CN102060777B - Novel phenytoin medicament eutecticum and preparation method thereof - Google Patents
Novel phenytoin medicament eutecticum and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicament eutecticum, in particular relating to a novel phenytoin medicament eutecticum and a preparation method thereof. In the invention, a phenytoin active pharmaceutical ingredient is utilized as an API, 4,4'-bipyridyl is selected as a medicament precursor, space group of the prepared phenytoin medicament eutecticum is of a monoclinic system, and the axial length satisfies that a=.0000-9.0000, b=25.000-27.000, and c=7.000-9.0000. The novel eutectic structure prepared by the method provided by the invention can effectively modify the active components of medicaments, and can not form other bonds together with water or other external interferences after forming eutecticum together with the 4,4'-bipyridyl through hydrogen bonds, thereby achieving the effect of ensuring the medicament to be more stable. The preparation method of the eutecticum provided by the invention comprises a normal temperature solvent slow vaporization method and a grinding method which are simple and convenient to operation and are practical, thus the method provided by the invention is convenient for wide popularization in industrial medicament preparation and is low in cost.
Description
Technical field
The invention belongs to medicine eutectic technical field, be specifically related to a kind of novel Phenytoin Sodium Salt medicine eutectic and preparation method thereof.
Background technology
Though the mensuration of crystalline structure has been one of scientific research instrument that is widely used since nineteen twenty always, the prediction of crystalline structure remains a problem that does not have realization.In addition, there is multiple crystal formation in many known compounds, are present in usually in polymorph or the solvolyte, and this point is particularly serious in the pharmaceutical industry performance.Bad physico-chemical property, physiological barrier or toxicity problem have often limited the advantage of pharmacological agent.This impels the drug manufacture systematic research to tend to study those to have the solvability of being difficult for, be difficult for absorptivity and instable medicine.Crystal self-assembly and preparation medicine eutectic then can improve the solubleness of medicine, and the defective that stability and bioavailability etc. exist makes medicine obtain using better widely.Because pharmaceutical properties such as active constituents of medicine (API) crystalline solubility, stability, sustained release rate, bioavailability are all undesirable; So the present invention is through preparation medicine eutectic; Improve the character of the aspect such as various physics, chemistry, biology of medicine; Make the character of API in the medicine eutectic molecule itself that certain change take place, different with the character of pure API self, and then improve pharmaceutical properties such as its solubility, stability, sustained release rate, bioavailability significantly.
Synthetic and the preparation of eutectic are equal to supramolecular synthesis model, and just crystal calls self-existing molecule assembling, and needn't break or form a kind of novel texture of non covalent bond.The interaction force that the medicine eutectic is present between crystal is that perhaps other have the interaction force of the non covalent bond of directivity to hydrogen bond.The novel drugs eutectic has not only kept the pharmacological properties of medicine itself, has also improved the character of the aspects such as physics, chemistry and biology of medicine, and the raising of drug effect is also had certain help.
The preparation method of eutectic comprises solvent evaporation method, solvent-thermal method, and subliming method, method of fusion, several different methods such as puddling all are applicable to the preparation of medicine eutectic.
The material that can be used as medicine eutectic presoma reaches kind more than 100; These materials must be the safe drugs (GRAS) of international approval; Comprise foodstuff additive and other easy absorbing materials, also have the medicine (like Frosst) and PARACETAMOL BP98) of the high safety performance that uses in the treatment etc.The eutectic presoma and the bulk drug that contain pharmaceutical cpd and ligand molecule have identical or different physics, chemical property.These novel medicine eutectics can be very big improve the character of medicine at aspects such as solubleness, scatter coefficient, stability and bioavailabilities.The design of new drug is exactly to utilize the fill-in of eutectic presoma as supramolecular chemistry, utilizes the molecule of medicine or ionic species to prepare the medicine eutectic.The molecule of medicine or ion tend to synthesize through crystal engineering in essence, because they comprise the molecular recognition performance, combine with biomacromolecule selectively, and are easy to carry out the supramolecule self-assembly and prepare the medicine eutectic.
Summary of the invention
The object of the present invention is to provide the preparation method of Phenytoin Sodium Salt medicine eutectic material, and its crystalline structure is tested, its performance is characterized.The preparation of this medicine eutectic has improved the performances such as stability, bioavailability, fusing point, solubleness, dissolution rate, chemicalstability and thermodynamic stability of bulk drug.
The existing preparation in the method for medicine eutectic, exist a lot of not enough: as synthesize the eutectic overlong time, technology is loaded down with trivial details, success ratio is low etc.The method that the present invention mainly adopts is solvent evaporation method and polishing, and two kinds of synthetic medicine eutectic structures that obtain of method are identical.The present invention is outstanding to utilize polishing to synthesize Phenytoin Sodium Salt medicine eutectic, and this method is simple and easy to do, is convenient to large-scale popularization in industrial pharmacy, has significantly reduced cost and experimental period, has avoided loaded down with trivial details technical process, has improved eutectic synthetic success ratio etc. greatly.Be suitable for a large amount of synthetic drugs eutectics of factory, have very strong application value realistic.And novel texture has characteristics such as improving its fusing point, solubleness, dissolution rate, chemicalstability, thermodynamic stability and bioavailability, and is different from the pharmacy molecule of existing solid form.
The present invention selects for use the Phenytoin Sodium Salt bulk drug as medicine API, and the medicine presoma of selecting for use is 4,4 '-dipyridyl.
Phenytoin Sodium Salt is as medicine API of the present invention, and English is called 5, and 5-Diphenylhydantoin or Phenytoin have another name called Phenytoin Sodium or dilantin, and molecular formula is C
15H
12N
2O
2, its structural formula is suc as formula shown in a.Phenytoin Sodium Salt is a kind of anticonvulsant drug, except spasmolytic, antiepileptic effect are arranged, and the effect of setting the mind at rest, expanding peripheral blood vessel in addition and bring high blood pressure down.The rhythm of the heart to treatment epileptic seizures and purple foxglove cause is too fast effectively.Phenytoin Sodium Salt is a kind of common safe drugs, can directly buy from market, and its shape and specification can be Powdered, also can be crystal.
4,4 '-dipyridyl is as presoma of the present invention, and English is called 4,4 ' Dipyridyl, gamma, gamma '-Dipyridyl or 4,4 ' Bipyridine, and molecular formula is C
10H
8N
2, its structural formula is suc as formula shown in the b.Be more common medicine intermediate, through being usually used in synthesizing new medicine eutectic.Can directly buy from market, its shape and specification can be pulverulent solids, also can be crystal.
Phenytoin Sodium Salt is a kind of common safe drugs.But Phenytoin Sodium Salt is having a lot of drawbacks aspect medical and clinical and even the storage.These drawbacks and unstable can improve through preparing its medicine eutectic.4,4 '-dipyridyl is more common medicine intermediate, through being usually used in synthesizing new medicine eutectic.From the structural formula a and 4 of Phenytoin Sodium Salt, the structural formula b of 4 '-dipyridyl can find out that its structure all meets the condition of preparation medicine eutectic.Phenytoin Sodium Salt contains functional group's carbonyl and amino, can be with 4, and 4 '-dipyridyl forms N ... H-O or H ... Hydrogen bonds such as O=C.
Phenytoin Sodium Salt medicine eutectic of the present invention, its spacer is an oblique system, its axial length a=7.0000～9.0000; B=25.0000～27.0000, c=7.0000～9.0000, shaft angle α=89.000～91.000; β=85.000～95.000, γ=89.000～91.000; There is the series of features peak in its XRD spectra between 9.00 °～9.30 °, 12.20 °～12.50 °, 18.00 °～18.50 °, 19.50 °～20.20 °, 25.00 °～25.50 ° and 28.50 °～29.00 °; Phenytoin Sodium Salt eutectic thermogravimetric curve (air atmosphere test condition), weightless 130 ℃～150 ℃ beginnings, to 170 ℃～190 ℃ weightlessness 70%～90%, decompose fully at 300 ℃～350 ℃ then; Its eutectic infrared spectrum is 3100～3200 and 1380～1450cm
-1Between go out the asymmetric and symmetrical stretching vibration that the peak is inferior acid amides, 3000～3050,2750～2800cm
-1Between go out the v=C-H peak that the peak is a phenyl ring, at 1720～1730cm
-1Characteristic peak occurring is C=O peak above the five-ring, at 1580～1610cm
-1Between go out the skeletal vibration that the peak is the aromatic series phenyl ring, at 730～750cm
-1Between to go out the peak be the outer δ=C-H vibration absorption peak of phenyl ring face, at 690～710cm
-1Between go out the peak and be that the phenyl ring list replaces the peak.
The preparation method of Phenytoin Sodium Salt medicine eutectic of the present invention is solvent evaporation method or polishing, and concrete experimentation is following:
Method 1: solvent evaporation method
(1) Phenytoin Sodium Salt and 4; 4 '-dipyridyl grinds to form 140～300 purpose powder respectively, places transparent glass container, is dissolved in the organic solvent jointly then; Wherein, Phenytoin Sodium Salt and 4, the mass ratio of 4 '-dipyridyl is 1: 1～1: 2, the mass concentration of Phenytoin Sodium Salt is 5g/l～8g/l in organic solvent;
The Glass Containers that (2) will fill above-mentioned mixing solutions places and stirs (10～30 minutes) on the whisking appliance or place ultrasonic instrument that ultrasonic (ultrasonic frequency is 70～90Hz; Ultrasonic 5～20 minutes); After treating that powder dissolves fully; With the Glass Containers covered and enclosed, making its internal pressure is 100～150KPa, places under 20 ℃～30 ℃ temperature condition and opens container cover after 1～5 day; Generate colourless ROD EUTECTIC after 1～15 day through solvent slow vaporization method, promptly obtain Phenytoin Sodium Salt medicine eutectic of the present invention.
Method 2: polishing
It with mass ratio 1: 1～1: 5 Phenytoin Sodium Salt and 4; 4 '-dipyridyl is inserted in the agate mortar that diameter is 8～20cm; Reactant is ground to form 140～300 purpose powder; Move in 5～100 μ L organic solvents to the above-mentioned powder with the micropipette rifle then, wherein the mass concentration of Phenytoin Sodium Salt in organic solvent is 2g/ml～18g/ml; Ground 0.5～30 minute uniformly rapidly more afterwards, the amorphous powder that obtains is Phenytoin Sodium Salt medicine eutectic of the present invention, and its eutectic structure with method 1 is identical, and has shortened experimental period and cost greatly.
Wherein being fit to organic solvent of the present invention comprises: the mixing of one or more in acetone, methyl alcohol, ethanol, acetate, methyl-sulphoxide (DMSO), Virahol (IPA), chloroform, N (DMF), pyridine, methylene dichloride, acetonitrile, propylamine, the methane amide.
The instrument that detects Phenytoin Sodium Salt medicine eutectic structure and performance among the present invention is following:
1, eutectic structure is measured by Brooker Apex II CCD X-ray single crystal diffractometer, full name Bruker SMART-APEX CCD Diffractometer
2, X-Ray DIFFRACTOMETER day island proper Tianjin company produces; Model is XRD-6000; Cu-K α
tube voltage 40kV; Tube current 30mA, 2 °/min of sweep velocity
3, SIMULTANEOUS DTA-TG APPARATUS, day island proper Tianjin company, the thermal weight loss of model DTG-60 (TGA) and differential thermal analyzer (DTA), the present invention adopts air atmosphere, and temperature rise rate is 8 ℃/min.
4, FOURIER TRANSFORM INFRARED SPECTROPHOTOMETER FTIR Spectrometer FTIR, IR Affinity-1, the KBr compressing tablet is collected 4000-400cm
-1Interval censored data
The novel eutectic structure that employing the present invention prepares is the activeconstituents of modified medicaments effectively; With 4; After 4 '-dipyridyl forms eutectic through hydrogen bond, can not form other keys with water or other external interference again, thereby can reach the effect that makes medicine more stable.The method for preparing eutectic in the invention comprises normal temperature solvent slow vaporization method and polishing.These two kinds of methods are easy to operation, are convenient to large-scale popularization in industrial pharmacy, and are with low cost.The transparent glass instrument that uses in the invention is U.S.'s import, and model 20～40ml has very strong stopping property, and under 0～120 ℃ of condition, still can keep its stopping property good.
Description of drawings
The Phenytoin Sodium Salt and 4 of Fig. 1: embodiment 1 preparation, the structural unit synoptic diagram of 4 '-dipyridyl eutectic; Phenytoin Sodium Salt forms heterodimer through carbonyl and amino hydrogen bond in this eutectic, and the while 4, the amino of 4 '-dipyridyl and the amino of Phenytoin Sodium Salt are connected to form hydrogen bond.Contain two Phenytoin Sodium Salts and two 4 in the structural unit, 4 '-dipyridyl forms a tetramer.Wherein Phenytoin Sodium Salt medicine eutectic spacer is an oblique system, its axial length a=8.0007, b=26.2258, c=7.9796, shaft angle α=90.000, β=91.054, γ=90.000.
The X-ray diffraction spectrogram (figure below) of the Phenytoin Sodium Salt eutectic of Fig. 2: embodiment 1 preparation, the XRD spectra (last figure) and 4 of Phenytoin Sodium Salt bulk drug, the XRD spectra of 4 '-dipyridyl (middle figure); From the XRD spectrum peak of synthetic Phenytoin Sodium Salt medicine eutectic, can find out the series of features peak about 9.14 °, 12.46 ° and 18.25 °, 19.96 °, 25.28 °, 28.77 °, to occur, conform to for 9.08 °, 12.63 ° and 18.30 °, 19.95 °, 25.23 °, 28.70 ° with the characteristic peak of simulating the medicine eutectic that comes out.There is very big change at the XRD of three curves spectrum peak among the figure, proves that cenotype generates, and is the Phenytoin Sodium Salt and 4 for preparing, 4-dipyridyl eutectic.
The thermogravimetric spectrogram of the Phenytoin Sodium Salt eutectic that Fig. 3: embodiment 1 prepares, the thermogravimetric spectrogram of Phenytoin Sodium Salt and, 4, the thermogravimetric spectrogram of 4 '-dipyridyl bulk drug; Under the air atmosphere test condition, Phenytoin Sodium Salt eutectic thermogravimetric curve: 135 ℃ of beginnings are weightless, to 188 ℃ of weightlessness 80%, decompose fully at 334 ℃ then.The thermogravimetric curve of Phenytoin Sodium Salt bulk drug: 197 ℃ of beginnings are weightless, and 332 ℃ are decomposed fully then.Also provable have cenotype to generate, and the new eutectic weightless temperature for preparing is higher than 4, the 4-dipyridyl, and stability has obtained large increase.
The infrared spectrum of Fig. 4: embodiment 1 synthetic Phenytoin Sodium Salt eutectic; 3157 and 1410cm
-1Be the asymmetric and symmetrical stretching vibration of inferior acid amides, 1594cm
-1Be the skeletal vibration of aromatic series phenyl ring, 3032,2767cm
-1Be the v=C-H peak of phenyl ring, 741cm
-1Be the outer δ=C-H vibration absorption peak of phenyl ring face, 702cm
-1For the phenyl ring list replaces peak, 1726cm
-1Be C=O peak above the five-ring.
Embodiment
The transparent glass instrument that uses in the invention is foreign import, and capacity 20ml has very strong stopping property, and still can keep its stopping property good below 120 ℃.
Following application implementation example is done further elaboration to the present invention, Phenytoin Sodium Salt and 4, and the experiment detailed process of 4 '-dipyridyl eutectic preparation is following:
Embodiment 1:
Use Phenytoin Sodium Salt and 4,4 '-dipyridyl synthesizes eutectic
Weighing:
Reactant is pressed Phenytoin Sodium Salt: 4, and the mass ratio of 4 '-dipyridyl=1: 1 feeds intake.Analytical balance accurately takes by weighing 0.1189mmol (30.0mg) Phenytoin Sodium Salt and 0.1613mmol (31.0mg) 4, and 4 '-dipyridyl is inserted in the Glass Containers.
The dissolving of bulk drug:
Accurately pipette the 5.00ml acetone solvent to Glass Containers with liquid-transfering gun, under 26 ℃ of temperature condition, place on the whisking appliance and stirred 30 minutes.
Solvent evaporation method:
After treating that powder dissolves fully, with the Glass Containers covered and enclosed, making its internal pressure is 101KPa; After under 26 ℃ of temperature condition 1 day, open container cover, place again under 26 ℃ of temperature condition,, generate colourless ROD EUTECTIC after 6 days through solvent slow vaporization method.
Embodiment 2:
Weighing:
Reactant is pressed Phenytoin Sodium Salt: 4, and the mass ratio of 4 '-dipyridyl=1: 1 feeds intake.
Analytical balance accurately takes by weighing 0.0793mmol (20.0mg) Phenytoin Sodium Salt and 0.0988mmol (19.0mg) 4, and the 4-dipyridyl is inserted in the transparent glass container.
The dissolving of bulk drug:
Accurately pipette the 3.00ml acetone solvent to Glass Containers with liquid-transfering gun, placed ultrasonic instrument (ultrasonic frequency is 80Hz, 30 ℃ under) ultrasonic 10 minutes.
Solvent evaporation method:
After treating that powder dissolves fully, with the Glass Containers covered and enclosed, making its internal pressure is 101KPa, places 26 ℃ of temperature condition to open container cover after following 1 day, places under 26 ℃ of temperature condition again, through solvent slow vaporization method, generates colourless ROD EUTECTIC after 2 days.Identical with embodiment 1 structure.The eutectic spacer still is an oblique system, axial length: a=8.0005, b=26.2259, c=7.9776, shaft angle α=90.000, β=91.032, γ=90.000.The XRD spectrum peak of eutectic the series of features peak occurs at 9.15 °, 12.49 ° and 18.24 °, 19.97 °, 25.27 °, 28.76 °.The eutectic thermogravimetric curve: 135 ℃ of beginnings are weightless, to 190 ℃ of weightlessness 80%, decompose fully at 335 ℃ then.The infrared spectrum of eutectic; 3156 and 1410cm
-1Be the asymmetric and symmetrical stretching vibration of inferior acid amides, 1599cm
-1Be the skeletal vibration of aromatic series phenyl ring, 3030,2767cm
-1Be the v=C-H peak of phenyl ring, 742cm
-1Be the outer δ=C-H vibration absorption peak of phenyl ring face, 705cm
-1For the phenyl ring list replaces peak, 1729cm
-1Be C=O peak above the five-ring.
Embodiment 3
Weighing:
Reactant is pressed Phenytoin Sodium Salt: 4, and the mass ratio of 4 '-dipyridyl=1: 1 feeds intake.Analytical balance accurately takes by weighing 0.1625mmol (41.0mg) Phenytoin Sodium Salt and 0.2081mmol (40.0mg) 4, and the 4-dipyridyl is inserted in the Glass Containers.
Insert in the transparent glass container.
The dissolving of bulk drug:
Accurately pipette 4ml acetone and 1ml methanol solvate to Glass Containers with liquid-transfering gun, under 26 ℃ of temperature condition, place on the whisking appliance and stirred 40 minutes.
Solvent evaporation method:
After treating that powder dissolves fully, with the Glass Containers covered and enclosed, making its internal pressure is 101KPa; Place 26 ℃ of temperature condition to open container cover after following 1 day, place again under 26 ℃ of temperature condition, through solvent slow vaporization method; Generate colourless ROD EUTECTIC after 1 day, identical with embodiment 1 structure.The eutectic spacer still is an oblique system, axial length: a=8.0007, b=26.2258, c=7.9796, shaft angle α=90.000, β=91.037, γ=90.000.The XRD spectrum peak of eutectic the series of features peak occurs at 9.16 °, 12.48 ° and 18.26 °, 19.99 °, 25.27 °, 28.77 °.The eutectic thermogravimetric curve: 135 ℃ of beginnings are weightless, to 189 ℃ of weightlessness 80%, decompose fully at 333 ℃ then.The infrared spectrum of eutectic; 3159 and 1412cm
-1Be the asymmetric and symmetrical stretching vibration of inferior acid amides, 1600cm
-1Be the skeletal vibration of aromatic series phenyl ring, 3033,2765cm
-1Be the v=C-H peak of phenyl ring, 740cm
-1Be the outer δ=C-H vibration absorption peak of phenyl ring face, 704cm
-1For the phenyl ring list replaces peak, 1727cm
-1Be C=O peak above the five-ring.
Embodiment 4:
Phenytoin Sodium Salt and 4,4 '-dipyridyl is through the synthetic eutectic of polishing
Weighing:
Reactant is pressed Phenytoin Sodium Salt: 4, and the mass ratio of 4 '-dipyridyl=1: 1 feeds intake.Analytical balance accurately takes by weighing 0.3171mmol (80.0mg) Phenytoin Sodium Salt and 0.4162mmol (80.0mg) 4, and 4 '-dipyridyl is inserted in the agate mortar, the careful grinding evenly and the porphyrize reactant.Move in 20 μ L methyl alcohol to the above-mentioned powder with the micropipette rifle, ground 3 minutes uniformly rapidly.The powder that obtains is identical with the eutectic structure of embodiment 1,2,3, and has shortened experimental period and cost greatly.
Use identical mass ratio to feed intake simultaneously, the careful grinding evenly and the porphyrize reactant.Move in 10 μ L acetate to the above-mentioned powder with the micropipette rifle, ground 5 minutes; 10 μ L methyl-sulphoxides (DMSO) ground 5 minutes; 10 μ L Virahols (IPA) ground 4 minutes; 20 μ L ethanol ground 3 minutes; 10 μ L chloroforms ground 3 minutes; 10 μ L Ns (DMF) ground 4 minutes; 20 μ L acetone ground 3 minutes; 10 μ L pyridines ground 3 minutes; 20 μ L methylene dichloride ground 3 minutes; 10 μ L acetonitriles (MeCN) ground 5 minutes; 20 μ L propylamine ground 5 minutes; 10 μ L methane amides ground 5 minutes.The powder that obtains all eutectic structure with embodiment 1,2,3 is identical.The XRD spectrum peak of eutectic the series of features peak occurs at 9.13 °, 12.486 ° and 18.26 °, 19.96 °, 25.26 °, 28.75 °.The eutectic thermogravimetric curve: 135 ℃ of beginnings are weightless, to 189 ℃ of weightlessness 80%, decompose fully at 335 ℃ then.The infrared spectrum of eutectic; 3156 and 1408cm
-1Be the asymmetric and symmetrical stretching vibration of inferior acid amides, 1603cm
-1Be the skeletal vibration of aromatic series phenyl ring, 3031,2766cm
-1Be the v=C-H peak of phenyl ring, 742cm
-1Be the outer δ=C-H vibration absorption peak of phenyl ring face, 702cm
-1For the phenyl ring list replaces peak, 1726cm
-1Be C=O peak above the five-ring.
The ratio and other reaction conditionss that change former dosage among the embodiment 1,2,3,4 be like temperature of reaction, ultrasonic frequency, and churning time behind the solvent species etc., all can obtain the medicine eutectic that stability, solvability improve greatly.Wherein, API and precursor better are dissolved in the solvent, obtain more stable eutectic through ultrasonic method; Change solvent species and possibly accelerate speed of reaction; On the other hand, use the Glass Containers of the special-purpose good airproof performance of experiment, high temperature high voltage resistant that reactant is better reacted, do not have the interference of outer bound pair crystal growth.The medicine eutectic for preparing through above method all can improve the solubleness of medicine, and performances such as stability and bioavailability make medicine obtain using better widely.
Claims (3)
1. Phenytoin Sodium Salt medicine eutectic, with the Phenytoin Sodium Salt bulk drug as active constituents of medicine, with 4; 4 '-dipyridyl is the medicine presoma, it is characterized in that: the spacer of eutectic is an oblique system, its axial length a=7.0000～9.0000; B=25.0000～27.0000, c=7.0000～9.0000, shaft angle α=89.000～91.000; β=85.000～95.000, γ=89.000～91.000; There is the series of features peak in its XRD spectra between 9.00 °～9.30 °, 12.20 °～12.50 °, 18.00 °～18.50 °, 19.50 °～20.20 °, 25.00 °～25.50 ° and 28.50 °～29.00 °; Its eutectic infrared spectrum is at 3100～3200cm
-1With 1380～1450cm
-1Between go out the asymmetric and symmetrical stretching vibration that the peak is inferior acid amides, at 3000～3050cm
-1, 2750～2800cm
-1Between go out the ν that the peak is a phenyl ring
=C-HThe peak is at 1720～1730cm
-1Characteristic peak occurring is C=O peak above the five-ring, at 1580～1610cm
-1Between go out the skeletal vibration that the peak is the aromatic series phenyl ring, at 730～750cm
-1Between to go out the peak be the outer δ of phenyl ring face
=C-HVibration absorption peak is at 690～710cm
-1Between go out the peak and be that the phenyl ring list replaces the peak.
2. the preparation method of the described Phenytoin Sodium Salt medicine of claim 1 eutectic the steps include:
(1) Phenytoin Sodium Salt and 4; 4 '-dipyridyl grinds to form 140～300 purpose powder respectively, places transparent glass container, is dissolved in the organic solvent jointly then; Wherein, Phenytoin Sodium Salt and 4, the mass ratio of 4 '-dipyridyl is 1: 1～1: 2, the mass concentration of Phenytoin Sodium Salt is 5g/L～10g/L in organic solvent; Organic solvent is acetone, methyl alcohol or ethanol;
The Glass Containers that (2) will fill above-mentioned mixing solutions places and stirs on the whisking appliance or place ultrasonic instrument ultrasonic; After treating that powder dissolves fully; With the Glass Containers covered and enclosed, making its internal pressure is 100～150kPa, places under 20 ℃～30 ℃ temperature condition and opens container cover after 1～5 day; Generate colourless ROD EUTECTIC after 1～15 day through solvent slow vaporization method, be Phenytoin Sodium Salt medicine eutectic.
3. the preparation method of the described Phenytoin Sodium Salt medicine of claim 1 eutectic the steps include:
(1) with mass ratio be 1: 1～1: 5 Phenytoin Sodium Salt and 4,4 '-dipyridyl is inserted in the agate mortar that diameter is 8～20cm, and reactant is ground to form 140～300 purpose powder;
(2) move in 5～100 μ L organic solvents to the above-mentioned powder with the micropipette rifle then, wherein the mass concentration of Phenytoin Sodium Salt in organic solvent is 2g/mL～18g/mL; Ground 0.5～30 minute uniformly rapidly more afterwards, the amorphous powder that obtains is Phenytoin Sodium Salt medicine eutectic; Organic solvent is one or more the mixing in acetone, methyl alcohol, ethanol, acetate, methyl-sulphoxide, Virahol, chloroform, N, pyridine, methylene dichloride, acetonitrile, propylamine, the methane amide.
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| JP4906233B2 (en) * | 2002-03-01 | 2012-03-28 | ユニバーシティー オブ サウス フロリダ | Multi-component solid phase containing at least one active pharmaceutical ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1111532A (en) * | 1993-12-06 | 1995-11-15 | 武田药品工业株式会社 | Composition containing water unsolable or micro-solable compound which is raised with water solability |
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