CN116808013A - Bulk pharmaceutical chemical of carglutamic acid, solid preparation of carglutamic acid and preparation method thereof - Google Patents
Bulk pharmaceutical chemical of carglutamic acid, solid preparation of carglutamic acid and preparation method thereof Download PDFInfo
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- CN116808013A CN116808013A CN202310647403.4A CN202310647403A CN116808013A CN 116808013 A CN116808013 A CN 116808013A CN 202310647403 A CN202310647403 A CN 202310647403A CN 116808013 A CN116808013 A CN 116808013A
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- Prior art keywords
- acid
- carboglutamic
- kaglutamic
- weight
- microcrystalline cellulose
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- 239000002253 acid Substances 0.000 title claims abstract description 284
- 238000002360 preparation method Methods 0.000 title claims abstract description 84
- 239000007787 solid Substances 0.000 title claims abstract description 67
- 239000000126 substance Substances 0.000 title claims abstract description 66
- 239000002245 particle Substances 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 40
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 37
- 229940079593 drug Drugs 0.000 claims abstract description 36
- 239000012043 crude product Substances 0.000 claims abstract description 33
- 238000005406 washing Methods 0.000 claims abstract description 20
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 96
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 96
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 95
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 95
- 238000003756 stirring Methods 0.000 claims description 69
- 239000000463 material Substances 0.000 claims description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 23
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 23
- 235000013922 glutamic acid Nutrition 0.000 claims description 23
- 239000004220 glutamic acid Substances 0.000 claims description 23
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 22
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 22
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 22
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 22
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 20
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000377 silicon dioxide Substances 0.000 claims description 13
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 13
- 229960003943 hypromellose Drugs 0.000 claims description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000000080 wetting agent Substances 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 230000004580 weight loss Effects 0.000 abstract description 27
- 238000004090 dissolution Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 105
- 239000000047 product Substances 0.000 description 38
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 29
- 229960002989 glutamic acid Drugs 0.000 description 25
- 238000002425 crystallisation Methods 0.000 description 23
- 230000008025 crystallization Effects 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 230000001276 controlling effect Effects 0.000 description 21
- 239000012295 chemical reaction liquid Substances 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 17
- 239000002002 slurry Substances 0.000 description 14
- 238000005303 weighing Methods 0.000 description 14
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000007873 sieving Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 238000007605 air drying Methods 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 230000007306 turnover Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000013461 design Methods 0.000 description 6
- 239000007935 oral tablet Substances 0.000 description 6
- 238000013329 compounding Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 4
- 229960000623 carbamazepine Drugs 0.000 description 4
- LCQLHJZYVOQKHU-VKHMYHEASA-N carglumic acid Chemical compound NC(=O)N[C@H](C(O)=O)CCC(O)=O LCQLHJZYVOQKHU-VKHMYHEASA-N 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 108010032178 Amino-acid N-acetyltransferase Proteins 0.000 description 3
- 102000007610 Amino-acid N-acetyltransferase Human genes 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000004143 urea cycle Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010020575 Hyperammonaemia Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 108700043217 N-acetyl glutamate synthetase deficiency Proteins 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Abstract
The application provides a method for preparing a bulk drug of kaglutamic acid with a D90 particle size of 200-600 mu m, which comprises the following steps: mixing ammonium salt of the carboglutamic acid, a crude product of the carboglutamic acid with acid liquor, crystallizing, collecting and washing crystals to obtain the carboglutamic acid bulk drug, wherein the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 1-9 based on the total molar weight of the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid: 1. the method can obtain the bulk pharmaceutical chemicals of the carboglutamic acid with the D90 particle size of 200-600 mu m, and the carboglutamic acid solid preparation prepared by the bulk pharmaceutical chemicals of the carboglutamic acid has little weight loss after being broken into 1/4 tablet, uniform weight of 1/4 tablet, short disintegration time, good dissolution uniformity and convenient administration. In addition, the preparation method has high yield, high purity, simple and convenient operation and low cost, and is suitable for industrial production.
Description
Case division information
The application relates to a patent application of a 'kaglutamic acid solid preparation and a preparation method thereof', which is filed to the intellectual property office of China on 11-23 days in 2020, and has the patent application number of 202011320830.4.
Technical Field
The invention relates to the field of medicine. In particular, the invention relates to a bulk drug of carboglutamic acid, a solid preparation of carboglutamic acid and a preparation method thereof.
Background
NAGS (acetylglutamate synthase) deficiency is one of the abnormal metabolic conditions of the urea cycle, which is caused by urea deficiency. NAGS deficiency results in insufficient NAG synthesis, affecting ammonia entry into urea cycle metabolism, resulting in accumulation of alanine, glutamine, glutamate, ammonia.
Kaglutamic acid, chemical name: N-carbamoyl-L-glutamic acid or (2S) -2- (carbamoylamino) glutaric acid, formula: c (C) 6 H 10 N 2 O 5 (the structural formula is shown as the following formula (I)). Mainly used for treating acute or chronic hyperammonemia caused by deficiency of N-acetylglutamate synthase (NAGS) of liver of children and adults.
The scored tablet is a relatively special tablet, which can be taken as a whole or after breaking the tablet(s). The appearance shape of the scored sheet is the same as that of a common sheet, and is round, elliptic or capsule, and one score (in a straight shape) or two scores (in a cross shape) are added on the common sheet, and more scores are also added. The scoring is used for identifying the non-scored sheet and is convenient for breaking the sheet. Elderly patients, children and some special patients sometimes have difficulty swallowing solid tablets, which can be solved by breaking the whole tablet into multiple pieces; some drugs are special and the production line cannot meet the minimum dose requirement for tablets, which can be solved by enlarging the dose through scored tablets.
However, there are problems with the scored sheet, for example, some scored sheets are not easily broken, so that most patients choose to discard the broken sheet, the scored sheet loses its scored value, and some doses are discarded; powder or fragments can appear in the process of breaking the scored sheet, so that weight loss is caused, the weight of the broken sheet is not uniform, and the drug effect and safety are affected.
For the glutamic acid tablet, the front and back sides of the glutamic acid tablet are provided with 3 scores along the longitudinal direction, the scores have the function of equally dividing the dosage, and the glutamic acid tablet can be broken into 1/2 pieces along the scores and further into 1/4 pieces. According to different weights of patients, the tablet is required to be broken into 1/4 tablet, if the weight of the broken tablet is not uniform or the weight loss is large, the drug effect can be seriously affected, and in addition, the tablet is in accordance with the general requirements of design and research of functional scores of imitated oral tablets issued by the drug evaluation center of the national drug administration: the quality of the divided portions should be such that they meet the quality criteria for the whole tablet. In combination with the requirements of the four general rules of the year 2020 edition of Chinese pharmacopoeia (weight difference), the weight difference limit of 1/4 tablet should be + -5%, and more than 2 tablets exceeding the weight difference limit are not needed, and 1 tablet exceeding the limit is not needed to be 1 time. In addition, the weight difference of 1/4 of the commercially available kaglutamic acid tablets does not meet the requirements of the fourth rule of the year 2020 edition of Chinese pharmacopoeia.
Therefore, it is necessary to develop a solid preparation of kaglutamic acid which has uniform weight of the breaking-off piece and small weight loss and meets the requirement and a preparation method thereof.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides a solid preparation of the carboglutamic acid, a preparation method thereof and a preparation method of the carboglutamic acid bulk drug, the carboglutamic acid bulk drug with the D90 grain diameter of 200-600 mu m can be obtained by using the method of the invention, and the carboglutamic acid bulk drug with the D90 grain diameter of 200-600 mu m can be prepared by using the carboglutamic acid bulk drug, and the carboglutamic acid solid preparation prepared by using the carboglutamic acid bulk drug has less weight loss after being broken into 1/4 tablet, 1/4 tablet weight is uniform, disintegration time is short, dissolution uniformity is good, and the administration is convenient; the preparation method of the bulk pharmaceutical chemical of the carboglutamic acid is simple and convenient to operate, and the particle size of the obtained bulk pharmaceutical chemical of the carboglutamic acid is controllable, so that the bulk pharmaceutical chemical of the carboglutamic acid is suitable for large-scale popularization and application.
In one aspect of the invention, the invention provides a method for preparing a raw material drug of the backup glutamic acid with the D90 particle size of 200-600 mu m. According to an embodiment of the invention, the method comprises: mixing ammonium salt of the carboglutamic acid, a crude product of the carboglutamic acid with acid liquor, crystallizing, collecting and washing crystals to obtain the carboglutamic acid bulk drug, wherein the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 1-9 based on the total molar weight of the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid: 1.
The inventor finds that the particle size of the bulk pharmaceutical chemical of the carboglutamic acid can influence the weight loss of the solid preparation of the carboglutamic acid after being divided, and when the particle size of the bulk pharmaceutical chemical of the carboglutamic acid D90 is 200-600 mu m, the weight loss of the solid preparation of the carboglutamic acid prepared by taking the bulk pharmaceutical chemical of the carboglutamic acid after being divided is less. Meanwhile, the solid preparation of the carboglutamic acid has short disintegration time, good solubility and convenient administration.
Further, the inventors found that the D90 particle size of the obtained crystals (bulk pharmaceutical chemicals of the carboglutamic acid) can be controlled to be 200-600 μm by carrying out an acid addition reaction by compounding an ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid. And the method has the advantages of high yield, high purity, simple and convenient operation and low cost, and is suitable for industrial production.
According to an embodiment of the invention, the mixing comprises: dissolving the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid in water, stirring, dripping acid liquor into the mixed liquor while stirring, stopping stirring when the reaction liquor reaches a preset pH value, and crystallizing; in the dropping process, the temperature of the reaction liquid is controlled to be 0-8 ℃.
According to an embodiment of the invention, the dropping speed of the acid solution is 10-80 g/min, preferably 10-66 g/min.
According to an embodiment of the invention, the rotational speed of the stirring is controlled to be 50 to 180 rpm, preferably 50 to 150 rpm.
In another aspect of the invention, the invention provides a bulk pharmaceutical of kaglutamic acid. According to the embodiment of the invention, the bulk pharmaceutical chemical of the kaglutamic acid is prepared by the method for preparing the bulk pharmaceutical chemical of the kaglutamic acid with the D90 particle size of 200-600 mu m.
In yet another aspect of the present invention, the present invention provides a solid preparation of kaglutamic acid. According to an embodiment of the present invention, the solid preparation of kaglutamic acid includes: the D90 particle size of the bulk pharmaceutical chemical of the kaglutamic acid is 200-600 mu m; the auxiliary material comprises microcrystalline cellulose, wherein the microcrystalline cellulose comprises first microcrystalline cellulose and second microcrystalline cellulose; the angle of repose of the first microcrystalline cellulose is 55 degrees or more and the angle of repose of the second microcrystalline cellulose is 46 degrees or less; or the first microcrystalline cellulose is of a type selected from at least one of PH-F20JP and KG 1000; and the second microcrystalline cellulose is of a type selected from at least one of pH101, pH102, pH112, pH200, pH301, pH302, UF701, and UF 702.
The inventor researches the bulk pharmaceutical chemicals and auxiliary materials of the carboglutamic acid in order to solve the technical problem that the weight loss of the carboglutamic acid solid preparation after being broken into 1/4 tablet does not meet the requirements of Chinese pharmacopoeia. The inventors found that the particle size of the bulk drug of the glutamic acid with the D90 particle size of 200-600 μm is used simultaneously,
At present, the auxiliary materials adopted in the field of solid preparations are numerous in types, the compounding relationship is more insufficient, and in the process of screening and optimizing the auxiliary materials, surprisingly, two different types of microcrystalline cellulose are adopted for compounding, so that the weight loss is small, wherein the first microcrystalline cellulose and the second microcrystalline cellulose are adopted for compounding, the obtained solid preparation is small in weight loss after being divided, good in effect, short in disintegration time, good in uniformity after being dissolved, and convenient to take.
According to the embodiment of the invention, the bulk pharmaceutical chemical of the kaglutamic acid is prepared by adopting the method for preparing the bulk pharmaceutical chemical of the kaglutamic acid with the D90 particle size of 200-600 mu m.
According to an embodiment of the invention, the auxiliary material further comprises at least one of a disintegrant, a binder, a wetting agent and a glidant.
According to an embodiment of the present invention, the disintegrant is selected from at least one of croscarmellose sodium, calcium carboxymethylcellulose, crospovidone and sodium carboxymethyl starch; the binder is at least one selected from hypromellose, povidone, hydroxypropyl cellulose and sodium carboxymethyl cellulose; the wetting agent is at least one of sodium dodecyl sulfate and sodium stearyl fumarate; the glidant is at least one selected from silicon dioxide and talcum powder.
According to an embodiment of the present invention, the first microcrystalline cellulose accounts for 1-50%, 5-45%, 10-40%, 10-35% of the total weight of the tablet.
According to an embodiment of the present invention, the solid preparation of kaglutamic acid comprises, based on the total mass of the solid preparation of kaglutamic acid: 30-50 mass% of a bulk pharmaceutical chemical of kaglutamic acid; and the balance of auxiliary materials.
According to an embodiment of the present invention, the solid preparation of kaglutamic acid includes: 30-50 parts by weight of a bulk pharmaceutical chemical of kaglutamic acid; 50-55 parts by weight of microcrystalline cellulose; 2-4 parts by weight of croscarmellose sodium; 1-4 parts by weight of hypromellose; 0.4 to 0.8 weight portion of sodium dodecyl sulfate; 0.2 to 0.6 part by weight of silica; and 0.1 to 2 parts by weight of sodium stearyl fumarate.
According to the embodiment of the invention, the dosage form of the solid preparation of the carbamazepine is a tablet, wherein the surface of the tablet is provided with scores, and preferably, the front side and the back side of the tablet are respectively provided with three parallel scores.
According to the embodiment of the present invention, when the tablet is broken into 1/4 pieces along the score, the weight difference limit of 1/4 pieces is ±5%, not more than 2 pieces exceeding the weight difference limit, and not more than 1 piece exceeding the limit by 1 time.
In yet another aspect of the present invention, the present invention provides a method for preparing the aforementioned solid preparation of kaglutamic acid. According to an embodiment of the invention, the method comprises: and mixing and tabletting the bulk pharmaceutical chemical of the carglutamic acid and auxiliary materials containing the first microcrystalline cellulose and the second microcrystalline cellulose. Therefore, the solid preparation obtained by the method provided by the embodiment of the invention has the advantages of small weight loss after being divided, good effect, short disintegration time, good uniformity after being dissolved and convenience in taking. In addition, the preparation method is simple and convenient to operate, quick, low in cost and suitable for large-scale production.
According to an embodiment of the present invention, the preparation method of the solid preparation of kaglutamic acid includes:
step 1: drying the second microcrystalline cellulose, the first microcrystalline cellulose, the croscarmellose sodium and the hypromellose;
step 2: uniformly mixing the bulk pharmaceutical chemical of kaglutamic acid, the dried second microcrystalline cellulose, the dried first microcrystalline cellulose, the cross-linked sodium carboxymethyl cellulose and the hydroxypropyl methylcellulose in a mixer;
step 3: sieving sodium dodecyl sulfate with a 60-mesh sieve, adding the sodium dodecyl sulfate into the mixed material in the step 2, and continuously and uniformly mixing;
Step 4: and (3) sieving the silicon dioxide and the sodium stearyl fumarate with a 80-mesh sieve, adding the silicon dioxide and the sodium stearyl fumarate into the mixed material in the step (3), uniformly mixing, and tabletting.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
The invention has the beneficial effects that:
1. the weight loss of the solid preparation of the carboglutamic acid is less after being divided, for example, when the tablet is broken into 1/4 tablets along the nick, the weight difference limit of the 1/4 tablets is +/-5 percent, the weight difference limit is not more than 2 tablets which exceed the weight difference limit, and not more than 1 tablet exceeds the limit by 1 time;
2. the solid preparation of the carboglutamic acid has short disintegration time limit;
3. the preparation method of the bulk pharmaceutical chemical of the carglutamic acid has simple and convenient operation, the particle size of the obtained bulk pharmaceutical chemical of the carglutamic acid is controllable, and the D90 particle size of the bulk pharmaceutical chemical of the carglutamic acid can be controlled to be 200-600 mu m.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first," "second," and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying a number of technical features being indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. Further, in the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.
The present invention provides a solid preparation of kaglutamic acid, a method for preparing a raw material drug of kaglutamic acid and a raw material drug of kaglutamic acid, which will be described in detail below, respectively.
Method for preparing bulk pharmaceutical chemical of kaglutamic acid
In one aspect of the invention, the invention provides a method for preparing a bulk drug of kaglutamic acid with a D90 particle size of 200-600 μm. According to an embodiment of the invention, the method comprises: mixing ammonium salt of the carboglutamic acid, a crude product of the carboglutamic acid and acid liquor, crystallizing, collecting and washing crystals to obtain the carboglutamic acid bulk drug, wherein the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 1-9 based on the total molar quantity of the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid: 1.
the inventor finds that the particle size of the bulk pharmaceutical chemical of the carboglutamic acid can influence the weight loss of the solid preparation of the carboglutamic acid after being divided, and when the particle size of the bulk pharmaceutical chemical of the carboglutamic acid D90 is 200-600 mu m, the weight loss of the solid preparation of the carboglutamic acid prepared by taking the bulk pharmaceutical chemical of the carboglutamic acid after being divided is less. Meanwhile, the solid preparation of the carboglutamic acid has short disintegration time, good solubility and convenient administration.
Further, the inventors found that the D90 particle size of the obtained crystals (bulk pharmaceutical chemicals of the carboglutamic acid) can be controlled to be 200-600 μm by carrying out an acid addition reaction by compounding an ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid. And the method has the advantages of high yield, high purity, simple and convenient operation and low cost, and is suitable for industrial production.
The term "crude product of carboglutamic acid" as used in the present invention refers to a product containing carboglutamic acid and having a high impurity content obtained by a chemical synthesis or biosynthesis method. Specifically, in the examples of the present invention, the crude carboglutamic acid is obtained by: and (3) reacting L-glutamic acid, alkali and cyanate to obtain the carbamates, and then carrying out acid adding reaction on the carbamates to obtain the crude carbamates. For example, the equation is as follows:
the term "ammonium salt of kavalate" as used herein refers to the crude product of kavalate as described above reacted with a base. Specifically, in the examples of the present invention, the ammonium salt of kaglutamate is obtained by: and (3) reacting the crude product of the carbamyl glutamate with ammonia water to obtain ammonium salt of the carbamyl glutamate.
The term "D90" as used herein refers to the particle size corresponding to a cumulative particle size distribution of the sample up to 90%. Its physical meaning is that the particles with a particle size smaller than that of it account for 90%. The inventor finds that the particle size of the raw material medicine D90 of the carglutamic acid cannot be effectively controlled by simply sieving in the research process, and the particle size is controlled by simply sieving, so that the particle size of the raw material medicine D90 of the carglutamic acid is usually too small, and the obtained raw material medicine of the carglutamic acid does not meet the requirements. For example, only the bulk pharmaceutical chemical of carboglutamic acid is screened through a 40 mesh screen to control the particle size, which corresponds to a mesh size of 425 μm, however, in many cases, the D90 particle size will be less than 200 μm.
According to an embodiment of the invention, the mixing comprises: dissolving the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid in water, stirring, dripping acid liquor into the mixed liquor while stirring, stopping stirring when the reaction liquor reaches a preset pH value, and crystallizing; in the dripping process, controlling the temperature of the reaction liquid to be 0-8 ℃; the dropping speed of the acid liquor is 10-80 g/min, preferably 10-66 g/min; the stirring speed is controlled to 50 to 180 rpm, preferably 50 to 150 rpm. The inventor finds that the temperature of the reaction liquid, the dropping speed of the acid liquid and the stirring speed in the dropping process can influence the particle size of the bulk pharmaceutical chemical of the glutamic acid, and when the conditions are adopted, the particle size of the obtained bulk pharmaceutical chemical of the glutamic acid D90 can reach 200-600 mu m.
Bulk drug of kaglutamic acid
In another aspect of the present invention, the present invention provides a bulk pharmaceutical chemical of kaglutamic acid. According to an embodiment of the present invention, a bulk pharmaceutical of kaglutamic acid is obtained by the method for preparing a bulk pharmaceutical of kaglutamic acid described above. Thus, the particle size of the bulk pharmaceutical chemical D90 of the carbamazepine according to the embodiment of the invention is 200-600 mu m.
Those skilled in the art will appreciate that the features and advantages described above with respect to the method of preparing a bulk pharmaceutical of kaglutamic acid are equally applicable to the bulk pharmaceutical of kaglutamic acid and are not described in detail herein.
Solid preparation of carboglutamic acid
In one aspect of the invention, the invention provides a solid preparation of kaglutamic acid. According to an embodiment of the present invention, a solid preparation of kaglutamic acid includes: the D90 particle size of the bulk pharmaceutical chemical of the kaglutamic acid is 200-600 mu m; the auxiliary material comprises microcrystalline cellulose, wherein the microcrystalline cellulose comprises first microcrystalline cellulose and second microcrystalline cellulose; the angle of repose of the first microcrystalline cellulose is 55 degrees or more and the angle of repose of the second microcrystalline cellulose is 46 degrees or less; or the first microcrystalline cellulose is of a type selected from at least one of PH-F20JP and KG 1000; and the second microcrystalline cellulose is of a type selected from at least one of pH101, pH102, pH112, pH200, pH301, pH302, UF701, and UF 702.
As described above, the inventors found that the particle size of the bulk pharmaceutical chemical of kaglutamic acid affects the weight loss of the solid formulation of kaglutamic acid after division, and that the solid formulation of kaglutamic acid prepared using it as a bulk pharmaceutical chemical has less weight loss after division when the particle size of the bulk pharmaceutical chemical of kaglutamic acid D90 is 200 to 600 μm. Meanwhile, the solid preparation of the carboglutamic acid has short disintegration time, good solubility and convenient administration.
Further, the inventor finds that by adopting the two microcrystalline celluloses with different repose angles to compound, the obtained solid preparation has the advantages of smaller weight loss after being divided, better effect, shorter disintegration time, good uniformity after being dissolved and convenient administration.
According to the embodiment of the invention, the bulk pharmaceutical chemical of the kaglutamic acid is prepared by adopting the method for preparing the bulk pharmaceutical chemical of the kaglutamic acid with the D90 particle size of 200-600 mu m.
According to an embodiment of the invention, the auxiliary material further comprises at least one of a disintegrant, a binder, a wetting agent and a glidant. The addition of the disintegrating agent is helpful for shortening the disintegration time of the tablet, rapidly dissolving and improving the bioavailability thereof. The addition of the binder can improve the hardness of the tablet, avoid the tablet from generating fragments during tabletting, avoid the tablet from being broken after being segmented, and reduce weight loss. The addition of a wetting agent wets the material to give sufficient strength to be tacky to facilitate tablet formation. The addition of the glidant can reduce the friction force among particles, improve the fluidity of powder (particles) and ensure that the difference of the tablet weights is qualified.
According to an embodiment of the invention, the disintegrant is selected from at least one of croscarmellose sodium, calcium carboxymethylcellulose, crospovidone and sodium carboxymethyl starch. Thus, the disintegration time of the tablet is shortened, the tablet is dissolved rapidly, and the bioavailability of the tablet is improved.
According to an embodiment of the invention, the wetting agent is selected from at least one of sodium dodecyl sulfate, sodium stearyl fumarate. Thus, the material may be moistened to impart sufficient strength to facilitate tablet formation.
According to an embodiment of the invention, the glidant is selected from at least one of silicon dioxide, talc. Can reduce the friction force among particles, improve the fluidity of powder (particles) and ensure the qualification of the difference of sheet weights.
According to an embodiment of the invention, the binder is selected from at least one of hypromellose, povidone, hydroxypropyl cellulose and sodium carboxymethyl cellulose. Therefore, the hardness of the tablet can be improved, the generation of fragments during tabletting is avoided, the crushing of the tablet after being divided is avoided, and the weight loss is reduced.
According to an embodiment of the present invention, the solid preparation of kaglutamic acid comprises, based on the total mass of the solid preparation of kaglutamic acid: 30-50 mass% of a bulk pharmaceutical chemical of kaglutamic acid; and the balance of auxiliary materials. Therefore, the weight loss of the carboglutamic acid solid preparation after being divided is less, the disintegration time is shorter, the dissolubility is good, the administration is convenient, the drug dissolution rate is high, and the bioavailability is high.
According to an embodiment of the present invention, a solid preparation of kaglutamic acid includes: 30-50 parts by weight of a bulk pharmaceutical chemical of kaglutamic acid; 50-55 parts by weight of microcrystalline cellulose; 2-4 parts by weight of croscarmellose sodium; 1-4 parts by weight of hypromellose; 0.4 to 0.8 weight portion of sodium dodecyl sulfate; 0.2 to 0.6 part by weight of silica; and 0.1 to 2 parts by weight of sodium stearyl fumarate. The inventor obtains the better proportion through a large number of experiments, so that the weight loss of the carboglutamic acid solid preparation after being divided is less, the disintegration time is shorter, the dissolubility is good, the administration is convenient, the drug dissolution rate is high, and the bioavailability is high.
According to an embodiment of the present invention, the first microcrystalline cellulose comprises 1 to 50%, 5 to 45%, 10 to 40%, 10 to 35% of the total weight of the tablet.
According to the embodiment of the invention, the dosage form of the solid preparation of the kaglutamic acid is a tablet, and the surface of the tablet is provided with scores. Thereby facilitating segmentation. Specifically, the front and back sides of the glutamic acid tablet (500 mg/tablet) are provided with three parallel scores, and can be broken into 1/2 tablet and further broken into 1/4 tablet. When the tablets are broken into 1/4 pieces along the score, the weight difference limit of 1/4 pieces is + -5%, not more than 2 pieces exceeding the weight difference limit, and not more than 1 piece exceeding the limit by 1 time.
Those skilled in the art will appreciate that the features and advantages described above with respect to the method for preparing a bulk pharmaceutical of carbamazepine are equally applicable to the solid dosage form of carbamazepine, and will not be described in detail herein.
Preparation method of solid preparation of carboglutamic acid
In yet another aspect of the present invention, the present invention provides a method for preparing the aforementioned solid preparation of kaglutamic acid. According to an embodiment of the invention, the method comprises: and mixing and tabletting the bulk pharmaceutical chemical of the carglutamic acid and auxiliary materials containing the first microcrystalline cellulose and the second microcrystalline cellulose. Therefore, the solid preparation obtained by the method provided by the embodiment of the invention has the advantages of small weight loss after being divided, good effect, short disintegration time, good uniformity after being dissolved and convenience in taking. In addition, the preparation method is simple and convenient to operate, quick, low in cost and suitable for large-scale production.
The preparation method of the solid preparation of the carboglutamic acid further comprises the following steps:
step 1: drying the second microcrystalline cellulose, the first microcrystalline cellulose, the croscarmellose sodium and the hypromellose;
step 2: uniformly mixing the bulk pharmaceutical chemical of kaglutamic acid, the dried second microcrystalline cellulose, the dried first microcrystalline cellulose, the cross-linked sodium carboxymethyl cellulose and the hydroxypropyl methylcellulose in a mixer;
step 3: sieving sodium dodecyl sulfate with a 60-mesh sieve, adding the sodium dodecyl sulfate into the mixed material in the step 2, and continuously and uniformly mixing;
step 4: and (3) sieving the silicon dioxide and the sodium stearyl fumarate with a 80-mesh sieve, adding the silicon dioxide and the sodium stearyl fumarate into the mixed material in the step (3), uniformly mixing, and tabletting.
According to an embodiment of the present invention, a bulk pharmaceutical of kaglutamic acid is obtained by the method for preparing a bulk pharmaceutical of kaglutamic acid as described above.
Those skilled in the art will appreciate that the features and advantages described above for the solid preparation of carglutamic acid and the method for preparing the bulk pharmaceutical of carglutamic acid are equally applicable to the method for preparing the solid preparation of carglutamic acid, and will not be described herein.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40％ |
| Microcrystalline cellulose PH101 | 200 | 40％ |
| Microcrystalline cellulose KG1000 | 50 | 10％ |
| Croscarmellose sodium | 20 | 4％ |
| Hydroxypropyl methylcellulose | 20 | 4％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the used bulk pharmaceutical chemical D90 of the carboglutamic acid is 556.7 mu m, the angle of repose of microcrystalline cellulose PH101 is 45 degrees, and the angle of repose of microcrystalline cellulose KG1000 is 57 degrees.
The preparation method comprises the following steps: step 1: drying the second microcrystalline cellulose (microcrystalline cellulose PH 101), the first microcrystalline cellulose (microcrystalline cellulose KG 1000), the croscarmellose sodium and the hypromellose at 60 ℃ for about 2 hours;
step 2: mixing bulk pharmaceutical chemical of kaglutamic acid (particle diameter D90 of 556.7 um) with the dried second microcrystalline cellulose (microcrystalline cellulose PH 101), first microcrystalline cellulose (microcrystalline cellulose KG 1000), croscarmellose sodium and hypromellose in a mixer for several minutes to uniformity;
step 3: sieving sodium dodecyl sulfate with a 60-mesh sieve, adding the sodium dodecyl sulfate into the mixed material in the step 2, and continuously and uniformly mixing;
step 4: and (3) sieving the silicon dioxide and the sodium stearyl fumarate with a 80-mesh sieve, adding the silicon dioxide and the sodium stearyl fumarate into the mixed material in the step (3), uniformly mixing, and tabletting.
The tablet breaking is carried out by taking 20 1/4 tablets (firstly breaking into 1/2 tablets and then breaking into 1/4 tablets) and precisely weighing the total weight, after obtaining the average tablet weight, precisely weighing each tablet, comparing each tablet weight with the average tablet weight, wherein the difference between the 1/4 tablet weight and the weight is shown in the table 1, and the method is as follows the general requirement of the "design and study of the functional scores of the imitated oral tablets" issued by the drug evaluation center of the national drug administration: the quality of the divided portions should be such that they meet the quality criteria for the whole tablet. In combination with the requirements of the four general rules of the year 2020 edition of Chinese pharmacopoeia (weight difference), the weight difference limit of 1/4 tablet should be + -5%, and more than 2 tablets exceeding the weight difference limit are not needed, and 1 tablet exceeding the limit is not needed to be 1 time. The inspection is carried out according to the method, and the inspection meets the regulations.
As can be seen from Table 1, the tablets obtained by the above formulation have less weight loss after being divided, meet the general requirements of design and research of functional scores of imitated oral tablets, and have a disintegration time limit of only 15s.
Table 1 1/4 sheet weight and weight difference
Example 2
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH112 | 150 | 30.0％ |
| Microcrystalline cellulose PH-F20JP | 125 | 25.0％ |
| Croscarmellose sodium | 10 | 2.0％ |
| Hydroxypropyl methylcellulose | 5 | 1.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the raw material D90 of the kaglutamic acid is 503.2 mu m, the angle of repose of microcrystalline cellulose PH112 is 33 degrees, and the angle of repose of microcrystalline cellulose PH-F20JP is more than 60 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 2.
As can be seen from Table 2, the tablets obtained by the above formulation have less weight loss after being divided, meet the general requirements of design and research of functional scores of imitated oral tablets, and have a disintegration time limit of only 16s.
Table 2 1/4 sheet weight and weight difference
Example 3
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline celluloseKG1000 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the bulk pharmaceutical D90 of the glutamic acid is 216.8 μm, the repose angle of the microcrystalline cellulose PH102 is 42 degrees, and the repose angle of the microcrystalline cellulose KG1000 is 57 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 3.
As can be seen from Table 3, the tablets obtained by the above formulation have less weight loss after being divided, meet the general requirements of design and research of functional scores of imitated oral tablets, and have disintegration time of only 12s.
Table 3 1/4 sheet weight and weight difference
Example 4
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline cellulose KG1000 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the bulk pharmaceutical D90 of the carboglutamic acid is 304.3 μm, the repose angle of the microcrystalline cellulose PH102 is 42 degrees, and the repose angle of the microcrystalline cellulose KG1000 is 57 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 4.
As can be seen from table 4, the tablets obtained with the above formulation had less weight loss after being divided and had a disintegration time of only 8s.
Table 4 1/4 sheet weight and weight difference
As is clear from comparison of example 4 and example 3, when the particle diameter D90 is further limited, the weight difference of 1/4 tablet is smaller and reaches within 2%, and the disintegration time is shorter.
Example 5
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline cellulose KG1000 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
The particle size of the bulk pharmaceutical chemical D90 of the carboglutamic acid is 398.7 μm, the angle of repose of microcrystalline cellulose PH102 is 42 degrees, and the angle of repose of microcrystalline cellulose KG1000 is 57 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 5.
As can be seen from Table 5, the tablets obtained with the above formulation had less weight loss after being divided and had a disintegration time of only 9s.
Table 5 1/4 sheet weight and weight difference
As is clear from comparison of example 5 and example 3, when the particle diameter D90 is further limited, the 1/4 tablet weight difference is smaller and reaches within 3%, and the disintegration time is shorter.
Comparative example 1
The raw materials and the amounts of the glutamic acid-blocking tablets of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline cellulose KG1000 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
The particle size of the bulk pharmaceutical chemical D90 of the carboglutamic acid is 177.8 μm, the angle of repose of microcrystalline cellulose PH102 is 42 degrees, and the angle of repose of microcrystalline cellulose KG1000 is 57 degrees.
The preparation is as in example 1.
The total weight of 20 pieces of the sheet is precisely weighed, the average weight of the sheet is obtained, each piece of the sheet is precisely weighed, and the weight of each piece of the sheet is compared with the average weight, and the weight difference between the 1/4 piece of the sheet and the weight is shown in Table 6.
As can be seen from Table 6, when the particle size of the adopted bulk drug of the glutamic acid D90 is smaller than 200 mu m, the weight difference of 10 tablets obtained after the tablet is divided exceeds +/-5%, and the tablet does not meet the general requirements of design and research of functional scores of imitated oral tablets. The disintegration time was 30s.
Table 6 1/4 sheet weight and weight difference
Comparative example 2
The raw materials and the amounts of the glutamic acid-blocking tablets of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion (%) |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline cellulose KG1000 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
The particle size of the bulk pharmaceutical chemical D90 of the carboglutamic acid is 659.7 mu m, the repose angle of the microcrystalline cellulose PH102 is 42 degrees, and the repose angle of the microcrystalline cellulose KG1000 is 57 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 7.
As can be seen from Table 7, the particle size of the glutamic acid D90 was larger than 600. Mu.m, and the weight difference of 12 tablets obtained by dividing the tablets was more than.+ -. 5%, which was not satisfactory. The disintegration time was 27s.
Table 7 1/4 sheet weight and weight difference
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Comparative example 3
The raw materials and the amounts of the glutamic acid-blocking tablets of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion (%) |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 155 | 31.0％ |
| Microcrystalline cellulose UF-702 | 100 | 20.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
The particle size of the used bulk pharmaceutical D90 of the carglutamic acid is 216.8 mu m, the repose angle of the microcrystalline cellulose PH102 is 42 degrees, and the repose angle of the microcrystalline cellulose UF-702 is 34 degrees.
The preparation is as in example 1.
The total weight of 20 pieces of the sheet is precisely weighed, the average weight of the sheet is obtained, each piece of the sheet is precisely weighed, and the weight of each piece of the sheet is compared with the average weight, and the weight difference between the 1/4 piece of the sheet and the weight is shown in Table 8.
As shown in the following table, it can be seen that the first microcrystalline cellulose (microcrystalline cellulose UF-702) used had an angle of repose of less than 55 degrees, and that the weight difference of 5 tablets obtained by the process of dividing the tablets was more than.+ -. 5%, which was not satisfactory. The disintegration time was 30s.
Table 8 1/4 sheet weight and weight difference
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Comparative example 4
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose PH102 | 255 | 51.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the used bulk pharmaceutical D90 of the carglutamic acid is 216.8 mu m, and the repose angle of the microcrystalline cellulose PH102 is 42 degrees.
The preparation is as in example 1.
Breaking off the sheets, precisely weighing 20 sheets 1/4 of the total weight, obtaining the average weight of the sheets, precisely weighing each sheet respectively, the weight of each sheet was compared with the average sheet weight, and the 1/4 sheet weight was different from the weight of each sheet as shown in Table 9.
As can be seen from Table 9, the weight difference of 5 tablets obtained by the above formulation after division was more than.+ -. 5% and was not satisfactory by using only one microcrystalline cellulose having an angle of repose of less than 46 degrees. The disintegration time was 33s.
Table 9 1/4 sheet weight and weight difference
Comparative example 5
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
| raw and auxiliary materials | 1000 tablets dosage (g) | Proportion of |
| Bulk drug of kaglutamic acid | 200 | 40.0％ |
| Microcrystalline cellulose KG1000 | 255 | 51.0％ |
| Croscarmellose sodium | 20 | 4.0％ |
| Hydroxypropyl methylcellulose | 15 | 3.0％ |
| Sodium dodecyl sulfate | 3 | 0.6％ |
| Silica dioxide | 2 | 0.4％ |
| Stearyl sodium fumarate | 5 | 1.0％ |
| Total weight of | 500 | 100％ |
Wherein the particle size of the used bulk pharmaceutical chemical D90 of the carboglutamic acid is 216.8 mu m, and the repose angle of the microcrystalline cellulose KG1000 is 57 degrees.
Preparation method steps methods 1 to 3 are as in example 1.
Step 4: the silicon dioxide and the sodium stearyl fumarate are sieved by a 80-mesh sieve and added into the mixed materials in the step 3, after being uniformly mixed, the materials are difficult to discharge in the tabletting process, and the successful tabletting can not be met by adjusting parameters and the like, namely the industrialization of the prescription is difficult.
The above results demonstrate that the single addition of microcrystalline cellulose having an angle of repose greater than 55 degrees is problematic for tabletting.
Comparative example 6
The amounts of the raw materials of the kaglutamic acid tablet of this example are as follows:
wherein the particle size of the bulk pharmaceutical D90 of the carboglutamic acid is 216.8 μm, the angle of repose of microcrystalline cellulose PH102 is 42 degrees, and the angle of repose of microcrystalline cellulose KG802 is 49 degrees.
The preparation is as in example 1.
The total weight of 20 pieces of the sheet is precisely weighed, the average weight of the sheet is obtained, each piece of the sheet is precisely weighed, and the weight of each piece of the sheet is compared with the average weight, and the weight difference of 1/4 piece of the sheet is shown in Table 10.
As can be seen from Table 10, the angle of repose of the first microcrystalline cellulose (microcrystalline cellulose KG 802) used was 49 degrees, and the weight difference of 9 tablets obtained after the division was more than.+ -. 5%, which was not satisfactory. The disintegration time was 38s.
TABLE 10 1/4 tablet weight and weight differences
Comparative example 7
The commercial card glutamic acid sheets are purchased abroad, 20 sheets of the glutamic acid sheets are split into sheets, 1/4 sheets of the glutamic acid sheets are precisely weighed, the weight of each sheet is precisely weighed after the average sheet weight is obtained, and the weight of each sheet is compared with the average sheet weight, and the weight difference of 1/4 sheets of glutamic acid sheets are shown in Table 11.
TABLE 11 1/4 tablet weight and weight differences
As can be seen from the table, the weight difference of 1/4 of the commercially available kaglutamic acid tablets does not meet the requirements of the fourth rule of the Chinese pharmacopoeia 2020 edition.
Example 6
Preparing a crude product of carboglutamic acid:
to a 500L reactor was added the formulated aqueous potassium hydroxide solution (18.8 kg potassium hydroxide and 165kg drinking water) and stirring was started. 40kg of L-glutamic acid was added to the reaction vessel at 25 ℃. After the addition, the temperature was raised, the solution was stirred at 30℃and the pH of the reaction solution was controlled to 8.5. 20.2kg of potassium cyanate is added into the reaction kettle, nitrogen protection is added, the temperature is raised to 50 ℃, and the reaction is carried out for 10 hours. Obtaining the preparation liquid of the carboglutamic acid.
The resulting kaglutamic acid preparation was cooled to 25 ℃. 70kg of methylene chloride was added to the reaction vessel and stirred for 15 minutes. Standing for layering, and discarding the lower layer (organic layer); 70kg of dichloromethane is added into the reaction kettle again, stirring is carried out for 15min, standing is carried out for layering, and the lower layer (organic layer) is discarded. The aqueous layer (upper layer) was stirred continuously and cooled to 10 ℃. Concentrated hydrochloric acid with mass fraction of 37% is added dropwise, the pH value of the reaction solution is regulated to 1.5, and the temperature of the reaction solution is controlled to 15 ℃ in the dropwise adding process. After the completion of the dropwise addition, stirring was continued at 15℃for 8min. Discharging and centrifuging. Washing the filter cake with drinking water and absolute ethyl alcohol for one time, and centrifuging and drying. The filter cake was air-dried at 30℃for 15h to give 43.4kg of crude carboglutamic acid in 83.9% yield. The purity of the crude product is 97.41 percent.
Wherein the yield of the crude carboglutamic acid was calculated as follows (the following experimental groups were calculated in the same manner):
the mass of the crude carboglutamic acid was calculated from the mass of L-glutamic acid (40 kg in this experimental group) as the theoretical mass of carboglutamic acid (51.7 kg in this experimental group), and then the mass of the actual carboglutamic acid (43.4 kg in this experimental group) was divided by the theoretical mass of carboglutamic acid multiplied by 100%, which was the yield of the crude carboglutamic acid.
Preparation of ammonium salts of kaglutamic acid:
132kg of absolute methanol was added to a 500L reactor, and after stirring was started, 37kg of crude carboglutamic acid (crude carboglutamic acid obtained in Experimental group 1) was charged. Slowly heating, and adding 94kg of strong ammonia water into the reaction kettle when the temperature of the reaction liquid is stabilized at 40 ℃. The solid in the reaction kettle is mostly dissolved, about 8.8kg of drinking water and about 11kg of strong ammonia water are respectively added, and the mixture is stirred until the solid is completely dissolved. After the dissolution, the reaction was carried out at 45℃for 40min. After the reaction, stopping heating and stirring, naturally cooling, and standing at 10 ℃ for crystallization for 21h. And after crystallization, centrifuging, washing a filter cake with absolute methanol, and centrifuging and spin-drying to obtain ammonium kaglutamate salt.
Experiment group 1
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 4:1) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 100 revolutions per minute, dropwise adding 1M dilute hydrochloric acid into the reaction kettle, controlling the dropwise adding speed to be 32.67g/min, controlling the temperature of the reaction liquid to be 4 ℃ in the dropwise adding process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at 3 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained bulk pharmaceutical chemical D90 of the carboglutamic acid is 341.6 mu m.
Therefore, the particle size of the D90 of the bulk pharmaceutical chemical of the kaglutamic acid obtained by the method is better controlled.
Experiment group 2
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 9:1) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to 150 revolutions per minute, dripping the prepared 1M dilute hydrochloric acid into the reaction kettle at the dripping speed of 65.33g/min, controlling the temperature of the reaction liquid to be 0 ℃ in the dripping process, adjusting the pH value of the reaction liquid to 1.5, stopping stirring, and standing at the temperature of 0 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 398.7 mu m.
Therefore, the particle size of the D90 of the bulk pharmaceutical chemical of the kaglutamic acid obtained by the method is better controlled.
Experiment group 3
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 1:1) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 50 revolutions per minute, dripping the prepared 1M dilute hydrochloric acid into the reaction kettle, controlling the dripping speed to be 10.89g/min, controlling the temperature of the reaction liquid to 8 ℃ in the dripping process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at the temperature of 5 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 304.3 mu m.
Therefore, the particle size of the D90 of the bulk pharmaceutical chemical of the kaglutamic acid obtained by the method is better controlled.
Experiment group 4
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 4:1) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 180 revolutions per minute, dropwise adding 1M dilute hydrochloric acid into the reaction kettle, controlling the dropwise adding speed to be 32.67g/min, controlling the temperature of the reaction liquid to be 4 ℃ in the dropwise adding process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at 3 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 216.8 mu m.
From this, it is found that the stirring speed affects the particle size of the final product, and if the stirring speed is too high, the stirring speed meets the requirement that the drug substance D90 be 200 to 600. Mu.m, but the particle size is low.
Experiment group 5
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water was added to a 1000L decolorizing kettle, stirring was started, and the resulting ammonium salt of carboglutamic acid and crude carboglutamic acid (molar ratio of ammonium salt of carboglutamic acid to crude carboglutamic acid 4:1) were added to the reaction kettle and stirred until the solids were completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 100 revolutions per minute, dropwise adding 1M dilute hydrochloric acid into the reaction kettle, controlling the dropwise adding speed to be 80g/min, controlling the temperature of the reaction liquid to be 4 ℃ in the dropwise adding process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at 3 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 556.7 mu m.
From this, it can be seen that the dropping speed of the diluted hydrochloric acid affects the particle size of the final product, and if the dropping speed is too high, the particle size is too high although it meets the requirement that the drug substance D90 is 200 to 600. Mu.m.
Experiment group 6
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 45:55) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 100 revolutions per minute, dropwise adding 1M dilute hydrochloric acid into the reaction kettle, controlling the dropwise adding speed to be 32.67g/min, controlling the temperature of the reaction liquid to be 4 ℃ in the dropwise adding process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at 3 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 659.7 mu m.
From this, it can be seen that the molar ratio of ammonium salt of kavallutamic acid to crude kavalamic acid affects the final drug substance D90 particle size. When the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is low, the particle size of the carboglutamic acid bulk drug D90 is too high.
Experiment group 7
Preparing a bulk pharmaceutical chemical product of the carboglutamic acid:
160kg of purified water is added into a 1000L decoloring kettle, stirring is started, and the obtained ammonium salt of the carboglutamic acid and a crude product of the carboglutamic acid (the molar ratio of the ammonium salt of the carboglutamic acid to the crude product of the carboglutamic acid is 4:1) are added into a reaction kettle, and stirring is carried out until the solid is completely dissolved. After dissolving, adding active carbon, decolorizing at 25deg.C for 25min, and filtering. Transferring the filtrate into a 1000L crystallization kettle, stirring, controlling the stirring rotation speed to be 100 revolutions per minute, dropwise adding 1M dilute hydrochloric acid into the reaction kettle, controlling the dropwise adding speed to be 32.67g/min, controlling the temperature of the reaction liquid to be 10 ℃ during the dropwise adding process, adjusting the pH value of the reaction liquid to be 1.5, stopping stirring, and standing at 3 ℃ for crystallization for 22 hours. And after crystallization, centrifuging to obtain a wet product of the glutamic acid.
Transferring the wet product of the carglutamic acid into a turnover barrel, adding absolute ethyl alcohol (the mass of the absolute ethyl alcohol is 1.19 times of that of the wet product of the carglutamic acid), carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, adding absolute ethyl alcohol with the mass of 1.19 times of that of the filter cake into the obtained filter cake, carrying out slurry washing at the temperature of 0 ℃ for about 2 hours under ice bath, properly stirring, centrifuging, and carrying out forced air drying at the temperature of 38 ℃ for 11 hours. The particle size of the obtained kaglutamic acid product is 177.8 mu m.
From this, it can be seen that the temperature of the reaction liquid during the process of adding dilute hydrochloric acid dropwise affects the particle size of the product, and if the temperature of the reaction liquid is too low, the particle size of the drug substance D90 is too low.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. A method for preparing a bulk drug of kaglutamic acid with a D90 particle size of 200-600 μm, which is characterized by comprising the following steps:
mixing ammonium salt of the carboglutamic acid, crude product of the carboglutamic acid with acid liquor, crystallizing, collecting and washing crystals to obtain the carboglutamic acid bulk drug,
based on the total molar weight of the ammonium salt of the carboglutamic acid and the crude carboglutamic acid, the molar ratio of the ammonium salt of the carboglutamic acid to the crude carboglutamic acid is 1-9: 1.
2. the method of claim 1, wherein the mixing comprises:
and (3) dissolving the ammonium salt of the carboglutamic acid and the crude product of the carboglutamic acid in water, stirring, dripping acid liquor into the mixed liquor while stirring, stopping stirring when the reaction liquor reaches a preset pH value, and crystallizing.
3. The method according to claim 2, wherein the temperature of the reaction solution is controlled to be 0-8 ℃ during the dropping.
4. The method according to claim 2, characterized in that the dropping speed of the acid solution is 10-80 g/min, preferably 10-66 g/min;
optionally, the rotational speed of the stirring is controlled to be 50 to 180 rpm, preferably 50 to 150 rpm.
5. A bulk pharmaceutical chemical of kaglutamic acid, characterized in that it is prepared by the method of any one of claims 1 to 4.
6. A solid preparation of kaglutamic acid, comprising: bulk drugs of stuck glutamic acid and auxiliary materials;
the D90 particle size of the bulk pharmaceutical chemical of the kaglutamic acid is 200-600 mu m;
the auxiliary material comprises microcrystalline cellulose, wherein the microcrystalline cellulose comprises first microcrystalline cellulose and second microcrystalline cellulose;
the angle of repose of the first microcrystalline cellulose is 55 degrees or more and the angle of repose of the second microcrystalline cellulose is 46 degrees or less; or the first microcrystalline cellulose is of a type selected from at least one of PH-F20JP and KG 1000; and the second microcrystalline cellulose is of a type selected from at least one of pH101, pH102, pH112, pH200, pH301, pH302, UF701, and UF 702.
7. The solid preparation of kaglutamic acid according to claim 6, wherein the raw material of kaglutamic acid is prepared by the method for preparing raw material of kaglutamic acid with D90 particle size of 200-600 μm according to any one of claims 1-4.
8. The solid preparation of kaglutamic acid according to claim 6, wherein the auxiliary material further comprises at least one of a disintegrant, a binder, a wetting agent, and a glidant;
optionally, the disintegrant is selected from at least one of croscarmellose sodium, calcium carboxymethylcellulose, crospovidone, and sodium carboxymethyl starch;
The binder is at least one selected from hypromellose, povidone, hydroxypropyl cellulose and sodium carboxymethyl cellulose;
the wetting agent is at least one of sodium dodecyl sulfate and sodium stearyl fumarate;
the glidant is at least one selected from silicon dioxide and talcum powder.
9. The solid preparation of kaglutamic acid according to claim 6, wherein the solid preparation of kaglutamic acid comprises, based on the total mass of the solid preparation of kaglutamic acid:
30-50 mass% of a bulk pharmaceutical chemical of kaglutamic acid; and
the balance of auxiliary materials;
preferably, the solid preparation of kaglutamic acid comprises:
30-50 parts by weight of a bulk pharmaceutical chemical of kaglutamic acid;
50-55 parts by weight of microcrystalline cellulose;
2-4 parts by weight of croscarmellose sodium;
1-4 parts by weight of hypromellose;
0.4 to 0.8 weight portion of sodium dodecyl sulfate;
0.2 to 0.6 part by weight of silica; and
0.1 to 2 parts by weight of sodium stearyl fumarate.
10. The solid preparation of kaglutamic acid according to claim 6, wherein the solid preparation of kaglutamic acid is in the form of a tablet, wherein the surface of the tablet is provided with scores, preferably three scores in parallel on the front and back sides;
Optionally, when the tablet is broken into 1/4 pieces along the score, the weight difference limit of 1/4 pieces is ±5%, no more than 2 pieces exceeding the weight difference limit, and no more than 1 piece exceeds the limit by 1 time.
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| US10064826B2 (en) * | 2013-03-15 | 2018-09-04 | Navinta, Llc | Direct compression and dry granulation processes for preparing carglumic acid tablets having less impurities than those produced by wet granulation process |
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| CN105056246A (en) * | 2015-08-18 | 2015-11-18 | 武汉武药科技有限公司 | Carglumic acid solid composition and preparation method thereof |
| EP3445337B1 (en) * | 2016-04-22 | 2021-03-24 | University Of Mississippi | Twin-screw dry granulation for producing solid formulations |
| CN108017561B (en) * | 2016-11-04 | 2021-03-30 | 武汉武药科技有限公司 | Method for refining carglutamic acid |
| CN110403911B (en) * | 2018-04-26 | 2021-11-26 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| CN111419815B (en) * | 2020-04-23 | 2022-03-11 | 永信药品工业（昆山）股份有限公司 | Etoricoxib tablet and optimization method thereof |
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2020
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| CN114522147B (en) | 2023-08-04 |
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