CN100567252C - Fenfluramine hydrochloride crude drug and tablet and preparation method thereof - Google Patents
Fenfluramine hydrochloride crude drug and tablet and preparation method thereof Download PDFInfo
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- CN100567252C CN100567252C CNB2004100670457A CN200410067045A CN100567252C CN 100567252 C CN100567252 C CN 100567252C CN B2004100670457 A CNB2004100670457 A CN B2004100670457A CN 200410067045 A CN200410067045 A CN 200410067045A CN 100567252 C CN100567252 C CN 100567252C
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- fenfluramine hydrochloride
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- fenfluramine
- starch
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- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960001877 fenfluramine hydrochloride Drugs 0.000 title claims abstract description 56
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 9
- 238000005516 engineering process Methods 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 238000007670 refining Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 229920002472 Starch Polymers 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000008107 starch Substances 0.000 claims description 16
- 235000019698 starch Nutrition 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 14
- 206010013786 Dry skin Diseases 0.000 claims description 12
- 229960004756 ethanol Drugs 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 9
- 235000000346 sugar Nutrition 0.000 claims description 9
- 229920001353 Dextrin Polymers 0.000 claims description 8
- 239000004375 Dextrin Substances 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 235000019425 dextrin Nutrition 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 239000012452 mother liquor Substances 0.000 claims description 8
- 239000002002 slurry Substances 0.000 claims description 8
- 238000010561 standard procedure Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- 235000008331 Pinus X rigitaeda Nutrition 0.000 claims description 4
- 235000011613 Pinus brutia Nutrition 0.000 claims description 4
- 241000018646 Pinus brutia Species 0.000 claims description 4
- 238000005267 amalgamation Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 210000003298 dental enamel Anatomy 0.000 claims description 4
- 230000000994 depressogenic effect Effects 0.000 claims description 4
- 238000007599 discharging Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 230000002349 favourable effect Effects 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000005259 measurement Methods 0.000 claims description 4
- 238000000643 oven drying Methods 0.000 claims description 4
- 238000010298 pulverizing process Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 239000011122 softwood Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 229910001220 stainless steel Inorganic materials 0.000 claims description 4
- 239000010935 stainless steel Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 235000020985 whole grains Nutrition 0.000 claims description 4
- 230000003068 static effect Effects 0.000 claims description 3
- 238000005382 thermal cycling Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims 2
- 208000008589 Obesity Diseases 0.000 abstract description 18
- 235000020824 obesity Nutrition 0.000 abstract description 18
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 238000009825 accumulation Methods 0.000 abstract description 3
- 230000001737 promoting effect Effects 0.000 abstract description 3
- 239000002775 capsule Substances 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002674 ointment Substances 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of raw material and medicinal preparation for oral administration for the treatment of simple obesity, by salt-forming reaction, refining, dry, pulverize, always mix, technology such as compressing tablet makes.Be a kind of absorption that can reduce fat, synthetic and cross blubbery accumulation, fat-splitting around promoting, the fenfluramine hydrochloride bulk drug and the tablet of treatment simple obesity.The preparation technology of fenfluramine hydrochloride bulk drug of the present invention is reasonable, simple and practical, safe and effective, the finished product stable in properties, be easy to detect.Except being applied to tablet, also can be widely used in the treatment simple obesity medicine production of multiple formulations such as capsule, granule, oral preparation and ointment.
Description
The present invention relates to a kind of raw material and medicinal preparation for oral administration for the treatment of simple obesity, is a kind of absorption that can reduce fat, synthetic and cross blubbery accumulation, fat-splitting around promoting, the fenfluramine hydrochloride bulk drug and the tablet of treatment simple obesity.
Obesity is that body fat gathers too much, and when the feed heat surpasses consumption, unnecessary material is converted into fat, and fat can not be fully utilized, and is deposited on human body and respectively organizes subcutaneously, and it is too fat to move to form the figure, and body weight obviously increases.It is overweight that general body weight surpasses 10% of arm's length standard, surpasses the obesity that is called more than 20%.Obesity can be divided into simple obesity and Secondary Obesity.What this case was touched upon is simple obesity.
Not only the figure is too fat to move in fat performance, loses fitness, be slow in action simultaneously, physically-draining, easily soaked with sweat, out of puff, fatiguability, easily doze off symptoms such as hypomnesis.If can not in time treat, a series of serious diseases such as atherosclerosis, coronary heart disease, essential hypertension, cholelithiasis, diabetes, multiple bone joint disease, hyperuricemia often can occur together.
The reason of simple obesity is very complicated, and general and inherited genetic factors, physical factors and dietary factor have substantial connection.
Fat treatment to keep a diet, increases amount of exercise usually, and improving the fat utilization rate is main principle.
It is safely and effectively a kind of that purpose of the present invention will provide exactly, can treat the fenfluramine hydrochloride bulk drug and the tablet of simple obesity.
The present invention treats the fenfluramine hydrochloride bulk drug of simple obesity and the principal feature of tablet is:
1. this product can reduce the absorption of fat, and is synthetic and cross blubbery accumulation, the steatolysis around promoting.
2. this product can be quickened peripheral organization and to the picked-up of glucose blood sugar concentration reduced.
3. this product can be strengthened the effect of antihypertensive drug and hypoglycemic agents.
4. be applicable to the treatment simple obesity, and, share, can be used for treating diabetes with tolbutamide (D860) or glyburide with diabetes, coronary heart disease and hypertensive obesity patient.
The present invention treats the fenfluramine hydrochloride bulk drug and the tablet of simple obesity and realizes by following formula rate and preparation technology.
1. salt-forming reaction
Formula rate:
Phenfluoramine free alkali: hydrochloric acid: toluene=0.8～1.2: 0.48～0.72: 2.8～4.2
The Phenfluoramine free alkali is dropped in the 500L enamel reactor, start stirring, open about chuck water quench to 10 ℃, begin slowly dripping hydrochloric acid, regulate pH value to 2, temperature is controlled at below 30 ℃, continues to stir half an hour, make acidifying complete, the repetition measurement pH value is 2, is acidifying and finishes.Acidizing fluid is used the 60kg toluene wash respectively three times, separates out as solid is arranged in the still, promptly is warming up to about 50 ℃ to stir 10 minutes, static 20 minutes, makes layering complete.Washing finishes, and decompression is earlier steamed water to most, and temperature is controlled at below 95 ℃, cold slightly back adds 240kg toluene, and underpressure distillation band water is to most, and temperature is controlled at below 95 ℃, about allowance 300kg, be cooled to about 10 ℃, discharging, whizzer gets rid of filter to doing, advance oven drying, 50 ℃ of dryings of elder generation 4 hours, back 90 ℃ of dryings 4 hours get the fenfluramine hydrochloride crude product.
2. refining
Formula rate:
Crude product: ethanol: gac=0.8～1.2: 1.2～1.8: 0.04～0.06
Fenfluramine hydrochloride crude product, ethanol and gac are dropped in the 500L reactor, open steam heating backflow (about 78-82 ℃) 45 minutes, take advantage of a favourable situation to filter, filtrate is depressed in the crystallizing pan, opens the refrigerated water cooling, is cooled to 20 ℃ of crystallization temperature in the kettle, get rid of filter with whizzer, and divide 2 washings with dehydrated alcohol, dry, the wet product of fenfluramine hydrochloride.Mother liquor is recyclable.
To reclaim mother liquor with in the vacuum suction pot, and open vacuum earlier, water of condensation is opened in the restir heating, and kettle temperature is controlled at below 95 ℃.From the material (major ingredient ethanol) that the prolong cooling is reclaimed, can apply mechanically.After reclaiming end, a feed liquid is directly put into the 50L stainless steel cask in the pot, and the gap is stirred to crystallization, adds a cover and spends the night.Next day, smash pine, pour whizzer into and get rid of filter.The reclaimed materials charging feedstock bag that throws away, weighing, oven dry is the fenfluramine hydrochloride crude product.
3. dry
The wet product of fenfluramine hydrochloride are paved equably on drip pan, push Hotaircirculatingoven and carry out drying, press the operation of Hotaircirculatingoven Standard operation procedure SOP, temperature was controlled at 40-50 ℃ in preceding 4 hours, and temperature was controlled at 80-90 ℃ in back 4 hours, and dry total time is 8h.
4. pulverize
The fenfluramine hydrochloride that drying is good is put into crushiing chamber, carries out after the pulverizing always mixing.
5. total mixing
The fenfluramine hydrochloride that crushes is put into three-dimensional motion mixer carry out always mixing, always doing time is 1 hour, and total amalgamation is criticized about general 100kg.Total mixing finishes to pack.
6. compacting fenfluramine hydrochloride tablets
Formula rate:
Fenfluramine hydrochloride 16kg～24kg
Icing Sugar 16kg～24kg
Starch 40kg～60kg
Dextrin 8kg～12kg
Microcrystalline Cellulose 16kg～24kg
Starch (10% slurry is used) 3.36kg～5.04kg
Magnesium Stearate 1.2kg～1.8kg
Raw material fenfluramine hydrochloride, Icing Sugar, starch, dextrin, Microcrystalline Cellulose are mixed, cross 16 mesh sieves, make softwood with 10% starch slurry, granulate,, cross the whole grain of 16 mesh sieves in 60～70 ℃ of dryings, add Magnesium Stearate, be pressed into the fenfluramine hydrochloride tablets agent, every heavy 20mg.
For the formula rate and the technological process that further specify fenfluramine hydrochloride, embodiment is as follows:
1. salt-forming reaction
Formula rate:
Phenfluoramine free alkali: hydrochloric acid: toluene=1: 0.6: 3.5
The Phenfluoramine free alkali is dropped in the 500L enamel reactor, start stirring, open about chuck water quench to 10 ℃, begin slowly dripping hydrochloric acid, regulate pH value to 2, temperature is controlled at below 30 ℃, continues to stir half an hour, make acidifying complete, the repetition measurement pH value is 2, is acidifying and finishes.Acidizing fluid is used the 60kg toluene wash respectively three times, separates out as solid is arranged in the still, promptly is warming up to about 50 ℃ to stir 10 minutes, static 20 minutes, makes layering complete.Washing finishes, and decompression is earlier steamed water to most, and temperature is controlled at below 95 ℃, cold slightly back adds 240kg toluene, and underpressure distillation band water is to most, and temperature is controlled at below 95 ℃, about allowance 300kg, be cooled to about i0 ℃, discharging, whizzer gets rid of filter to doing, advance oven drying, 50 ℃ of dryings of elder generation 4 hours, back 90 ℃ of dryings 4 hours get the fenfluramine hydrochloride crude product.
2. refining
Formula rate:
Crude product: ethanol: gac=1: 1.5: 0.05
Fenfluramine hydrochloride crude product, ethanol and gac are dropped in the 500L reactor, open steam heating backflow (about 78-82 ℃) 45 minutes, take advantage of a favourable situation to filter, filtrate is depressed in the crystallizing pan, opens the refrigerated water cooling, is cooled to 20 ℃ of crystallization temperature in the kettle, get rid of filter with whizzer, and divide 2 washings with dehydrated alcohol, dry, the wet product of fenfluramine hydrochloride.Mother liquor is recyclable.
To reclaim mother liquor with in the vacuum suction pot, and open vacuum earlier, water of condensation is opened in the restir heating, and kettle temperature is controlled at below 95 ℃.From the material (major ingredient ethanol) that the prolong cooling is reclaimed, can apply mechanically.After reclaiming end, a feed liquid is directly put into the 50L stainless steel cask in the pot, and the gap is stirred to crystallization, adds a cover and spends the night.Next day, smash pine, pour whizzer into and get rid of filter.The reclaimed materials charging feedstock bag that throws away, weighing, oven dry is the fenfluramine hydrochloride crude product.
3. dry
The wet product of fenfluramine hydrochloride are paved equably on drip pan, push Hotaircirculatingoven and carry out drying, by the operation of thermal cycling baking oven Standard operation procedure SOP, temperature was controlled at 40-50 ℃ in preceding 4 hours, and temperature was controlled at 80-90 ℃ in back 4 hours, and dry total time is 8h.
4. pulverize
The fenfluramine hydrochloride that drying is good is put into crushiing chamber, carries out after the pulverizing always mixing.
5. total mixing
The fenfluramine hydrochloride that crushes is put into three-dimensional motion mixer carry out always mixing, always doing time is 1 hour, and total amalgamation is criticized about general 100kg.Total mixing finishes to pack.
6. compacting fenfluramine hydrochloride tablets
Formula rate:
Fenfluramine hydrochloride 20kg
Icing Sugar 20kg
Starch 50kg
Dextrin 10kg
Microcrystalline Cellulose 20kg
Starch (10% slurry is used) 4.2kg
Magnesium Stearate 1.5kg
Raw material fenfluramine hydrochloride, Icing Sugar, starch, dextrin, Microcrystalline Cellulose are mixed, cross 16 mesh sieves, make softwood with 10% starch slurry, granulate,, cross the whole grain of 16 mesh sieves in 60～70 ℃ of dryings, add Magnesium Stearate, be pressed into the fenfluramine hydrochloride tablets agent, every heavy 20mg.
The preparation technology of fenfluramine hydrochloride bulk drug of the present invention is reasonable, simple and practical, safe and effective, the finished product stable in properties, be easy to detect.Except being applied to tablet, also can be widely used in the treatment simple obesity medicine production of multiple formulations such as capsule, granule, oral preparation and ointment.
Claims (2)
1, a kind of preparation method of fenfluramine hydrochloride medicine realizes by following preparation technology, it is characterized in that:
A. salt-forming reaction
Formula rate:
Phenfluoramine free alkali: hydrochloric acid: toluene=0.8～1.2: 0.48～0.72: 2.8～4.2
The Phenfluoramine free alkali is dropped in the 500L enamel reactor, start stirring, open chuck water quench to 10 ℃, begin slowly dripping hydrochloric acid, regulate pH value to 2, temperature is controlled at below 30 ℃, continues to stir half an hour, make acidifying complete, the repetition measurement pH value is 2, is acidifying and finishes; Acidizing fluid is used the 60kg toluene wash respectively three times, separates out as solid is arranged in the still, promptly is warming up to 50 ℃ and stirs 10 minutes, static 20 minutes, makes layering complete; Washing finishes, and decompression is earlier steamed water to most, and temperature is controlled at below 95 ℃, cold slightly back adds 240kg toluene, and underpressure distillation is treated water to most, and temperature is controlled at below 95 ℃, allowance 300kg, be cooled to 10 ℃, discharging, whizzer gets rid of filter to doing, advance oven drying, 50 ℃ of dryings of elder generation 4 hours, back 90 ℃ of dryings 4 hours get the fenfluramine hydrochloride crude product;
B. refining
Formula rate:
Crude product: ethanol: gac=0.8～1.2: 1.2～1.8: 0.04～0.06
Fenfluramine hydrochloride crude product, ethanol and gac are dropped in the 500L reactor, open steam 78-82 ℃ of reflux 45 minutes, take advantage of a favourable situation to filter, filtrate is depressed in the crystallizing pan, opens the refrigerated water cooling, is cooled to 20 ℃ of crystallization temperature in the kettle, get rid of filter with whizzer, and divide 2 washings with dehydrated alcohol, dry, the wet product of fenfluramine hydrochloride; Mother liquor is recyclable;
To reclaim mother liquor with in the vacuum suction pot, and open vacuum earlier, water of condensation is opened in the restir heating, and kettle temperature is controlled at below 95 ℃; From the material major ingredient ethanol that the prolong cooling is reclaimed, can apply mechanically; After reclaiming end, a feed liquid is directly put into the 50L stainless steel cask in the pot, and the gap is stirred to crystallization, adds a cover and spends the night; Next day, smash pine, pour whizzer into and get rid of filter; The reclaimed materials charging feedstock bag that throws away, weighing, oven dry is the fenfluramine hydrochloride crude product;
C. dry
The wet product of fenfluramine hydrochloride are paved equably on drip pan, push Hotaircirculatingoven and carry out drying, by the operation of thermal cycling baking oven Standard operation procedure SOP, temperature was controlled at 40-50 ℃ in preceding 4 hours, and temperature was controlled at 80-90 ℃ in back 4 hours, and dry total time is 8h;
D. pulverize
The fenfluramine hydrochloride that drying is good is put into crushiing chamber, carries out after the pulverizing always mixing;
E. always mix
The fenfluramine hydrochloride that crushes is put into three-dimensional motion mixer carry out always mixing, always doing time is 1 hour, and general 100kg is criticized in total amalgamation; Total mixing finishes to pack;
F. suppress fenfluramine hydrochloride tablets
Formula rate:
Fenfluramine hydrochloride 16kg～24kg
Icing Sugar 16kg～24kg
Starch 40kg～60kg
Dextrin 8kg～12kg
Microcrystalline Cellulose 16kg～24kg
Starch, 10% slurry 3.36kg～5.04kg
Magnesium Stearate 1.2kg～1.8kg
Raw material fenfluramine hydrochloride, Icing Sugar, starch, dextrin, Microcrystalline Cellulose are mixed, cross 16 mesh sieves, make softwood with 10% starch slurry, granulate,, cross the whole grain of 16 mesh sieves in 60～70 ℃ of dryings, add Magnesium Stearate, be pressed into the fenfluramine hydrochloride tablets agent, every heavy 20mg.
2, according to the preparation method of the fenfluramine hydrochloride medicine described in the claim 1, its preparation technology is:
A. salt-forming reaction
Formula rate:
Phenfluoramine free alkali: hydrochloric acid: toluene=1: 0.6: 3.5
The Phenfluoramine free alkali is dropped in the 500L enamel reactor, start stirring, open chuck water quench to 10 ℃, begin slowly dripping hydrochloric acid, regulate pH value to 2, temperature is controlled at below 30 ℃, continues to stir half an hour, make acidifying complete, the repetition measurement pH value is 2, is acidifying and finishes; Acidizing fluid is used the 60kg toluene wash respectively three times, separates out as solid is arranged in the still, promptly is warming up to 50 ℃ and stirs 10 minutes, quiet 20 minutes, makes layering complete; Washing finishes, and decompression is earlier steamed water to most, and temperature is controlled at below 95 ℃, cold slightly back adds 240kg toluene, and underpressure distillation is treated water to most, and temperature is controlled at below 95 ℃, allowance 300kg, be cooled to 10 ℃, discharging, whizzer gets rid of filter to doing, advance oven drying, 50 ℃ of dryings of elder generation 4 hours, back 90 ℃ of dryings 4 hours get the fenfluramine hydrochloride crude product;
B. refining
Formula rate:
Crude product: ethanol: gac=1: 1.5: 0.05
Fenfluramine hydrochloride crude product, ethanol and gac are dropped in the 500L reactor, open steam 78-82 ℃ of reflux 45 minutes, take advantage of a favourable situation to filter, filtrate is depressed in the crystallizing pan, opens the refrigerated water cooling, is cooled to 20 ℃ of crystallization temperature in the kettle, get rid of filter with whizzer, and divide 2 washings with dehydrated alcohol, dry, the wet product of fenfluramine hydrochloride; Mother liquor is recyclable;
To reclaim mother liquor with in the vacuum suction pot, and open vacuum earlier, water of condensation is opened in the restir heating, and kettle temperature is controlled at below 95 ℃; From the material major ingredient ethanol that the prolong cooling is reclaimed, can apply mechanically; After reclaiming end, a feed liquid is directly put into the 50L stainless steel cask in the pot, and the gap is stirred to crystallization, adds a cover and spends the night; Next day, smash pine, pour whizzer into and get rid of filter; The reclaimed materials charging feedstock bag that throws away, weighing, oven dry is the fenfluramine hydrochloride crude product;
C. dry
The wet product of fenfluramine hydrochloride are paved equably on drip pan, push Hotaircirculatingoven and carry out drying, by the operation of thermal cycling baking oven Standard operation procedure SOP, temperature was controlled at 40-50 ℃ in preceding 4 hours, and temperature was controlled at 80-90 ℃ in back 4 hours, and dry total time is 8h;
D. pulverize
The fenfluramine hydrochloride that drying is good is put into crushiing chamber, carries out after the pulverizing always mixing;
E. always mix
The fenfluramine hydrochloride that crushes is put into three-dimensional motion mixer carry out always mixing, always doing time is 1 hour, and general 100kg is criticized in total amalgamation; Total mixing finishes to pack;
F. suppress fenfluramine hydrochloride tablets
Formula rate:
Fenfluramine hydrochloride 20kg
Icing Sugar 20kg
Starch 50kg
Dextrin 10kg
Microcrystalline Cellulose 20kg
Starch, 10% slurry 4.2kg
Magnesium Stearate 1.5kg
Raw material fenfluramine hydrochloride, Icing Sugar, starch, dextrin, Microcrystalline Cellulose are mixed, cross 16 mesh sieves, make softwood with 10% starch slurry, granulate,, cross the whole grain of 16 mesh sieves in 60～70 ℃ of dryings, add Magnesium Stearate, be pressed into the fenfluramine hydrochloride tablets agent, every heavy 20mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100670457A CN100567252C (en) | 2004-10-11 | 2004-10-11 | Fenfluramine hydrochloride crude drug and tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100670457A CN100567252C (en) | 2004-10-11 | 2004-10-11 | Fenfluramine hydrochloride crude drug and tablet and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634857A CN1634857A (en) | 2005-07-06 |
| CN100567252C true CN100567252C (en) | 2009-12-09 |
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| US9549909B2 (en) | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
| HUE071191T2 (en) * | 2015-12-22 | 2025-08-28 | Zogenix International Ltd | Fenfluramine compositions and processes for their preparation |
| US12144787B2 (en) | 2018-11-19 | 2024-11-19 | Zogenix International Limited | Method of treating patients with a mutation in cyclin-dependent kinase-like 5 (CDKL5) |
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| Title |
|---|
| 新药指南. 国家医药管理局等，272-273，中国医药科技出版社. 1989 * |
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| CN1634857A (en) | 2005-07-06 |
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