CN113230220A - Preparation method of pregabalin - Google Patents
Preparation method of pregabalin Download PDFInfo
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- CN113230220A CN113230220A CN202110580180.5A CN202110580180A CN113230220A CN 113230220 A CN113230220 A CN 113230220A CN 202110580180 A CN202110580180 A CN 202110580180A CN 113230220 A CN113230220 A CN 113230220A
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- pregabalin
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- microcrystalline cellulose
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 46
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 52
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 40
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 39
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 39
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 39
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 39
- 239000000843 powder Substances 0.000 claims abstract description 37
- 238000002156 mixing Methods 0.000 claims abstract description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 22
- 235000010355 mannitol Nutrition 0.000 claims abstract description 22
- 238000005469 granulation Methods 0.000 claims abstract description 21
- 230000003179 granulation Effects 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 235000011121 sodium hydroxide Nutrition 0.000 claims abstract description 20
- 239000011812 mixed powder Substances 0.000 claims abstract description 12
- 239000004376 Sucralose Substances 0.000 claims abstract description 11
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims abstract description 11
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims abstract description 11
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 11
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 11
- 235000013599 spices Nutrition 0.000 claims abstract description 11
- 235000019408 sucralose Nutrition 0.000 claims abstract description 11
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims abstract description 11
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 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 abstract description 10
- 229940085605 saccharin sodium Drugs 0.000 claims abstract description 10
- 239000008187 granular material Substances 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 30
- 238000012216 screening Methods 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 235000010980 cellulose Nutrition 0.000 claims description 15
- 229920002678 cellulose Polymers 0.000 claims description 15
- 239000001913 cellulose Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 15
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 13
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 239000004202 carbamide Substances 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000011148 porous material Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 238000003828 vacuum filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims 1
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 108090000312 Calcium Channels Proteins 0.000 description 2
- 102000003922 Calcium Channels Human genes 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 208000028329 epileptic seizure Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005381 potential energy Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
- C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Polymers & Plastics (AREA)
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Abstract
The invention discloses a preparation method of pregabalin, which comprises the following steps: step one, granulation: granulating screened products of pregabalin, D-mannitol, hardened oil, a glycerol monostearate screen and talcum powder to obtain granular powder; step two, granule finishing: combining the undersize into a granular powder; step three, mixing: mixing granular powder, D-mannitol, modified microcrystalline cellulose, crotonone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice, adding sodium stearyl fumarate and magnesium stearate, and continuously mixing to obtain mixed powder; step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness of the sample tablet is controlled to be 10-37N.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of pregabalin.
Background
Pregabalin belongs to non-gamma-aminobutyric acid (GABA) receptor agonists or antagonists, is a novel calcium ion channel regulator, and can block voltage-dependent calcium channels and reduce the release of neurotransmitters. The preparation method is mainly used for treating neuralgia related to diabetic peripheral neuropathy, postherpetic neuralgia and adjuvant therapy of adult partial epileptic seizure, generalized anxiety disorder, central neuralgia (including neuralgia accompanied by spinal cord injury, apoplexy and multiple sclerosis) and fibromyalgia, and the preparation process of the pregabalin preparation has the following difficulties: (1) primary amino and carboxyl exist in pregabalin molecules, so that intramolecular condensation is easy to occur to generate lactam, and the moist heat effect and filler auxiliary materials can accelerate the pregabalin to generate intramolecular cyclization to generate lactam impurities; (2) the pregabalin raw material is crystalline powder particles, has poor compressibility and flowability, and cannot meet the requirements of conventional powder direct compression or dry granulation. Thus, improving stability, compressibility and flowability are difficulties in preparing pregabalin formulations.
Orally disintegrating tablets are tablets which can be swallowed to achieve the effect in the stomach by means of swallowing after the tablets are placed on the tongue surface and rapidly dissolved or disintegrated in saliva without water or a small amount of water or chewing. Compared with the common tablet, the orally disintegrating tablet has the advantages of quick response, high bioavailability, convenient taking, low first-pass effect and the like, and is more suitable for the old, children and patients in special environments with dysphagia or inconvenient drinking and the like.
Disclosure of Invention
The invention provides a preparation method of pregabalin.
The technical problems to be solved by the invention are as follows:
compared with the common tablet, the orally disintegrating tablet is a tablet which does not need water or a small amount of water, does not need to be chewed, is placed on the surface of the tongue, is quickly dissolved or disintegrated in saliva and can enter the stomach to take effect by virtue of swallowing power. The pregabalin raw material is crystalline powder particles, has poor compressibility and flowability, and cannot meet the requirements of conventional powder direct compression or dry granulation.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of pregabalin comprises the following steps:
step one, granulation: feeding the screened product of pregabalin, D-mannitol, hardened oil, a glycerol monostearate sieve and talcum powder into a fluidized bed granulation dryer ((220L), granulating at the air supply temperature of 90 ℃, and cooling to room temperature to obtain granular powder;
step two, granule finishing: putting the granular powder generated in the granulation process into a classifier, and classifying, wherein the size of a screen is 1 mm; putting the rest part on the sieve into a granulator, crushing the rest part with the sieve pore size of 1mm, and combining the sieved parts into granular powder;
step three, mixing: putting the granular powder generated in the granulation process, D-mannitol, modified microcrystalline cellulose, crotonalone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice into a container rotary mixer (300L) to mix for 15min, and then adding sodium stearyl fumarate and magnesium stearate to mix for 3min to obtain mixed powder;
step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness of the sample tablet is controlled to be 10-37N.
Further, in the first step, the dosage mass ratio of the screened product of pregabalin, D-mannitol, hardened oil, the glycerol monostearate screen to the talcum powder is 31-32: 15.1-15.3: 1.5-1.6: 3-3.1: 0.6.
further, in the third step, the dosage mass ratio of the granular powder, the D-mannitol, the modified microcrystalline cellulose, the crotonalone, the magnesium aluminum metasilicate, the saccharin sodium hydrate, the sucralose and the spice is 41-42: 34-34.3: 5: 5: 2: 0.12-0.13: 0.7-0.8: 0.1; the dosage mass ratio of the granular powder, the sodium stearyl fumarate and the magnesium stearate is 41-42: 1.5-2: 0.24-0.3.
Further, the pregabalin screening product is obtained by putting pregabalin into a classifier, and screening out a sieve with the size of 1mm to obtain the pregabalin screening product; screening the glyceryl monostearate: putting the glyceryl monostearate into a classifier, and screening to obtain a glyceryl monostearate screening product with the mesh size of 1 mm; the prepared sample piece was immersed in water, and when the pressure was reduced to-66.65 kPa or less, no bubbles were observed.
Further, the modified microcrystalline cellulose is prepared by the steps of:
step S11, adding epoxy chloropropane and isopropanol into a reaction kettle, then adding dodecylamine, setting the temperature at 60 ℃ and the rotating speed at 300r/min, stirring for reacting for 2 hours, transferring the obtained reaction liquid into a rotary evaporator after the reaction is finished, removing redundant epoxy chloropropane and isopropanol by rotary evaporation, then adding acetone for recrystallization, finally washing with anhydrous ether, and drying to obtain an intermediate 1;
step S12, adding sodium hydroxide and urea into deionized water at the temperature of 0 ℃ for mixing, adding microcrystalline cellulose after mixing, keeping the temperature at-12 ℃ for 2min, then heating to room temperature, stirring for 20-30min to obtain a cellulose solution, and storing at the temperature of 0-5 ℃;
and step S13, adding the intermediate 1 into a cellulose solution, stirring and reacting for 24 hours at the temperature of 25 ℃ and the rotating speed of 300r/min, after the reaction is finished, carrying out vacuum filtration on the obtained reaction liquid, and drying the obtained filter cake to constant weight at the temperature of 25 ℃ to obtain the modified microcrystalline cellulose.
Further, in step S11, the molar ratio of the epichlorohydrin to the dodecylamine is 2.5: 1; the using ratio of the epichlorohydrin to the isopropanol is 1 g: 10-15 mL; in the step S12, the dosage ratio of the sodium hydroxide, the urea, the deionized water and the microcrystalline cellulose is 7 g: 12 g: 100mL of: 1-3 g; the dosage ratio of the intermediate 1 to the cellulose solution in the step S13 is 1 g: 3-4 mL.
The invention has the beneficial effects that:
according to the invention, epichlorohydrin and dodecylamine react to prepare an intermediate 1, the intermediate 1 contains a quaternary ammonium salt structure, chlorine and hydroxyl on the intermediate 1 generate an epoxy structure under an alkaline condition, then microcrystalline cellulose is added to increase the charge density of the surface of the intermediate, the microcrystalline cellulose contains a large amount of hydroxyl, so that the microcrystalline cellulose has strong hydrophilicity, the dispersibility of the microcrystalline cellulose in an organic solvent and the compatibility of a nonpolar matrix are limited, positive ions are easily introduced into the surface of the microcrystalline cellulose, the charge density of the microcrystalline cellulose is increased, the microcrystalline cellulose has good dispersibility and stability, the surface potential energy of the microcrystalline cellulose can be coordinated, the compatibility with other substances is improved, and the stability is further improved.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Step one, granulation: feeding the screened product of pregabalin, D-mannitol, hardened oil, a glycerol monostearate sieve and talcum powder into a fluidized bed granulation dryer ((220L), granulating at the air supply temperature of 90 ℃, and cooling to room temperature to obtain granular powder;
step two, granule finishing: putting the granular powder generated in the granulation process into a classifier, and classifying, wherein the size of a screen is 1 mm; putting the rest part on the sieve into a granulator, crushing the rest part with the sieve pore size of 1mm, and combining the sieved parts into granular powder;
step three, mixing: putting the granular powder generated in the granulation process, D-mannitol, modified microcrystalline cellulose, crotonalone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice into a container rotary mixer (300L) to mix for 15min, and then adding sodium stearyl fumarate and magnesium stearate to mix for 3min to obtain mixed powder;
step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness is 10N.
Wherein in the first step, the dosage mass ratio of the screened product of pregabalin, D-mannitol, hardened oil, the glycerol monostearate screen to the talcum powder is 31: 15.1: 1.5: 3: 0.6.
wherein in the third step, the dosage mass ratio of the granular powder, the D-mannitol, the modified microcrystalline cellulose, the crotonalone, the magnesium aluminum metasilicate, the saccharin sodium hydrate, the sucralose and the spice is 41: 34: 5: 5: 2: 0.12: 0.7: 0.1; the dosage mass ratio of the granular powder, the sodium stearyl fumarate and the magnesium stearate is 41: 1.5: 0.24.
the screening product of the pregabalin is obtained by putting the pregabalin into a classifier, and screening out a sieve with the size of 1mm to obtain the screened product of the pregabalin; screening the glyceryl monostearate: putting the glyceryl monostearate into a classifier, and screening to obtain a glyceryl monostearate screening product with the mesh size of 1 mm; the prepared sample piece was immersed in water, and when the pressure was reduced to-66.65 kPa or less, no bubbles were observed.
Wherein the modified microcrystalline cellulose is prepared by the following steps:
step S11, adding epoxy chloropropane and isopropanol into a reaction kettle, then adding dodecylamine, setting the temperature at 60 ℃ and the rotating speed at 300r/min, stirring for reacting for 2 hours, transferring the obtained reaction liquid into a rotary evaporator after the reaction is finished, removing redundant epoxy chloropropane and isopropanol by rotary evaporation, then adding acetone for recrystallization, finally washing with anhydrous ether, and drying to obtain an intermediate 1;
step S12, adding sodium hydroxide and urea into deionized water at the temperature of 0 ℃ for mixing, adding microcrystalline cellulose after mixing, keeping the temperature at-12 ℃ for 2min, then heating to room temperature, stirring for 20min to obtain a cellulose solution, and storing at the temperature of 0 ℃;
and step S13, adding the intermediate 1 into a cellulose solution, stirring and reacting for 24 hours at the temperature of 25 ℃ and the rotating speed of 300r/min, after the reaction is finished, carrying out vacuum filtration on the obtained reaction liquid, and drying the obtained filter cake to constant weight at the temperature of 25 ℃ to obtain the modified microcrystalline cellulose.
Wherein, the molar ratio of the epoxy chloropropane to the dodecylamine used in the step S11 is 2.5: 1; the using ratio of the epichlorohydrin to the isopropanol is 1 g: 10 mL; in the step S12, the dosage ratio of the sodium hydroxide, the urea, the deionized water and the microcrystalline cellulose is 7 g: 12 g: 100mL of: 1g of a compound; the dosage ratio of the intermediate 1 to the cellulose solution in the step S13 is 1 g: 3 mL.
Example 2
Step one, granulation: feeding the screened product of pregabalin, D-mannitol, hardened oil, a glycerol monostearate sieve and talcum powder into a fluidized bed granulation dryer ((220L), granulating at the air supply temperature of 90 ℃, and cooling to room temperature to obtain granular powder;
step two, granule finishing: putting the granular powder generated in the granulation process into a classifier, and classifying, wherein the size of a screen is 1 mm; putting the rest part on the sieve into a granulator, crushing the rest part with the sieve pore size of 1mm, and combining the sieved parts into granular powder;
step three, mixing: putting the granular powder generated in the granulation process, D-mannitol, modified microcrystalline cellulose, crotonalone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice into a container rotary mixer (300L) to mix for 15min, and then adding sodium stearyl fumarate and magnesium stearate to mix for 3min to obtain mixed powder;
step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness is controlled to be 20N.
Wherein in the first step, the dosage mass ratio of the screened product of pregabalin, D-mannitol, hardened oil, the glycerol monostearate screen to the talcum powder is 31: 15.2: 1.5: 3: 0.6.
wherein in the third step, the dosage mass ratio of the granular powder, the D-mannitol, the modified microcrystalline cellulose, the crotonalone, the magnesium aluminum metasilicate, the saccharin sodium hydrate, the sucralose and the spice is 41: 34.2: 5: 5: 2: 0.12: 0.7: 0.1; the dosage mass ratio of the granular powder, the sodium stearyl fumarate and the magnesium stearate is 41: 1.8: 0.26.
the screening product of the pregabalin is obtained by putting the pregabalin into a classifier, and screening out a sieve with the size of 1mm to obtain the screened product of the pregabalin; screening the glyceryl monostearate: putting the glyceryl monostearate into a classifier, and screening to obtain a glyceryl monostearate screening product with the mesh size of 1 mm; the prepared sample piece was immersed in water, and when the pressure was reduced to-66.65 kPa or less, no bubbles were observed.
Wherein the modified microcrystalline cellulose is prepared by the following steps:
step S11, adding epoxy chloropropane and isopropanol into a reaction kettle, then adding dodecylamine, setting the temperature at 60 ℃ and the rotating speed at 300r/min, stirring for reacting for 2 hours, transferring the obtained reaction liquid into a rotary evaporator after the reaction is finished, removing redundant epoxy chloropropane and isopropanol by rotary evaporation, then adding acetone for recrystallization, finally washing with anhydrous ether, and drying to obtain an intermediate 1;
step S12, adding sodium hydroxide and urea into deionized water at the temperature of 0 ℃ for mixing, adding microcrystalline cellulose after mixing, keeping the temperature at-12 ℃ for 2min, then heating to room temperature, stirring for 25min to obtain a cellulose solution, and storing at 5 ℃;
and step S13, adding the intermediate 1 into a cellulose solution, stirring and reacting for 24 hours at the temperature of 25 ℃ and the rotating speed of 300r/min, after the reaction is finished, carrying out vacuum filtration on the obtained reaction liquid, and drying the obtained filter cake to constant weight at the temperature of 25 ℃ to obtain the modified microcrystalline cellulose.
Wherein, the molar ratio of the epoxy chloropropane to the dodecylamine used in the step S11 is 2.5: 1; the using ratio of the epichlorohydrin to the isopropanol is 1 g: 12 mL; in the step S12, the dosage ratio of the sodium hydroxide, the urea, the deionized water and the microcrystalline cellulose is 7 g: 12 g: 100mL of: 2g of the total weight of the mixture; the dosage ratio of the intermediate 1 to the cellulose solution in the step S13 is 1 g: 3.5 mL.
Example 3
Step one, granulation: feeding the screened product of pregabalin, D-mannitol, hardened oil, a glycerol monostearate sieve and talcum powder into a fluidized bed granulation dryer ((220L), granulating at the air supply temperature of 90 ℃, and cooling to room temperature to obtain granular powder;
step two, granule finishing: putting the granular powder generated in the granulation process into a classifier, and classifying, wherein the size of a screen is 1 mm; putting the rest part on the sieve into a granulator, crushing the rest part with the sieve pore size of 1mm, and combining the sieved parts into granular powder;
step three, mixing: putting the granular powder generated in the granulation process, D-mannitol, modified microcrystalline cellulose, crotonalone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice into a container rotary mixer (300L) to mix for 15min, and then adding sodium stearyl fumarate and magnesium stearate to mix for 3min to obtain mixed powder;
step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness is controlled to be 37N.
Wherein in the first step, the dosage mass ratio of the screened product of pregabalin, D-mannitol, hardened oil, the glycerol monostearate screen to the talcum powder is 32: 15.3: 1.6: 3.1: 0.6.
wherein in the third step, the dosage mass ratio of the granular powder, the D-mannitol, the modified microcrystalline cellulose, the crotonalone, the magnesium aluminum metasilicate, the saccharin sodium hydrate, the sucralose and the spice is 42: 34.3: 5: 5: 2: 0.13: 0.8: 0.1; the dosage mass ratio of the granular powder, the sodium stearyl fumarate and the magnesium stearate is 42: 2: 0.3.
the screening product of the pregabalin is obtained by putting the pregabalin into a classifier, and screening out a sieve with the size of 1mm to obtain the screened product of the pregabalin; screening the glyceryl monostearate: putting the glyceryl monostearate into a classifier, and screening to obtain a glyceryl monostearate screening product with the mesh size of 1 mm; the prepared sample piece was immersed in water, and when the pressure was reduced to-66.65 kPa or less, no bubbles were observed.
Wherein the modified microcrystalline cellulose is prepared by the following steps:
step S11, adding epoxy chloropropane and isopropanol into a reaction kettle, then adding dodecylamine, setting the temperature at 60 ℃ and the rotating speed at 300r/min, stirring for reacting for 2 hours, transferring the obtained reaction liquid into a rotary evaporator after the reaction is finished, removing redundant epoxy chloropropane and isopropanol by rotary evaporation, then adding acetone for recrystallization, finally washing with anhydrous ether, and drying to obtain an intermediate 1;
step S12, adding sodium hydroxide and urea into deionized water at the temperature of 0 ℃ for mixing, adding microcrystalline cellulose after mixing, keeping the temperature at-12 ℃ for 2min, then heating to room temperature, stirring for 30min to obtain a cellulose solution, and storing at 5 ℃;
and step S13, adding the intermediate 1 into a cellulose solution, stirring and reacting for 24 hours at the temperature of 25 ℃ and the rotating speed of 300r/min, after the reaction is finished, carrying out vacuum filtration on the obtained reaction liquid, and drying the obtained filter cake to constant weight at the temperature of 25 ℃ to obtain the modified microcrystalline cellulose.
Wherein, the molar ratio of the epoxy chloropropane to the dodecylamine used in the step S11 is 2.5: 1; the using ratio of the epichlorohydrin to the isopropanol is 1 g: 15 mL; in the step S12, the dosage ratio of the sodium hydroxide, the urea, the deionized water and the microcrystalline cellulose is 7 g: 12 g: 100mL of: 3g of the total weight of the mixture; the dosage ratio of the intermediate 1 to the cellulose solution in the step S13 is 1 g: 4 mL.
Comparative example 1
The comparative example is a common pregabalin orally disintegrating tablet on the market.
The test pieces of examples 1 to 3 were tested to disintegrate in 900mL water at 22 ℃ for 24s and 100mL water at 20 ℃ for 75s (6 pieces), and were in compliance with the standards; the stability tests were carried out on the coupons prepared in examples 1-3 and comparative example 1: storing for 1 month at 40 deg.C and 75% relative humidity, and storing; disintegration times(s) were tested in 900mL water at 20 ℃. The test results are shown in table 1 below:
TABLE 1
| Categories | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Initial | 22 | 22 | 22 | 26 |
| 40℃、75％RH | 24 | 24 | 24 | 30 |
From the above table 1, it can be seen that the sample wafer of the present invention has good stability and better application prospect.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean 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 invention. In this specification, the schematic representations of the terms used above do not necessarily refer 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.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.
Claims (6)
1. A preparation method of pregabalin is characterized by comprising the following steps:
step one, granulation: feeding the screened product of pregabalin, D-mannitol, hardened oil, a glycerol monostearate sieve and talcum powder into a fluidized bed granulation dryer, granulating at the air supply temperature of 90 ℃, and cooling to room temperature to obtain granular powder;
step two, granule finishing: putting the granular powder generated in the granulation process into a classifier, and classifying, wherein the size of a screen is 1 mm; putting the rest part on the sieve into a granulator, crushing the rest part with the sieve pore size of 1mm, and combining the sieved parts into granular powder;
step three, mixing: putting the granular powder generated in the granulation process, D-mannitol, modified microcrystalline cellulose, crotonyl ketone, magnesium aluminum metasilicate, saccharin sodium hydrate, sucralose and spice into a container rotary mixer, mixing for 15min, and then adding sodium stearyl fumarate and magnesium stearate, and mixing for 3min to obtain mixed powder;
step four, tabletting: and tabletting the mixed powder generated in the mixing process with a 6.0mm phi pestle by using a rotary tablet machine to prepare a sample tablet, wherein the average mass of the sample tablet is controlled to be 80 +/-2 mg, the thickness of the sample tablet is controlled to be 3 +/-0.2 mm, and the hardness of the sample tablet is controlled to be 10-37N.
2. The method for preparing pregabalin according to claim 1, wherein the amount by mass ratio of the pregabalin screening product, the D-mannitol, the hardened oil, the glycerol monostearate screening and the talc in the first step is 31-32: 15.1-15.3: 1.5-1.6: 3-3.1: 0.6.
3. the method for preparing pregabalin according to claim 1, wherein in the third step, the dosage mass ratio of the granular powder, the D-mannitol, the modified microcrystalline cellulose, the crotonalone, the magnesium aluminum metasilicate, the sodium saccharin hydrate, the sucralose and the spice is 41-42: 34-34.3: 5: 5: 2: 0.12-0.13: 0.7-0.8: 0.1; the dosage mass ratio of the granular powder, the sodium stearyl fumarate and the magnesium stearate is 41-42: 1.5-2: 0.24-0.3.
4. The method for preparing pregabalin according to claim 1, wherein the pregabalin screening product is obtained by placing pregabalin into a classifier, and screening the pregabalin with a sieve mesh size of 1 mm; screening the glyceryl monostearate: putting the glyceryl monostearate into a classifier, and screening to obtain a glyceryl monostearate screening product with the mesh size of 1 mm.
5. The method for preparing pregabalin of claim 1, wherein the modified microcrystalline cellulose is prepared by the following steps:
step S11, adding epoxy chloropropane and isopropanol into a reaction kettle, then adding dodecylamine, setting the temperature at 60 ℃ and the rotating speed at 300r/min, stirring for reacting for 2 hours, transferring the obtained reaction liquid into a rotary evaporator after the reaction is finished, removing redundant epoxy chloropropane and isopropanol by rotary evaporation, then adding acetone for recrystallization, finally washing with anhydrous ether, and drying to obtain an intermediate 1;
step S12, adding sodium hydroxide and urea into deionized water at the temperature of 0 ℃ for mixing, adding microcrystalline cellulose after mixing, keeping the temperature at-12 ℃ for 2min, then heating to room temperature, stirring for 20-30min to obtain a cellulose solution, and storing at the temperature of 0-5 ℃;
and step S13, adding the intermediate 1 into a cellulose solution, stirring and reacting for 24 hours at the temperature of 25 ℃ and the rotating speed of 300r/min, after the reaction is finished, carrying out vacuum filtration on the obtained reaction liquid, and drying the obtained filter cake to constant weight at the temperature of 25 ℃ to obtain the modified microcrystalline cellulose.
6. The method for preparing pregabalin of claim 5, wherein the epichlorohydrin and the dodecylamine are used in a molar ratio of 2.5 in step S11: 1; the using ratio of the epichlorohydrin to the isopropanol is 1 g: 10-15 mL; in the step S12, the dosage ratio of the sodium hydroxide, the urea, the deionized water and the microcrystalline cellulose is 7 g: 12 g: 100mL of: 1-3 g; the dosage ratio of the intermediate 1 to the cellulose solution in the step S13 is 1 g: 3-4 mL.
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