CN115490706A - Preparation method of amoxicillin crystal - Google Patents
Preparation method of amoxicillin crystal Download PDFInfo
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- CN115490706A CN115490706A CN202211037561.XA CN202211037561A CN115490706A CN 115490706 A CN115490706 A CN 115490706A CN 202211037561 A CN202211037561 A CN 202211037561A CN 115490706 A CN115490706 A CN 115490706A
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- amoxicillin
- crystals
- ammonia water
- crystal
- condensation
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- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 143
- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 139
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 139
- 239000013078 crystal Substances 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000007788 liquid Substances 0.000 claims abstract description 46
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 43
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 43
- 238000009833 condensation Methods 0.000 claims abstract description 37
- 230000005494 condensation Effects 0.000 claims abstract description 37
- 239000002245 particle Substances 0.000 claims abstract description 30
- 230000002255 enzymatic effect Effects 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 21
- 239000000843 powder Substances 0.000 claims description 17
- 230000020477 pH reduction Effects 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 5
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 5
- 108010073038 Penicillin Amidase Proteins 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- SZBDOFWNZVHVGR-MRVPVSSYSA-N methyl (2r)-2-amino-2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)[C@H](N)C1=CC=C(O)C=C1 SZBDOFWNZVHVGR-MRVPVSSYSA-N 0.000 claims description 3
- 238000001471 micro-filtration Methods 0.000 claims description 3
- 239000002775 capsule Substances 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 description 21
- 230000008025 crystallization Effects 0.000 description 21
- 239000012530 fluid Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000012982 microporous membrane Substances 0.000 description 7
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 6
- 238000006911 enzymatic reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 235000011837 pasties Nutrition 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- -1 amoxicillin ions Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of preparation of medicinal compound crystals, and relates to a preparation method of amoxicillin crystals, which comprises the following steps: acidifying the amoxicillin enzymatic condensation liquid by hydrochloric acid to ensure that the pH of the condensation liquid is less than 0.2, and the molar ratio of amoxicillin to HCl is 1:5.8 to 7.6; then ammonia water is dripped to the isoelectric point to separate out amoxicillin crystal. The amoxicillin crystal has a proper large particle size, wherein the Dv (10) is 10-15 μm, the Dv (50) is 45-60 μm, and the Dv (90) is 145-165 μm, the amoxicillin with a proper large particle size can be effectively used for preparing amoxicillin medicinal preparations, especially capsule preparations, and the yield of the preparation method is improved.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical compound crystals, and particularly relates to a preparation method of an amoxicillin crystal with effectively increased particle size and high purity, wherein the amoxicillin crystal has a suitably large particle size, wherein Dv (10) is 10-15 μm, dv (50) is 45-60 μm, dv (90) is 145-165 μm, and the amoxicillin with suitably large particle size can be effectively used for preparing amoxicillin pharmaceutical preparations, especially capsule preparations.
Background
Amoxicillin (Amoxicillin), also known as Amoxicillin or Amoxicillin, is one of the most commonly used broad-spectrum beta-lactam antibiotics of the penicillins. The amoxicillin has strong sterilization effect, has the characteristics of broad spectrum, high efficiency and small toxic and side effect, is widely applied in the field of medicine and health, and the preparation mainly comprises capsules, tablets, granules, dispersible tablets and the like.
The method for synthesizing amoxicillin mainly comprises two methods: one is a chemical synthesis method, and the other is an enzyme-catalyzed synthesis method (enzymatic method for short). The amoxicillin is synthesized by the enzymatic method, the use of organic solvents can be avoided, the reaction conditions are mild, the energy consumption is low, the operation is easy, the whole process is green and environment-friendly, meanwhile, the purity of the amoxicillin synthesized by the enzymatic method is higher than that of a product synthesized by a chemical method, and the safety and the stability of the medicine are greatly improved, so that the enzymatic method gradually replaces the chemical synthesis method to become the most main method for producing the amoxicillin.
In the process for synthesizing amoxicillin by an enzymatic method, D-p-hydroxyphenylglycine methyl ester is mostly adopted as an acyl side chain donor, and condensed with 6-APA (6-aminopenicillanic acid) under the catalytic action of immobilized penicillin acylase for synthesis to generate amoxicillin, and then the amoxicillin crystal is obtained by crystallization. In the traditional crystallization process, acid/alkali liquor is added into amoxicillin condensation liquid to adjust the pH value to 4-5 of the isoelectric point of amoxicillin, under the condition of the isoelectric point, the charge of amoxicillin is zero, at the moment, crystals begin to form, and the nucleation and growth are controlled by controlling the pH, temperature and stirring in the crystallization process.
The amoxicillin with proper large particle size has positive influence on filtration, washing, drying and packaging after crystallization and preparation of amoxicillin medicinal preparations (particularly canning of capsule preparations), avoids dust flying in the operating environment and ensures the consistency of the amoxicillin amount of unit preparations.
In the study on improving the quality of amoxicillin by changing the crystallization process (the chemical industry in Hebei, vol.33, no. 8, 8 months 2010, 27-31), qiangwenqing, baijun and the like report an amoxicillin crystallization process with large crystal form and good stability, an amoxicillin hydrochloride aqueous solution with the pH of 1.0 and ammonia water (the concentration is 10% -12%) are simultaneously and slowly added into a reaction kettle, the pH value is controlled to be kept between 5.0 and 5.10, the temperature is controlled to be between 1 and 5 ℃ for crystal growing, and then the amoxicillin dry powder is obtained by filtering, washing and drying. However, no specific particle size and yield are mentioned herein.
The research on the crystallization of amoxicillin (the chemical industry in Hebei, vol.30, no. 1, 2007, no. 1, no. 27-31) by Wang Yan, juke et al reported the influence of stirring speed, stirring intensity, seed crystal, cooling temperature, etc. on crystallization. The research of the amoxicillin crystallization process by the royal brilliance, the jujudae and the like still stays in the control of the process conditions of the stirring speed, the stirring intensity, the seed crystal, the cooling temperature and the like of the process, and belongs to the fine adjustment of the crystallization process.
Amoxicillin is a broad-spectrum penicillin antibiotic, has wide application and is produced by a plurality of manufacturers. Only the product has good quality and high yield and can be competitive in the fierce market. Therefore, various manufacturers are continuously studying and improving the amoxicillin crystallization process.
Disclosure of Invention
In view of the above problems, it is an object of the present invention to provide a process for producing amoxicillin crystals having an effectively increased particle size and high purity, which have a suitably large particle size, wherein Dv (10) is 10 to 15 μm, dv (50) is 45 to 60 μm, and Dv (90) is 145 to 165 μm, and which can be effectively used for producing amoxicillin pharmaceutical preparations, particularly capsule preparations, and which has an improved yield.
According to the invention, the preparation method of the amoxicillin crystal provided by the invention comprises the following steps: acidifying the amoxicillin enzymatic condensation liquid by hydrochloric acid at 20-30 ℃ to ensure that the pH of the condensation liquid is less than 0.2, and the molar ratio of amoxicillin to HCl is 1:5.8 to 7.6; then, ammonia water is dripped into the acidified condensation liquid under stirring till the pH value is 2-3, and when turbidity begins to appear, the dripping of the ammonia water is stopped, and crystal growth is carried out for 20-40 minutes; and continuously dropwise adding ammonia water until the pH value is 4-5, cooling to 0-10 ℃, stirring for growing crystals, filtering, washing and drying to obtain amoxicillin crystal powder.
The process for producing amoxicillin crystals of the present invention is described in more detail below.
In the invention, the amoxicillin enzymatic condensation liquid is a condensation reaction liquid obtained by carrying out condensation reaction on 6-APA (6-aminopenicillanic acid) and D-p-hydroxyphenylglycine methyl ester under the catalytic action of immobilized penicillin acylase for synthesis and filtering the immobilized penicillin acylase for synthesis, wherein the amoxicillin content is 100-110 mg/ml, the pH value is 6-7, preferably 6.5-6.9, and the amoxicillin enzymatic condensation liquid is a suspension.
And (3) acidifying the amoxicillin enzymatic condensation solution by adopting hydrochloric acid so as to completely dissolve the amoxicillin. The hydrochloric acid used is generally a commercially available concentrated hydrochloric acid, for example a hydrochloric acid with a mass fraction of 32% to 35%. In the acidification treatment, hydrochloric acid can be added under stirring, the stirring speed is generally controlled to be 250-400 r/min, preferably 250-300 r/min, so that the pH of the condensation liquid is less than 0.2, preferably 0.1-0.19, and the molar ratio of amoxicillin to HCl is 1:5.8 to 7.6, preferably 1:6.2 to 6.9. The amoxicillin enzymatic condensation liquid is a clear solution after acidification treatment, and in order to ensure that the solution is clear and clear so as to obtain pure amoxicillin crystals during crystallization, an organic microfiltration membrane (for example, a 0.45 mu m microfiltration membrane) is preferably adopted to filter the acidified condensation liquid, and the amoxicillin content in the filtered condensation liquid is 85-95 mg/ml.
In the acidification treatment, as amoxicillin hydrochloride is easy to separate out, the temperature is controlled to be 20-30 ℃; adding hydrochloric acid at 20-30 ℃ to acidify until the pH is less than 0.2, wherein the HCl amount is 5.8-7.6 times (molar multiple) of the amount of the amoxicillin substance, and filtering the acidized solution by using a 0.45 mu m organic microporous membrane, wherein the acidification process is to ensure that the amoxicillin is completely dissolved and becomes a single molecular state, so as to avoid the amoxicillin hydrochloride from being separated out due to the mutual collision of amoxicillin molecules and amoxicillin molecules which are not completely dissolved.
Then, ammonia water is dripped into the acidified and filtered condensation liquid at the temperature of 20-30 ℃ under stirring, and the used ammonia water is generally commercial strong ammonia water, such as 23-26% by mass. The stirring speed is generally controlled to 20 to 50r/min. In the process, ammonia water is dropwise added into the acidified condensation liquid until the pH value is 2-3, when turbidity begins to appear, the dropwise addition of the ammonia water is stopped, and the mixture is stirred for crystal growth for 20-40 minutes, so that amoxicillin hydrochloride is changed into amoxicillin molecules and ammonium chloride inorganic salt, the process is slowly carried out by depending on the dropwise addition time of the ammonia water, and then the collision probability among the amoxicillin molecules is regulated and controlled, so that the crystals are gradually increased; and then, continuously dripping ammonia water until the pH value is 4-5, the pH value is about the best, and the larger or smaller pH value can cause the amoxicillin crystal to be dissolved, so that the product yield is reduced, therefore, the most important thing in the process is to stabilize the pH value, reduce the temperature to 0-10 ℃, preferably 4-5 ℃, stir and grow the crystal at 20-50 r/min, and then obtain the amoxicillin crystal powder through filtering, washing and drying.
Advantageous effects
The preparation method of the amoxicillin crystal mainly improves and is characterized in that:
in the acidification treatment process, hydrochloric acid with high molar number is added into the amoxicillin enzymatic condensation liquid, so that firstly, amoxicillin can be dissolved more quickly and completely, and amoxicillin crystal impurities are prevented from being increased because undissolved amoxicillin coated with impurities is used as crystal nucleus to adsorb the dissolved amoxicillin; secondly, the concentration of the amoxicillin is reduced, the collision probability and frequency of the amoxicillin are reduced, the crystallization is relatively slow, the condition of crystal explosion is avoided, and the further improvement of the crystal grain size is facilitated; thirdly, after the acidizing fluid is added with ammonia water, more ammonium chloride inorganic salts can be formed, and on one hand, the inorganic salts can reduce the solubility of amoxicillin and improve the yield; on the other hand, more crystalline frameworks can be provided for amoxicillin ions, which is beneficial to the adhesion of amoxicillin ions, so that crystals are easy to collide and grow up, and the grain size of the crystals is further improved.
According to the invention, the obtained amoxicillin crystal has a proper large particle size, wherein the Dv (10) is 10-15 μm, the Dv (50) is 45-60 μm, and the Dv (90) is 145-165 μm, and the amoxicillin with a proper large particle size can be effectively used for preparing amoxicillin medicinal preparations, especially capsule preparations; in addition, the obtained amoxicillin crystal has high yield of 92-95 percent and high purity.
Detailed Description
The process for the preparation of amoxicillin crystals according to the invention is further illustrated in detail below by means of examples, without limiting the scope of protection of the invention to the following examples, which are given for illustrative purposes only and do not limit the invention in any way.
Example 1
190mL of amoxicillin enzymatic condensation solution (wherein the amoxicillin content is 104.35mg/mL, the pH value is 6.79) is placed in a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by using a water bath, stirring is started for 300r/min, 34.0mL of hydrochloric acid (commercially available, the mass fraction is 33.2%) is added within 2 minutes, the condensation solution is completely dissolved and clear, and the amoxicillin content in the acidification solution is 88.21mg/mL, the pH value is 0.15, the temperature is 28.5 ℃, and amoxicillin: the HCl molar ratio is 1.
Filtering the acidized fluid by using a 0.45-micron microporous membrane, placing the acidized fluid in a 500mL four-neck flask, adjusting the temperature of the acidized fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, beginning to dropwise add ammonia water (commercially available, with the mass fraction of 25%) after the temperature and the rotating speed are stable, and when 27mL of ammonia water is added, the pH value is 2.41, the temperature is 28.5 ℃, starting to be turbid from clear and transparent, stopping dropwise adding the ammonia water at the same time, and carrying out preliminary stirring and crystal growth; after 32 minutes, the pH value is stabilized at 1.85, the particles in the crystallization liquid are sand-shaped, and at the moment, if the stirring is stopped, the crystals can quickly settle to the bottom of the bottle; keeping the stirring speed, and continuously dropwise adding 4.5mL of ammonia water, wherein the pH value is 4.98 and the temperature is 28.0 ℃; then starting secondary crystal growing, slowly cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growing for 2 hours.
And then, filtering the crystal liquid by using common filter paper, wherein amoxicillin crystals are granular and are easy to pump and filter, and drying after washing to obtain 21.23g amoxicillin trihydrate dry powder.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
The contents and related impurities were analyzed by Agilent high performance liquid chromatography (equipment model 1260), and the results are shown in Table 2 below.
Example 2
190mL of amoxicillin enzymatic condensation solution (wherein the amoxicillin content is 106.78mg/mL, the pH value is 6.88) is placed in a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by using a water bath, stirring is started for 300r/min, 34.2mL of hydrochloric acid (commercially available, the mass fraction is 33.2%) is added within 2 minutes, the condensation solution is completely dissolved and clear, and the amoxicillin content in the acidification solution is 90.18mg/mL, the pH value is 0.17, the temperature is 28.5 ℃, and amoxicillin: the HCl molar ratio is 1.
Filtering the acidized fluid by using a 0.45-micron microporous membrane, placing the acidized fluid in a 500mL four-neck flask, adjusting the temperature of the acidized fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, beginning to dropwise add ammonia water (commercially available, mass fraction of 25%) after the temperature and the rotating speed are stable, and when 27.5mL of ammonia water is added, the pH value is 2.55, the temperature is 29.0 ℃, at the moment, turbidity starts from clarification and transparency, the dropwise addition of the ammonia water is stopped at the same time, and performing preliminary stirring and crystal growth; after 29 minutes, the pH value is stabilized at 1.88, the particles in the crystallization liquid are sand-shaped, and at the moment, if the stirring is stopped, the crystals can quickly settle to the bottom of the bottle; keeping the stirring speed, and continuously dropwise adding 4.6mL of ammonia water, wherein the pH value is 5.04 and the temperature is 28.0 ℃; then starting secondary crystal growing, slowly cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growing for 2 hours.
And then, filtering the crystallization liquid by using common filter paper, wherein amoxicillin crystals are granular and are easy to pump and filter, and drying after washing to obtain 21.45g amoxicillin trihydrate dry powder.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
An agilent high performance liquid chromatograph (equipment model 1260) was used to analyze the content and related impurities, and the results are shown in table 2 below.
Example 3
190mL of amoxicillin enzymatic condensation solution (wherein the amoxicillin content is 107.28mg/mL, pH 6.77) is put into a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by a water bath, stirring is started for 300r/min, 34.1mL of hydrochloric acid (commercially available, with the mass fraction of 33.2%) is added within 2 minutes, at the moment, the condensation solution is completely dissolved and clear, and the amoxicillin content in the acidification solution is detected to be 90.32mg/mL, the pH is 0.17, the temperature is 28.5 ℃, and amoxicillin: the HCl molar ratio is 1.
Filtering the acidized fluid by using a 0.45-micron microporous membrane, placing the acidized fluid in a 500mL four-neck flask, adjusting the temperature of the acidized fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, beginning to dropwise add ammonia water (commercially available, with the mass fraction of 25%) after the temperature and the rotating speed are stable, and when 27.0mL of ammonia water is added, the pH value is 2.35, the temperature is 29.0 ℃, at the moment, starting to be turbid from clear and transparent, stopping dropwise adding the ammonia water, and carrying out preliminary stirring and crystal growth; after 35 minutes, the pH value is stabilized at 1.91, particles in the crystallization liquid are sand-shaped, and at the moment, if the stirring is stopped, crystals can quickly settle to the bottom of a bottle; keeping the stirring speed, and continuously dropwise adding 4.5mL of ammonia water, wherein the pH value is 5.02 and the temperature is 28.0 ℃; then starting secondary crystal growing, slowly cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growing for 2 hours.
And then, filtering the crystal liquid by using common filter paper, wherein amoxicillin crystals are granular, are easy to pump and filter, and are dried after being washed by water to obtain 21.78g amoxicillin trihydrate dry powder.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
The contents and related impurities were analyzed by Agilent high performance liquid chromatography (equipment model 1260), and the results are shown in Table 2 below.
Comparative example 1 (conventional crystallization Process)
190mL of amoxicillin enzymatic condensation liquid (wherein the amoxicillin content is 106.42mg/mL, the pH value is 6.79) is placed in a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by using a water bath, stirring is started for 300r/min, 9.0mL of hydrochloric acid (commercially available, the mass fraction is 33.2%) is added within 2 minutes, the appearance of the condensation liquid is clear, and the amoxicillin content in the acidification liquid is detected to be 101.58mg/mL, the pH value is 0.93, the temperature is 28.5 ℃, the amoxicillin: HCl molar ratio 1.73.
Filtering the acidized fluid by using a 0.45-micron microporous membrane, placing the acidized fluid in a 500mL four-neck flask, adjusting the temperature of the acidized fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, beginning to dropwise add ammonia water (commercially available, with the mass fraction of 25%) after the temperature and the rotating speed are stable, and when 4mL of ammonia water is added, the pH value is 1.45, the temperature is 28.0 ℃, starting to be turbid from clear and transparent, stopping dropwise adding the ammonia water at the same time, and carrying out preliminary stirring and crystal growth; after 30 minutes, the pH value is stabilized at 1.35, and the crystal liquid is pasty; keeping stirring at the same speed, and continuously dropwise adding 4.3mL of ammonia water, wherein the pH value is 4.98 and the temperature is 28.0 ℃; and starting secondary crystal growth, cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growth for 2 hours.
And then, filtering the crystal liquid by using common filter paper, wherein the amoxicillin crystal is planar and is difficult to pump and filter, and after washing by water, drying to obtain 20.34g of amoxicillin trihydrate dry powder.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
The contents and related impurities were analyzed by Agilent high performance liquid chromatography (equipment model 1260), and the results are shown in Table 2 below.
Comparative example 2 (conventional crystallization Process)
190mL of amoxicillin enzymatic condensation liquid (wherein the amoxicillin content is 108.57mg/mL, and the pH value is 6.81) is placed in a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by using a water bath, stirring is started for 300r/min, 8.8mL of hydrochloric acid (commercially available, the mass fraction is 33.2%) is added within 2 minutes, and at the moment, the appearance of the condensation liquid is clear, and the amoxicillin content in the acidification liquid is detected to be 103.64mg/mL, the pH value is 0.98, the temperature is 28.5 ℃, amoxicillin: the HCl molar ratio is 1.66.
Filtering the acidized fluid by using a 0.45-micron microporous membrane, placing the acidized fluid in a 500mL four-neck flask, adjusting the temperature of the acidized fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, beginning to dropwise add ammonia water (commercially available, with the mass fraction of 25%) after the temperature and the rotating speed are stable, and when 3.9mL of ammonia water is added, the pH value is 1.51, the temperature is 28.0 ℃, starting to be turbid from clear and transparent, stopping dropwise adding the ammonia water at the same time, and carrying out preliminary stirring and crystal growth; after 35 minutes, the pH value is stabilized at 1.42, and the crystal liquid is pasty; stirring at the same speed, and continuously dropwise adding 4.2mL of ammonia water, wherein the pH value is 4.91 and the temperature is 28.0 ℃; and starting secondary crystal growth, cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growth for 2 hours.
And then, filtering the crystal liquid by using common filter paper, wherein the amoxicillin crystal is planar and is difficult to pump and filter, and the amoxicillin trihydrate dry powder of 20.79g is obtained after washing and drying.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
The contents and related impurities were analyzed by Agilent high performance liquid chromatography (equipment model 1260), and the results are shown in Table 2 below.
Comparative example 3 (conventional crystallization Process)
190mL of amoxicillin enzymatic condensation liquid (wherein the amoxicillin content is 106.88mg/mL, the pH value is 6.74) is placed in a 500mL four-neck flask, the temperature is adjusted to 28.0 ℃ by using a water bath, stirring is started for 300r/min, 8.9mL of hydrochloric acid (commercially available, the mass fraction is 33.2%) is added within 2 minutes, the appearance of the condensation liquid is clear, and the amoxicillin content in the acidification liquid is detected to be 101.54mg/mL, the pH value is 0.81, the temperature is 28.5 ℃, the amoxicillin: HCl molar ratio 1.71.
Filtering the acidizing fluid by using a 0.45-micron microporous membrane, putting the filtered acidizing fluid into a 500-mL four-neck flask, adjusting the temperature of the acidizing fluid by using a water bath, keeping the temperature at 28.0 ℃, starting stirring for 30r/min, starting to dropwise add ammonia water (sold in the market, the mass fraction is 25%) after the temperature and the rotating speed are stable, and when 4.2mL of ammonia water is added, the pH is 1.67, the temperature is 28.0 ℃, starting to turbidity from clear and transparent, stopping dropwise adding the ammonia water at the same time, and carrying out preliminary stirring and crystal growth; after 33 minutes, the pH value is stabilized at 1.31, and the crystallization liquid is pasty; keeping stirring at the same speed, and continuously dropwise adding 4.0mL of ammonia water, wherein the pH value is 4.92 and the temperature is 28.0 ℃; starting secondary crystal growing, cooling the crystal liquid to 4-5 ℃, and stirring at the same speed for crystal growing for 2 hours.
And then, filtering the crystal liquid by using common filter paper, wherein the amoxicillin crystal is planar and is difficult to pump and filter, and the amoxicillin trihydrate dry powder of 20.01g is obtained after washing and drying.
The particle size of the dry powder obtained above was measured using a malvern laser particle sizer (Mastersizer 3000), and the results are shown in table 1 below.
Agilent high performance liquid chromatography (equipment model 1260), content and related impurities, was used and the results are shown in table 2 below.
TABLE 1 Amoxicillin Crystal particle size prepared in examples 1-3 and comparative examples 1-3
TABLE 2 yield and purity of amoxicillin crystals prepared in examples 1-3 and comparative examples 1-3
| Item | Yield% | Water content% | Dry content% | Single hetero% | Total miscellaneous% |
| Example 1 | 93.75 | 12.5 | 99.85 | 0.06 | 0.11 |
| Example 2 | 92.92 | 12.6 | 99.91 | 0.07 | 0.10 |
| Example 3 | 93.75 | 12.6 | 99.78 | 0.06 | 0.11 |
| Comparative example 1 | 87.50 | 12.8 | 99.65 | 0.06 | 0.11 |
| Comparative example 2 | 87.92 | 12.7 | 99.71 | 0.08 | 0.13 |
| Comparative example 3 | 86.67 | 12.5 | 99.82 | 0.07 | 0.12 |
It can be seen that according to examples 1 to 3 of the method for preparing amoxicillin crystals of the present invention, the prepared amoxicillin crystals have suitably large particle sizes, dv (10) is 10 to 15 μm, dv (50) is 45 to 60 μm, and Dv (90) is 145 to 165 μm, and amoxicillin having suitably large particle sizes can be effectively used for preparing amoxicillin pharmaceutical preparations, particularly capsule preparations, and the preparation method has improved yield and good product quality.
Claims (10)
1. A preparation method of amoxicillin crystals comprises the following steps: acidifying the amoxicillin enzymatic condensation liquid by hydrochloric acid at 20-30 ℃ to ensure that the pH of the condensation liquid is less than 0.2, and the molar ratio of amoxicillin to HCl is 1:5.8 to 7.6; then ammonia water is dripped into the acidified condensation liquid under stirring till the pH value is 2-3, and when turbidity begins to appear, the dripping of the ammonia water is stopped, and crystal growth is carried out for 20-40 minutes; and continuously dropwise adding ammonia water until the pH value is 4-5, cooling to 0-10 ℃, stirring for growing crystals, filtering, washing and drying to obtain amoxicillin crystal powder.
2. The method for preparing amoxicillin crystals as claimed in claim 1, wherein the amoxicillin enzymatic condensation solution is a condensation reaction solution obtained by carrying out a condensation reaction between 6-aminopenicillanic acid and D-p-hydroxyphenylglycine methyl ester under the catalytic action of immobilized penicillin acylase for synthesis, and filtering the immobilized penicillin acylase for synthesis.
3. The method for preparing amoxicillin crystals as claimed in claim 2, wherein the amoxicillin content in the amoxicillin enzymatic condensation solution is 100-110 mg/ml, and the pH is 6-7.
4. The process for preparing amoxicillin crystals according to claim 1, wherein hydrochloric acid is added during the acidification treatment at a stirring speed controlled between 250 and 400r/min so that the pH of the condensation solution is between 0.1 and 0.19 and the molar ratio of amoxicillin to HCl is 1:6.2 to 6.9.
5. The method for preparing amoxicillin crystals according to claim 1, wherein the hydrochloric acid is 32 to 35 mass percent hydrochloric acid in the acidification treatment.
6. The process for preparing amoxicillin crystals according to claim 1, further comprising filtering the acidified condensation solution with an organic microfiltration membrane after the acidification treatment of the amoxicillin enzymatic condensation solution.
7. The process for preparing amoxicillin crystals according to claim 1 or 4, characterized in that ammonia water is added dropwise to the acidified condensation solution under stirring at a rate controlled between 20 and 50r/min.
8. The process for preparing amoxicillin crystals according to claim 1, wherein the ammonia water is 23 to 26 mass percent ammonia water.
9. The preparation method of amoxicillin crystals as claimed in claim 1, characterized in that the amoxicillin crystal is cooled to 4-5 ℃ and stirred at 20-50 r/min for growing crystals, and then filtered, washed and dried to obtain amoxicillin crystal powder.
10. The process for the preparation of amoxicillin crystals as claimed in claim 1, characterized in that said amoxicillin crystals have suitably large particle sizes, wherein Dv (10) is 10 to 15 μm, dv (50) is 45 to 60 μm and Dv (90) is 145 to 165 μm.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020137926A1 (en) * | 1998-06-01 | 2002-09-26 | Smithkline Beecham Corporation | Process for preparing crystalline salts of amoxycillin |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
| CN111518119A (en) * | 2020-05-26 | 2020-08-11 | 联邦制药(内蒙古)有限公司 | Continuous amoxicillin crystallization process |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020137926A1 (en) * | 1998-06-01 | 2002-09-26 | Smithkline Beecham Corporation | Process for preparing crystalline salts of amoxycillin |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
| CN111518119A (en) * | 2020-05-26 | 2020-08-11 | 联邦制药(内蒙古)有限公司 | Continuous amoxicillin crystallization process |
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