid, sodium pyrosulfite and Cefaclor salting liquid
Mass ratio be 1: 100～2: 100.
(7) crystallization: the temperature controlling destainer is 20～35 DEG C, with the ammoniacal liquor tune that volume fraction is 10～25%
Crystalline substance, controlling temperature is 10～35 DEG C, and growing the grain is centrifugal, and water washs 3 times, and 40～50 DEG C are dried, obtain cephalo
Clo crystal.
Angle of repose in the present invention, bulk density, tight ness rating, assay method powder tester for overall characteristic method,
The assay method of size distribution is: 2015 editions Chinese Pharmacopoeia general rule 0982 granularities and particle size distribution method the 3rd
Method.
Below in conjunction with embodiment, the present invention is described in further details.
Embodiment 1
The present embodiment is the preparation embodiment of cefaclor crystals, and using 7-ACCA, dane potassium salts is raw material, its
In: the content (HPLC) >=98.0% of 7-ACCA, moisture content≤1.0%, content >=99% of dane potassium salts, moisture≤0.5%.
The preparation of cefaclor crystals include Silanization reaction, acylation reaction, condensation reaction, acidolysis reaction,
Abstraction impurity removal, decolour and crystallize seven steps.
1.1 Silanization reaction
Adding 40ml dichloromethane solvent in reactor, it is 25 DEG C that temperature controls, precise 20.00g's
7-ACCA also joins in reactor, obtains 7-ACCA solution, and it is 25 DEG C that temperature controls, and adds compound
Silylating reagent, comprehensive silicon Alkylators includes 6.33g trim,ethylchlorosilane, 3.60g hexamethyldisilazane,
The double trimethylsilyl acetamide of 0.083gN, O-, controlling reaction temperature is 40 DEG C, begins to warm up back flow reaction, instead
Complete should be cooled to-15 DEG C.
1.2, mixed acid anhydride is prepared
Being added in 70ml dichloromethane solvent in reactor, the dane potassium salts of precise 28.75g also joins
In reaction vessel, it is cooled to-70 DEG C, obtains dane potassium salts solution.Then temperature control-70 DEG C, first to dane potassium salts solution
Middle addition 11L ethyl chloroformate, stirring reaction 10min.It is then slowly added into 1-METHYLPYRROLIDONE solution,
Wherein, 1-METHYLPYRROLIDONE solution is to have 0.3ml 1-METHYLPYRROLIDONE to be dissolved in 30ml DMF (N, N-
Dimethylformamide) in prepare solution.Control temperature and be-30 DEG C, stirring reaction 30min, add 30ml
DMF as diluent, control temperature and be-35 DEG C, continuation stirring is reacted to terminal.
1.3, condensation reaction
Continue to be cooled to-60 DEG C by the mixed acid anhydride in step 1.2, by the Silanization reaction product in step 1.1
Proceed in mixed acid anhydride, be slowly ramped to-20 DEG C, stirring, carry out condensation reaction.
1.4, acidolysis reaction
6.55ml hydrochloric acid is added 90ml water configuration hydrochloric acid solution, the condensation reaction products in step 1.3 is turned
Moving in hydrochloric acid solution, temperature controls-25 DEG C, and controlling pH is 0.3, and stirring 30min carries out acidolysis reaction.
1.5, abstraction impurity removal
Acidolysis reaction product in step 1.4 is stood after 30min, split-phase, obtain an aqueous phase and the most molten
Agent phase, adds 30ml water, stirring in a solvent phase, stands, and split-phase obtains secondary aqueous phase and secondary is molten
Agent phase, merges an aqueous phase and secondary aqueous phase and adds 120ml dichloromethane solvent, stirring, stands, point
Obtain three aqueous phases and three solvent phases mutually, in three aqueous phases, add 40ml hydrochloric acid solution and add 60ml
Dichloromethane solvent, stirring, stand, split-phase obtains four aqueous phases and four solvent phases, in four aqueous phases
Adding 29.5ml dichloromethane solvent, stirring, stand, split-phase obtains five aqueous phases and five solvent phases, right
Five times aqueous phase carries out vacuum outgas, obtains Cefaclor crude salt solution.
1.6, decolouring
Cefaclor crude salt solution addition 1.6g activated carbon in step 1.5,0.125g ethylenediamine tetra-acetic acid,
0.394g sodium pyrosulfite, continues stirring, stands, and separates, molten with the hydrochloric acid that 60ml pH is 0.7～1.0
Liquid washing filter residue, merges aqueous phase, obtains destainer.
1.7, crystallization
Controlling temperature is 20 DEG C, adjusts crystalline substance with the ammoniacal liquor that volume fraction is 10%, and controlling temperature is 10 DEG C.Growing the grain,
Centrifugal, water washs 3 times, and 40～50 DEG C are dried, obtain finished product.
Embodiment 2
The present embodiment is the preparation embodiment of cefaclor crystals, and using 7-ACCA, dane potassium salts is raw material, its
In: using 7-ACCA, dane potassium salts is raw material, wherein: the content (HPLC) >=98.0% of 7-ACCA, water
Part≤1.0%, content >=99% of dane potassium salts, moisture≤0.5%.
The preparation of cefaclor crystals include Silanization reaction, acylation reaction, condensation reaction, acidolysis reaction,
Abstraction impurity removal, decolour and crystallize seven steps.
1.1 Silanization reaction
Adding 100ml dichloromethane solvent in reactor, it is 25 DEG C that temperature controls, precise 20.00g's
7-ACCA also joins in reactor, obtains 7-ACCA solution, and it is 30 DEG C that temperature controls, and adds compound
Silylating reagent, comprehensive silicon Alkylators includes 10.00g trim,ethylchlorosilane, 9.40g hexamethyldisilazane,
The double trimethylsilyl acetamide of 0.200gN, O-, controlling reaction temperature is 46 DEG C, begins to warm up back flow reaction, instead
Complete should be cooled to-15 DEG C.
1.2, mixed acid anhydride is prepared
Being added in 200ml dichloromethane solvent in reactor, the dane potassium salts of precise 35.00g also adds
In reaction vessel, it is cooled to-70 DEG C, obtains dane potassium salts solution.Then temperature control-70 DEG C, the most molten to dane potassium salts
Liquid adds 11L ethyl chloroformate, stirring reaction 10min.It is then slowly added into 1-METHYLPYRROLIDONE molten
Liquid, wherein, 1-METHYLPYRROLIDONE solution is to have 0.3ml 1-METHYLPYRROLIDONE to be dissolved in 30ml DMF
The solution prepared in (DMF).Control temperature and be-55 DEG C, stirring reaction 60min, add
The DMF entering 50ml is-55 DEG C as diluent, control temperature, continues stirring and is reacted to terminal.
1.3, condensation reaction
Continue to be cooled to-95 DEG C by the mixed acid anhydride in step 1.2, by the Silanization reaction product in step 1.1
Proceed in mixed acid anhydride, be slowly ramped to-45 DEG C, stirring, carry out condensation reaction.
1.4, acidolysis reaction
6.55ml hydrochloric acid is added 90ml water configuration hydrochloric acid solution, the condensation reaction products in step 1.3 is turned
Moving in hydrochloric acid solution, temperature controls 10 DEG C, and controlling pH is 0.5, and stirring 30min carries out acidolysis reaction.
1.5, abstraction impurity removal
Acidolysis reaction product in step 1.4 is stood after 30min, split-phase, obtain an aqueous phase and the most molten
Agent phase, adds 50ml water, stirring in a solvent phase, stands, and split-phase obtains secondary aqueous phase and secondary is molten
Agent phase, merges an aqueous phase and secondary aqueous phase and adds 200ml dichloromethane solvent, stirring, stands, point
Obtain three aqueous phases and three solvent phases mutually, in three aqueous phases, add 100ml hydrochloric acid solution and add 60ml
Dichloromethane solvent, stirring, stand, split-phase obtains four aqueous phases and four solvent phases, in four aqueous phases
Adding 29.5ml dichloromethane solvent, stirring, stand, split-phase obtains five aqueous phases and five solvent phases, right
Five times aqueous phase carries out vacuum outgas, obtains Cefaclor crude salt solution.
1.6, decolouring
Cefaclor crude salt solution addition 1.6g activated carbon in step 1.5,0.125g ethylenediamine tetra-acetic acid,
0.394g sodium pyrosulfite, continues stirring, stands, and separates, molten with the hydrochloric acid that 60ml pH is 0.7～1.0
Liquid washing filter residue, merges aqueous phase, obtains destainer.
1.7, crystallization
Controlling temperature is 35 DEG C, adjusts crystalline substance with the ammoniacal liquor that volume fraction is 25%, and controlling temperature is 35 DEG C.Growing the grain,
Centrifugal, water washs 3 times, and 40～50 DEG C are dried, obtain finished product.
In embodiment 1 and embodiment 2, the specific performance parameter of the cefaclor crystals prepared is:
| Embodiment 1 | Embodiment 2 | Existing chemical synthesis | Catalyzed by biological enzyme | |
| Conversion ratio % | 98.0 | 98.5 | 96.0 | 97.2 |
| Purity % | 99.8% | 99.8% | 99.1% | 99.5% |
| Angle of repose (is spent) | 29 | 30 | 42 | 38 |
| Bulk density (g/ml) | 0.55 | 0.56 | 0.35 | 0.40 |
| Tight ness rating (g/ml) | 0.75 | 0.74 | 0.55 | 0.62 |
| D10(um) | 50 | 52 | 25 | 39 |
| D50(um) | 120～140 | 120～140 | 80 | 115 |
| D90(um) | 210～230 | 210～230 | 150 | 200 |
Fig. 1 is the micro-enlarged drawing of the cefaclor crystals of the embodiment of the present invention 1 preparation, and Fig. 2 is existingization
Learn the micro-enlarged drawing of the cefaclor crystals of synthetic method；According to the requirement of preparation packing, above index is respectively
In angle of repose≤33；Bulk density: 0.50～0.60g/ml；Tight ness rating 0.70～0.80g/ml；Size distribution D10:
40～60 μm；D50:120～140 μm；D90:210～230 μm, the most suitable in the range of above-mentioned parameter, from
Upper table data are it can be seen that Cefaclor prepared by this technology is more suitable for formulation requirements.
Embodiment 3
The present embodiment is the preparation of Cefaclor Capsules.The raw material composition of preparation includes preparation in embodiment 1
Cefaclor crystals and auxiliary material, specific as follows: Cefaclor 250 parts (giving money as a gift pure), starch 20 parts,
Sodium carboxymethyl starch 10 parts, lauryl sodium sulfate 1 part, magnesium stearate 1 part, talcum powder 1 part.
The Cefaclor Capsules preparation process of the present embodiment is:
A, the preparation of cefaclor crystals, be specifically shown in embodiment 1.
The pretreatment of B, major ingredient and auxiliary material: sieve, first carries out auxiliary material and sieves process, after carry out major ingredient and sieve place
Reason: lauryl sodium sulfate, talcum powder, magnesium stearate, carboxyrnethyl starch sodium (Extra Sodium Carboxylmethyl Starch) cross 60 mesh sieves；Form sediment
Powder carries out Φ 2.0mm through pelletizing machine after fluidized drying and sieves, and dried starch moisture controls≤3%；Head
Spore clo crosses 16 mesh sieves.
C, weighing: by supplementary material precise.Must double carry out when weighing operation.
D, mixing: load weighted supplementary material is placed mix and blend 15min in mixer, and rotating speed is 10rpm,
It is made fully to mix.
E, shaping: the forming process of Cefaclor Capsules is pouring process: according to result of laboratory test, calculate loading amount,
Carry out filling after loading amount debugging is qualified.
F, packaging: according to plastic-aluminum, mounted box, check weighing, tie up, barcode scanning, vanning order carry out.
Cefaclor Capsules performance data comparison sheet
By in Cefaclor Capsules performance data comparison sheet it can be seen that the Cefaclor Capsules impurity of the present invention
Content is low, and dissolution rate is high, and moisture is low, and combination property is preferable.
Embodiment 4
The present embodiment is the preparation of Cefaclor tablet.The raw material composition of preparation includes preparation in embodiment 1
Cefaclor crystals and auxiliary material, label composition is specific as follows: Cefaclor 250 parts, lactose 76 parts, micro-
Crystalline cellulose 164 parts, sodium carboxymethyl starch 26 parts, superfine silica gel powder 5.2 parts, magnesium stearate 4.8 parts.Bag
Clothing film forming agent selects stomach dissolved film coating pre-mix dose (Opadry XY yellow), and molten in water and ethanol
Solve.
The preparation process of the present embodiment Cefaclor tablet is:
A, the preparation of cefaclor crystals, be specifically shown in embodiment 1.
The pretreatment of B, major ingredient and auxiliary material: supplementary material all crosses 40 mesh～80 mesh sieves process.
C, weighing: pretreated supplementary material is pressed proportioning process instruction precise.
D, mixing: the supplementary material (in addition to magnesium stearate and silica) after weighing according to proportioning process instruction
Adding mixer hopper to premix, incorporation time 5～20min, rotating speed is 5～15rpm.After mixing,
Weigh magnesium stearate and silica to add mixer hopper and always mixes, incorporation time 5～20min rotating speed be 5～
15rpm。
E, shaping: the forming process of Cefaclor tablet is compressing tablet: calculate sheet according to intermediate products result of laboratory test
Weight, pressing tablet technological order, carry out compressing tablet with tablet press machine, punch die specification is of bonding.
F, packaging: preparation 5～15% Opadry alcoholic solution (60～80% ethanol solution), insert intermediate sheet
In coating pan, spray coating solution, film coating sheet.Arranging pot rotating speed is 3～10rpm；EAT is about
25～70 DEG C；Intake volume is about 500～1100m3/h；Negative pressure-40pa～-80pa in pot, atomizing pressure 0.5～3.0
Bar, film flow quantity is 100～500ml/min, sheet bed tempertaure 30～37 DEG C, and coating weight gain is 0.5～3%.
Embodiment 5
The present embodiment is the preparation of Cefaclor dry suspensoid agent.The raw material composition of preparation includes making in embodiment 2
Standby cefaclor crystals and auxiliary material, specific as follows: Cefaclor 625 parts, hydroxypropyl methyl cellulose
414 parts, superfine silica gel powder 48 parts, 70 parts of orange essence, sunset yellow 2.8 parts, sucrose 7840 parts.
The present embodiment is that Cefaclor dry suspensoid agent preparation process is:
A, the preparation of cefaclor crystals, be specifically shown in embodiment 2.
The pretreatment of B, major ingredient and auxiliary material: supplementary material all crosses 120 mesh～200 mesh sieves process.
C, weighing: pretreated supplementary material is pressed proportioning process instruction precise.
D, mixing: the supplementary material after weighing according to proportioning process instruction enters mixer hopper with the equivalent method of progressively increasing
Carrying out incorporation time 5～20min rotating speed is 5～15rpm.
E, packaging.
Claims (9)
1. Cefaclor preparation, described preparation comprises cefaclor crystals major ingredient and auxiliary material, it is characterised in that:
Angle of repose≤33 degree of described cefaclor crystals, bulk density 0.50～0.60g/ml, tight ness rating
0.70～0.80g/ml, the D10 in size distribution are 40～60um, and D50 is 120～140um, and D90 is
210～230um.
Cefaclor preparation the most according to claim 1, it is characterised in that: described Cefaclor preparation
Type be Cefaclor Capsules, Cefaclor tablet, Cefaclor dry suspensoid agent.
3. the preparation method of Cefaclor preparation, it is characterised in that: described preparation method includes that Cefaclor is brilliant
The pretreatment of the preparation of body, major ingredient and auxiliary material, weighing, mix, be molded, pack, described Cefaclor is brilliant
The preparation of body is with 7-ACCA, dane potassium salts as raw material, via Silanization reaction, acylation reaction, condensation reaction,
Acidolysis reaction, abstraction impurity removal, decolouring and crystallisation step, prepare cefaclor crystals.
The preparation method of Cefaclor preparation the most according to claim 3, it is characterised in that: described head
The preparation method of spore clo crystal specifically includes following processing step,
(1) Silanization reaction: joined by 7-ACCA in dichloromethane, when solution temperature is 25～30 DEG C
Dissolving obtains 7-ACCA solution, adds silylating reagent in 7-ACCA solution, and reaction temperature is 40～46 DEG C
Shi Jinhang Silanization reaction, is cooled to-15 DEG C after completion of the reaction；
(2) prepare mixed acid anhydride: joined by dane potassium salts in dichloromethane, be cooled to-40～-70 DEG C obtain Deng
Potassium salt soln, first adds ethyl chloroformate in dane potassium salts solution, is then slowly added into 1-METHYLPYRROLIDONE,
Reaction temperature is-30～stirring reaction 30～60min when-55 DEG C, adds diluent and controls temperature and be
-35～-55 DEG C, continue stirring and be reacted to terminal；
(3) condensation reaction: the mixed acid anhydride in step (2) continues to be cooled to-60～-95 DEG C, by step
(1) the Silanization reaction product in proceeds in mixed acid anhydride, stir and be to slowly warm up to-20～-45 DEG C contract
Close reaction；
(4) acidolysis reaction: the condensation reaction products in step (3) is joined certain density hydrochloric acid molten
In liquid, controlling temperature is-25～10 DEG C, and controlling pH is 0.3～0.5, and stirring carries out acidolysis reaction；
(5) abstraction impurity removal: after being stood by the acidolysis reaction product in step (4), split-phase, and if carrying out
Dry extraction, obtains the thick solution of Cefaclor salt；
(6) decolouring: add activated carbon, ethylenediamine tetra-acetic acid, pyrosulfurous acid in the thick solution of Cefaclor salt
Sodium, continues stirring, stands, separates to obtain filtrate and filter residue, with the hydrochloric acid solution washing filter that pH is 0.7～1.0
Slag, merges into destainer by cleaning solution and filtrate；
(7) crystallization: the temperature controlling destainer is 20～35 DEG C, with the ammoniacal liquor tune that volume fraction is 10～25%
Crystalline substance, controlling temperature is 10～35 DEG C, and growing the grain is centrifugal, and water washs 3 times, and 40～50 DEG C are dried, obtain cephalo
Clo crystal.
The preparation method of Cefaclor the most according to claim 4, it is characterised in that: described step (1)
The mass percentage concentration of middle 7-ACCA solution is 10～30%, and silylating reagent is trim,ethylchlorosilane, pregnancy
Base disilazane and N, the comprehensive silicon Alkylators of O-double trimethylsilyl acetamide composition, wherein, trimethyl chlorine
Silane is 31: 100～50: 100 with the mass ratio of 7-ACCA, and HMDS is with 7-ACCA's
Mass ratio is 18: 100～47: 100, and the double trimethylsilyl acetamide of N, O-with the mass ratio of 7-ACCA is
4: 1000～10: 1000.
The preparation method of Cefaclor the most according to claim 4, it is characterised in that: described step (2)
The mass percentage concentration of middle dane potassium salts solution is 5～30%, and ethyl chloroformate is 12 with the mass ratio of dane potassium salts:
29, described 1-METHYLPYRROLIDONE be concentration expressed in percentage by volume be the DMF solution of 0.5～1.5%, described dilution
Agent is DMF solvent and diluent and the volume ratio of dane potassium salts solution is 15～100～75～100.
The preparation method of Cefaclor the most according to claim 4, it is characterised in that: described step (4)
The concentration expressed in percentage by volume of middle hydrochloric acid solution is 5～10%, condensation reaction products with hydrochloric acid solution volume ratio be
1.5: 1～2.5: 1.
The preparation method of Cefaclor the most according to claim 4, it is characterised in that: described step (5)
Concretely comprise the following steps, by acidolysis reaction product stand after split-phase, obtain an aqueous phase and a dichloromethane phase,
To the dichloromethane middle water that adds, a stirring mutually, standing, split-phase obtains secondary aqueous phase and secondary dichloromethane
Phase, merges an aqueous phase and secondary aqueous phase and adds dichloromethane, stirring, stands, and split-phase obtains three water
Mutually with three dichloromethane phases, in three aqueous phases, add hydrochloric acid solution and add dichloromethane, stirring, quiet
Putting, split-phase obtains four aqueous phases and four dichloromethane phases, adds dichloromethane, stir in four aqueous phases,
Standing, split-phase obtains five aqueous phases and five dichloromethane phases, five aqueous phases is carried out vacuum outgas, obtains
Cefaclor salting liquid.
The preparation method of Cefaclor the most according to claim 4, it is characterised in that: described step (6)
Middle activated carbon is 3: 100～6: 100 with the mass ratio of Cefaclor salting liquid, ethylenediamine tetra-acetic acid and Cefaclor
The mass ratio of salting liquid is 2: 1000～4: 1000, and sodium pyrosulfite is 1 with the mass ratio of Cefaclor salting liquid:
100～2: 100.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610154698.1A CN105769873B (en) | 2016-03-17 | 2016-03-17 | Cefaclor preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610154698.1A CN105769873B (en) | 2016-03-17 | 2016-03-17 | Cefaclor preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105769873A true CN105769873A (en) | 2016-07-20 |
| CN105769873B CN105769873B (en) | 2017-04-05 |
Family
ID=56392912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610154698.1A Active CN105769873B (en) | 2016-03-17 | 2016-03-17 | Cefaclor preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105769873B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107523603A (en) * | 2017-08-04 | 2017-12-29 | 长沙凯晓生物科技有限公司 | A kind of method that enzyme process prepares Cefaclor |
| JP2020079238A (en) * | 2018-11-13 | 2020-05-28 | 大塚化学株式会社 | Crystallization method controlling crystallization rate of 3-alkenylcephem compound |
| CN112574233A (en) * | 2020-12-30 | 2021-03-30 | 苏州盛达药业有限公司 | Cefaclor bulk drug |
| CN113912625A (en) * | 2021-10-25 | 2022-01-11 | 华北制药河北华民药业有限责任公司 | Method for purifying cefadroxil |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1982315A (en) * | 2005-12-14 | 2007-06-20 | 陈舒明 | Synthesis of cefaclor |
| CN102793687A (en) * | 2012-08-24 | 2012-11-28 | 哈药集团制药总厂 | Cefaclor capsule and preparation method thereof |
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
-
2016
- 2016-03-17 CN CN201610154698.1A patent/CN105769873B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1982315A (en) * | 2005-12-14 | 2007-06-20 | 陈舒明 | Synthesis of cefaclor |
| CN102793687A (en) * | 2012-08-24 | 2012-11-28 | 哈药集团制药总厂 | Cefaclor capsule and preparation method thereof |
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
Non-Patent Citations (2)
| Title |
|---|
| 头孢克洛的合成;许思忠;《国外医药抗生素分册》;19941215;第15卷(第6期);第414-418,421页 * |
| 许思忠: "头孢克洛的合成", 《国外医药抗生素分册》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107523603A (en) * | 2017-08-04 | 2017-12-29 | 长沙凯晓生物科技有限公司 | A kind of method that enzyme process prepares Cefaclor |
| JP2020079238A (en) * | 2018-11-13 | 2020-05-28 | 大塚化学株式会社 | Crystallization method controlling crystallization rate of 3-alkenylcephem compound |
| JP7431015B2 (en) | 2018-11-13 | 2024-02-14 | 大塚化学株式会社 | Crystallization method that controls the crystallization rate of 3-alkenyl cephem compounds |
| CN112574233A (en) * | 2020-12-30 | 2021-03-30 | 苏州盛达药业有限公司 | Cefaclor bulk drug |
| CN113912625A (en) * | 2021-10-25 | 2022-01-11 | 华北制药河北华民药业有限责任公司 | Method for purifying cefadroxil |
| CN113912625B (en) * | 2021-10-25 | 2023-03-14 | 华北制药河北华民药业有限责任公司 | Method for purifying cefadroxil |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105769873B (en) | 2017-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105769873A (en) | Cefaclor preparation and preparation method thereof | |
| CN104876947A (en) | Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof | |
| CN113952305B (en) | Arbidol hydrochloride granules and preparation method thereof | |
| CN103012434A (en) | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof | |
| CN105085549B (en) | The pharmaceutical composition and its preparation of a kind of Cefaclor compound, the compound and bromhexine hydrochloride | |
| CN104447795B (en) | A kind of cefadroxil benzyl compound and pharmaceutical composition thereof | |
| CN104540822B (en) | Crystal formation of dabrafenib mesylate and preparation method thereof | |
| CN103524533A (en) | Cefprozil compound, and dispersible tablets, dry suspension and preparation method thereof | |
| CN103145735B (en) | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof | |
| CN106511288A (en) | Preparation method of febuxostat tablets | |
| CN103142617B (en) | Cefuroxime lysine medicinal composition | |
| CN104926835A (en) | Cefotiam hydrochloride compound, method for preparing same and pharmaceutical composition with cefotiam hydrochloride compound | |
| CN107007568A (en) | The novel processing step of Aprepitant capsule | |
| CN105496984B (en) | A kind of Cefixime Capsules and preparation method thereof that quality is stable | |
| CN102351812A (en) | Methanesulfonic acid cinepazide crystal form III and preparation method thereof | |
| CN103224504A (en) | Injection sodium cefonicid compound, preparation method and pharmaceutical composition | |
| CN117045608A (en) | Quick-release preparation of vitamin B2 and preparation method thereof | |
| CN106397455B (en) | A kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof | |
| CN106432278A (en) | Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections | |
| CN106432279A (en) | Method for preparing medicine ceftriaxone sodium crystal compound for treating surgical infection | |
| CN103304580B (en) | Cefepime dihydrochloride compound as well as preparation method and medicine composition thereof | |
| CN101357926A (en) | Method for preparing tardocillin | |
| CN105796526A (en) | Cephalosporin medicine capsule and preparing method thereof | |
| CN104311447B (en) | Acetaminophen novel crystal forms, its preparation method and compound paracetamol and amantadine hydrochloride preparations | |
| CN104971053A (en) | Ranitidine hydrochloride composition tablet medicine for treating digestive system diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Hu Limin Inventor after: Zhang Libin Inventor after: Liu Shiping Inventor after: Li Min Inventor after: Zhang Wensheng Inventor after: Wei Baojun Inventor after: Tian Hongnian Inventor after: Hu Shaohua Inventor after: Liu Ping Inventor after: Liu Haixi Inventor after: Ma Yasong Inventor after: Zhou Xiaobing Inventor after: Du Jinsong Inventor after: Liu Rongliang Inventor after: Zhang Suoqing Inventor after: Gao Yanxia Inventor after: Gong Junbo Inventor after: Hu Weiguo Inventor after: Yang Mengde Inventor after: Jia Quan Inventor before: Hu Limin Inventor before: Wei Baojun Inventor before: Tian Hongnian Inventor before: Hu Shaohua Inventor before: Liu Ping Inventor before: Liu Haixi Inventor before: Ma Yasong Inventor before: Du Jinsong Inventor before: Zhang Suoqing Inventor before: Hu Weiguo Inventor before: Yang Mengde Inventor before: Jia Quan Inventor before: Zhang Libin Inventor before: Liu Shiping Inventor before: Li Min Inventor before: Zhang Wensheng |