CN105687140A - Vinpocetine fine powder preparation method - Google Patents
Vinpocetine fine powder preparation method Download PDFInfo
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- CN105687140A CN105687140A CN201610147524.2A CN201610147524A CN105687140A CN 105687140 A CN105687140 A CN 105687140A CN 201610147524 A CN201610147524 A CN 201610147524A CN 105687140 A CN105687140 A CN 105687140A
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- vinpocetine
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
Abstract
The invention provides a vinpocetine fine powder preparation method and relates to the field of raw medicine fine powder preparation. The method includes the following steps that firstly, dissolution is conducted, wherein vinpocetine raw medicine is completely dissolved in an organic solvent, the organic solvent and water are mutually soluble, and a vinpocetine solution is obtained; secondly, dropwise addition is conducted, wherein the vinpocetine solution is added into water dropwise and quickly stirred; thirdly, crystallization is conducted, wherein stirring is performed for crystallization after dropwise addition, temperature is lowered, stirring continues for crystallization, and drying and filtering are conducted. The method has the advantages that the preparation method is simple, the yield is high, requirements for equipment are low, and prepared vinpocetine fine powder is small in particle size.
Description
Technical field
The present invention relates to crude drug micropowder preparation field, particularly to the preparation method of a kind of Vinpocetione crude drug micropowder。
Background technology
Vinpocetine is that the indole alkaloid vincamine of extraction, through structure of modification gained derivant, is a kind of excellent cerebrovascular disease medicament from Apocynaceae periwinkle。This medicine since within 1978, being succeeded in developing by GedeonRichter company of Hungary, because of clinical effectiveness is notable and safety and toleration good, clinical application range constantly expands, and has now become the routine administration of American-European countries and Japan。Clinically, vinpocetine is usually used in the disturbance of cerebral circulation disease such as treatment cerebral arteriosclerosis, cerebral ischemia and hemorrhagic apoplexy sequela, transient ischemic attack and for treating the symptom that circulatory disturbance is brought out, as aphasia, use can not, poor memory, cognitive dysfunction, dizziness and other brain vestibule problem and headache etc.。Additionally, vinpocetine is also used for the acute and chronic ophthalmic diseases that treatment many reasons causes, treats sensory nerve hearing impairment。Research shows, vinpocetine has fat-solubility, easily enters cerebral tissue by blood brain barrier, but does not accumulate tendency in vivo, is suitable for long-term taking, on heart rate and blood pressure almost without impact。
At present, domestic vinpocetine preparation is with tablet and two kinds of forms of injection for main flow, and is mostly injection dosage form。Injection needs to be dissolved in water for injection by crude drug when producing, and the dissolubility of medicine is most important to the production of injection with dissolution velocity。The medicine of low molten speed can cause that the course of dissolution time of medicine is longer, and to producing, production capacity restriction is bigger。Specific surface area is as affecting one of drug solubility influence factor with dissolution velocity, and the dissolution velocity of medicine is affected relatively big by the specific surface area size of medicine, and the dissolution velocity that specific surface area is big is relatively fast, and the material dissolution speed that specific surface area is little is relatively slow。The size of specific surface area and the crystal formation of material, grain size are closely related。The crystal formation granularity of material is more little, and specific surface area is more big。The vinpocetine of small grain size crystal grain is higher 2-3 times than big granularity vinpocetine dissolution velocity in sour water。Traditional drug micronization technology includes mechanical crushing method, supercritical fluid technology and the liquid-phase precipitation methods such as ball-milling method, low-temperature airflow comminuting method, high pressure homogenize。The granularity of the sold Vinpocetione crude drug in current market is all about 200 orders, and the preparation of this micropowder all adopts the mode of mechanical activation comminution or the mode of comminution by gas stream to achieve the goal。Vinpocetione crude drug mostly adopts single solvent in Crystallization Process, and the Vinpocetione crude drug crystal formation granularity that single solvent precipitates out is relatively big, is approximately in about 80 orders, it is impossible to reach the production requirement of the dosage forms such as vinpocetine injection。
The patent or the document that improve the dissolution velocity of Vinpocetione crude drug are little, and only preparation aspect has freeze drying technology acquisition superfine powder to achieve the goal, and research vinpocetine crystal formation achieves the goal。
Publication number is the extraordinary superfine powder lyophilized formulations that the Chinese patent of CN104083329A discloses a kind of vinpocetine, it is characterized in that: the extraordinary superfine powder of described vinpocetine becomes the vinpocetine of purification after a series of eluting, concentration, cooling, after drying, air flow super, lyophilizing, obtain the extraordinary superfine powder lyophilized formulations of vinpocetine。Purpose is in that extraordinary superfine powder lyophilized formulations providing a kind of vinpocetine and preparation method thereof, makes the advantages such as vinpocetine has purity height, granule is little, powder sizing good, dissolubility is good, biological activity is good。Solve the problems such as vinpocetine purity is low, granule is big, poor, the production cycle length of the qualitative difference of powder, product stability。The preparation of this patent becomes the vinpocetine of purification after a series of eluting, concentration, cooling, the extraordinary superfine powder lyophilized formulations of vinpocetine is obtained after drying, air flow super, lyophilizing, but this technique is loaded down with trivial details, flow process is complicated, and energy expenditure is higher, especially equipment aspect, comminution by gas stream needs jet mill, equipment price is expensive, and the input of production cost is relatively big, is not suitable for industrialized production。
The Chinese patent that publication number is CN104725370A discloses a kind of vinpocetine tubular crystal and preparation method, it is characterized in that joining in solvent by vinpocetine, open stirring 100-800rpm, raising temperature makes it dissolve, and obtains the concentration range vinpocetine solution at 16mg/ml～50mg/ml；By above-mentioned solution adds water, filtration washing after constant temperature 5～60min, 20-80 DEG C of dry 2-8h in vacuum drying oven, obtain vinpocetine tubular crystal。Vinpocetine prepared by this invention is that product have crystal structure, has Guan Bi or non-closed duct；Yield is 60～85%, is applied to drug world, improves the problem that vinpocetine dissolution rate in water is low, promotes drug absorption, improves drug effect and bioavailability。This patent is by under 100-800rpm speed conditions, solvent dissolves vinpocetine, obtain the vinpocetine of 16mg/ml～50mg/ml concentration, in the solvent of this concentration vinpocetine, then add poor solvent water, filter after constant temperature 5～60min, wash, dry。Obtain that there is the vinpocetine having Guan Bi or non-closed duct crystal structure, low to solve vinpocetine dissolubility in water, dissolution rate is slow, very easily causes that the dosage form results of use such as injection are not good, not easily it is absorbed by the body and plays drug effect, the problem that bioavailability is relatively low。This patent has certain operability in course of industrialization, increases dissolubility and bioavailability by changing crystal shape, its crystal size be there is no statement。And this patent yield is too low, only 60-85%, for the vinpocetine industrialization high cost that added value is higher, can be full of without profit。Therefore, developing the preparation method of the vinpocetine micropowder that a kind of dissolubility is high, dissolution rate is fast, yield is high is new problem urgently to be resolved hurrily at present。
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of vinpocetine micropowder, the method has that preparation method is simple, yield is high, low for equipment requirements, the feature such as the vinpocetine grain size of micropowder for preparing is little。
The object of the present invention is achieved like this: the preparation method of a kind of vinpocetine micropowder, described method comprises the steps of
(1) dissolve: Vinpocetione crude drug is dissolved completely in the organic solvent that can dissolve each other with water, obtains vinpocetine solution；
(2) dropping: described vinpocetine solution is dropped in water, quickly stirs；
(3) crystallize: dropwise rear stirring and crystallizing, cooling, continues stirring and crystallizing, filters, dries；
In step (1), one or more in methanol, ethanol, propanol, isopropanol, acetone, oxolane, dimethylformamide of described organic solvent；The quality of described Vinpocetione crude drug and the volume ratio of organic solvent are 1:12-25, it is preferred that the quality of Vinpocetione crude drug and the volume ratio of organic solvent are 1:17-25, and the unit of described quality is g, and the unit of described volume is ml；In step (1), the temperature of described organic solvent is 40-100 DEG C；In step (1), the temperature of described organic solvent is 65-95 DEG C；In step (2), the volume ratio of described vinpocetine solution and water is 1:1-10, it is preferred that the volume ratio of described vinpocetine solution and water is 1:1.6-7.9；Described wet concentration is from purified water or deionized water；Described vinpocetine solution is dropped in water as to be dropped to while hot in water by described vinpocetine solution；In step (2), the temperature of described water is 0-50 DEG C, it is preferable that temperature is 25-45 DEG C；The rotating speed of described stirring is 150 revs/min 600 revs/min, it is preferred that rotating speed is 200 revs/min 380 revs/min；In step (3), described in dropwise the temperature of rear stirring and crystallizing and be 20-30 DEG C, it is preferable that temperature is 23-27 DEG C；In step (3), the described time dropwising rear stirring and crystallizing is 20-40 minute, it is preferred that the time is 30 minutes；In step (3), the temperature after described cooling is-5～40 DEG C, it is preferable that temperature is 0-35 DEG C；The time of described continuation stirring and crystallizing is 1-3 hour, it is preferable that the time is 2 hours。
The present invention is characterized by the preparation method providing a kind of vinpocetine micropowder, its principle is: (1) present invention adopts the organic solvent dissolved each other with water to dissolve Vinpocetione crude drug, then it is added dropwise in purified water under rapid mixing conditions, crystallize, filtration, dry, obtained Vinpocetione crude drug granularity can reach about 200 orders, and yield is between 98%-100%, open a kind of new method for preparing high yield vinpocetine micropowder。Meanwhile, the method that this kind of anti-solvent method prepares high yield vinpocetine micropowder solves the problem that dependence equipment could solve, departing from the restriction of equipment。This method solve traditional single solvent crystallize, the problem that crystal formation is excessive；Avoid loss of material and thermal sensitivity problem that Vinpocetione crude drug brings under mechanical activation comminution simultaneously。(2) through XRD (X-ray diffractometer) scanning analysis, brilliant with the anti-solvent method acetone elutriation adopting the present invention with the single solvent crystallize of acetone, both peak positions are basically identical, it is believed that in two, method products obtained therefrom is identical product。(3) through adopting differentia scanning calorimetry scanning can be seen that, use ethanol/water anti-solvent method crystallize and the acetone/water anti-solvent method crystallize of the present invention, the first of two products melts temperature Onset point essentially identical (145 DEG C-155 DEG C), and solvation phenomenon had not occurred yet；The single solvent acetone crystallize anti-solvent method acetone elutriation crystalline substance with the present invention is adopted to melt temperature Onset point essentially identical (145-155 DEG C) just。(4) from grain size analysis, using the vinpocetine granularity of single solvent (acetone crystallize) gained about 80 orders, use the acetone water anti-solvent method crystallize of the present invention, the vinpocetine granularity of gained can reach more than 97% less than 200 purposes。
The preparation method of a kind of vinpocetine micropowder compared with prior art has that preparation method is simple, yield is high, low for equipment requirements, the feature such as the vinpocetine grain size of micropowder for preparing is little, by the preparation field being widely used in Vinpocetione crude drug micropowder。
Detailed description of the invention
Embodiment one
Take crystal formation granularity Vinpocetione crude drug 50g about 80 orders, be placed in 1000ml single port bottle, add dehydrated alcohol 823ml, stirring and dissolving under 82 DEG C of conditions, until material complete molten clear after, be added dropwise in the purified water of 25 DEG C of 1300ml while hot, quickly stirring, speed of agitator is at 200 revs/min, after dropwising, 23-27 DEG C is stirred 30 minutes, will be equipped with the single port bottle of material and be cooled to 0 DEG C, stirring and crystallizing 2 hours, filters, dry, obtain finished product。Product yield: 98.5%, carries out granularity Detection, and granularity occupies 95% below 200 orders。
Embodiment two
Take crystal formation granularity Vinpocetione crude drug 50g about 80 orders, be placed in 1000ml single port bottle, add absolute methanol 950ml, stirring and dissolving under 70 DEG C of conditions, until material complete molten clear after, be added dropwise in the purified water of 35 DEG C of 2250ml while hot, quickly stirring, speed of agitator is at 300 revs/min, after dropwising, 23-27 DEG C is stirred 30 minutes, will be equipped with the single port bottle of material and be cooled to 15 DEG C, stirring and crystallizing 2 hours, filters, dry, obtain finished product。Product yield: 98.8%, carries out granularity Detection, and granularity occupies 96% below 200 orders。
Embodiment three
Take crystal formation granularity Vinpocetione crude drug 50g about 80 orders, be placed in 1000ml single port bottle, add acetone 1140ml, stirring and dissolving under 65 DEG C of conditions, until material complete molten clear after, be added dropwise in the purified water of 40 DEG C of 4500ml while hot, quickly stirring, speed of agitator is at 350 revs/min, after dropwising, 23-27 DEG C is stirred 30 minutes, will be equipped with the single port bottle of material and be cooled to 25 DEG C, stirring and crystallizing 2 hours, filters, dry, obtain finished product。Product yield: 99.2%, carries out granularity Detection, and granularity occupies 94% below 200 orders。
Embodiment four
Take crystal formation granularity Vinpocetione crude drug 50g about 80 orders, be placed in 1000ml single port bottle, add isopropanol 1270ml, stirring and dissolving under 95 DEG C of conditions, until material complete molten clear after, be added dropwise in the purified water of 45 DEG C of 10L while hot, quickly stirring, speed of agitator is at 380 revs/min, after dropwising, mix 30 minutes for 23-27 DEG C, will be equipped with the single port bottle of material and be cooled to 35 DEG C, stirring and crystallizing 2 hours, filters, dry, obtain finished product。Product yield: 99.8%, carries out granularity Detection, and granularity occupies 97% below 200 orders。
Claims (9)
1. the preparation method of a vinpocetine micropowder, it is characterised in that described method comprises the steps of
(1) dissolve: Vinpocetione crude drug is dissolved completely in the organic solvent that can dissolve each other with water, obtains vinpocetine solution；
(2) dropping: described vinpocetine solution is dropped in water, quickly stirs；
(3) crystallize: dropwise rear stirring and crystallizing, cooling, continues stirring and crystallizing, filters, dries。
2. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterized in that, in step (1), one or more in methanol, ethanol, propanol, isopropanol, acetone, oxolane, dimethylformamide of described organic solvent；The quality of described Vinpocetione crude drug and the volume ratio of organic solvent are 1:12-25, it is preferred that the quality of Vinpocetione crude drug and the volume ratio of organic solvent are 1:17-25, and the unit of described quality is g, and the unit of described volume is ml。
3. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterised in that in step (1), the temperature of described organic solvent is 40-100 DEG C。
4. the preparation method of a kind of vinpocetine micropowder according to claim 3, it is characterised in that in step (1), the temperature of described organic solvent is 65-95 DEG C。
5. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterized in that, in step (2), the volume ratio of described vinpocetine solution and water is 1:1-10, it is preferred that the volume ratio of described vinpocetine solution and water is 1:1.6-7.9；Described wet concentration is from purified water or deionized water；Described vinpocetine solution is dropped in water as to be dropped to while hot in water by described vinpocetine solution。
6. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterised in that in step (2), the temperature of described water is 0-50 DEG C, it is preferable that temperature is 25-45 DEG C；The rotating speed of described stirring is 150 revs/min 600 revs/min, it is preferred that rotating speed is 200 revs/min 380 revs/min。
7. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterised in that in step (3), described in dropwise the temperature of rear stirring and crystallizing and be 20-30 DEG C, it is preferable that temperature is 23-27 DEG C。
8. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterised in that in step (3), the described time dropwising rear stirring and crystallizing is 20-40 minute, it is preferred that the time is 30 minutes。
9. the preparation method of a kind of vinpocetine micropowder according to claim 1, it is characterised in that in step (3), the temperature after described cooling is-5～40 DEG C, it is preferable that temperature is 0-35 DEG C；The time of described continuation stirring and crystallizing is 1-3 hour, it is preferable that the time is 2 hours。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479867A (en) * | 2020-12-30 | 2021-03-12 | 武汉诺安药业有限公司 | Chemical preparation method of adapalene micronization |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479867A (en) * | 2020-12-30 | 2021-03-12 | 武汉诺安药业有限公司 | Chemical preparation method of adapalene micronization |
| CN112479867B (en) * | 2020-12-30 | 2024-03-29 | 武汉诺安药业有限公司 | Chemical preparation method for micronization of adapalene |
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