CN104151163B - A kind of crystal formation of aspirin and its preparation method and application - Google Patents
A kind of crystal formation of aspirin and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
- C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
nullThe present invention provides crystal formation of a kind of aspirin and its preparation method and application，Aspirin crude drug is dissolved in dehydrated alcohol，Then reflux in 75～85 DEG C of water-baths，4 DEG C of distilled water of 1～3 times of volume are added after backflow，Then crystallization is stood in 0～15 DEG C，7～9h it are vacuum dried under room temperature，The X-ray powder diffraction figure of crystal formation is about in 2 θ=15.5 °、23.3°、23.4°、Characteristic peak is shown at 27.1 ° and 31.4 °，The inventive method is simple、Environmental protection，Especially selecting ethanol is recrystallisation solvent，Safe and easily separated，It is applicable to industrialized great production，Crystal formation dissolution test in vitro has quick-releasing property，Have rapid-action in animal body、Drug effect is high、The advantage of persistent，Solid preparation and pharmaceutical composition thereof can be manufactured as active constituents of medicine，Antipyretic、Analgesia、Antiinflammatory and preventing and treating cardiovascular and cerebrovascular disease play more preferable clinical efficacy.
Description
Technical field
The invention belongs to medicine production technical field, novel crystal forms being specifically related to a kind of aspirin and preparation method thereof and
Application.
Background technology
Aspirin (aspirin), systematic chemical name is: Aspirin, and structural formula is as shown in Equation 1.
Aspirin, in listing in 1898, is classical antipyretic-antalgic anti-inflammatory agent, discovered in recent years it also there is anti-platelet aggregation
Effect, is extensively recommended the prevention for cardiovascular disease by domestic and international Medical guidelines, again causes the attention of people.
Found by patent retrieval, record " the second of Fred .P. Du Kateman invention at Chinese patent CN86102837A
The preparation of acyl sodium salicylate stable crystalline body ", it is directed to the preparation method of the flaky crystal of a kind of sodium asprinin；China is specially
Profit CN101977888A records " the noncrystalline aspirin of room-temperature stable " of tod .F. Ao Wokaitaisi invention, relates to sending out
The armorphous solid existence of existing aspirin and preparation method；Chinese patent CN103613500A records Shandong Xinhua system
" preparation method of aspirin fine crystallization " of medicine limited company invention, relates to a kind of side preparing aspirin fine crystallization
Method.
Do not find that the Chinese literature in terms of aspirin novel crystal forms discovery is recorded through retrieval；Retrieval foreign language is sent out further
There is the data of 2 kinds of crystal formations in existing pass aspirin, the aspirin of Bayer is former grind medicine and domestic aspirin crude drug and
Involved by preparation is all crystal formation I known to aspirin；At Science (1968,76:160) and
J.PHarm.PHarmacol.Lett. two articles on (1969,21:701-702) disclose aspirin the earliest and there is crystal formation
II, and by the blood drug level in test healthy volunteer's body, find that crystal formation I blood drug level the most medicinal for crystal formation II is high
Go out 70%.The crystal formation II of aspirin is studied by the most substantial amounts of scholar, such as Bundgaard,
H.J.PHarm.PHarmacol.,1974,26,535-540；Braga,D；A.D.Bond,R.Boese and
G.R.Desiraju,Angew.Chem.,Int.Ed.,2007,46,615.；Grepioni,F.；Maini,
L.Chem.Commun., 2010,46,6232-6242 etc..But above-mentioned document provides aspirin crystal formation II characteristic information and does not unite
One, and preparation method is loaded down with trivial details, stability of crystal form is bad, the most quickly turns crystalline substance and becomes crystal formation I；Partha in 2012
Pratim Bag and C.Malla Reddy is published in a news flash (Cryst.Growth in " crystal growth and design "
Des.2012,12,2740-2743) the most clearly providing fusing point and the XRD information of crystal formation II, preparation method is rapid evaporation method, knot
Brilliant solvent is ether or dichloromethane, but the recrystallisation solvent toxicity involved by this method is very big, is not particularly suited for industrialized production
Aspirin crystal formation II, so the medicinal of crystal formation II is very limited.Therefore, research drug effect more preferably aspirin novel crystal forms
And invent a kind of simple, environmental protection and the preparation method of production suitable for industrialized, significant to pharmaceutical industry.
It is known that recrystallisation solvent is different or method for crystallising difference can produce different crystal formations, may between different crystal forms
There is bigger physicochemical property and drug effect difference.At present, without pertinent literature report aspirin polymorphic In Vitro Dissolution and internal
The research of drug effect.In view of the market application foreground of aspirin, the novel crystal forms of research aspirin and environmental protection, the easily side of preparation
Method, and in depth probe into the dissolved corrosion between polymorphic and drug effect difference, the physicochemical property of the most different aspirin crystal formations,
The similarities and differences of pharmaceutical preparation performance, can be crude drug and the production technology of pharmaceutical industry offer advantage medicinal crystal-form.Employing advantage is brilliant
The aspirin crude drug of type is possible not only to improve drug effect, and can reduce the generation of adverse effect.
Summary of the invention
It is an object of the invention to provide crystal formation of a kind of aspirin and its preparation method and application.
For reaching above-mentioned purpose, present invention employs techniques below scheme:
The crystal formation (crystal formation III) of a kind of aspirin, the X-ray powder diffraction figure of this crystal formation is about in 2 θ=15.54 °
(15.5 °), 23.35 ° (23.3 °), 23.42 ° (23.4 °), 27.09 ° (27.1 °) and 31.40 ° of (31.4 °) places show feature
Peak.
The described crystal formation X-ray powder diffraction figure concrete diffraction maximum position in the range of 2 θ are 10～50 ° and relative intensity
As shown in table 1:
Table 1 aspirin crystal formation III2 θ XRD peak value in the range of 10～50 °
The endothermic transition temperature of described crystal formation is 139～141 DEG C.
The infrared absorption spectroscopy of described crystal formation is about at 3487cm-1、3462cm-1、3446cm-1、3431cm-1、3421cm-1、
3057cm-1、3020cm-1、2999cm-1、2962cm-1、2943cm-1、2891cm-1、2871cm-1、2835cm-1、2698cm-1、
2669cm-1、2588cm-1、2548cm-1、2361cm-1、1753cm-1、1693cm-1、1654cm-1、1604cm-1、1576cm-1、
1558cm-1、1541cm-1、1533cm-1、1522cm-1、1516cm-1、1483cm-1、1458cm-1、1435cm-1、1420cm-1、
1371cm-1、1308cm-1、1256cm-1、1221cm-1、1188cm-1、1136cm-1、1095cm-1、1013cm-1、970cm-1、
918cm-1、885cm-1、841cm-1、804cm-1、791cm-1、756cm-1、706cm-1、667cm-1、644cm-1、600cm-1、
563cm-1、544cm-1、515cm-1、424cm-1There is absworption peak at place, wherein at 3421cm-1、3020cm-1、2999cm-1、2962cm-1、2871cm-1、1753cm-1、1693cm-1、1604cm-1、1576cm-1、1458cm-1、1420cm-1、1371cm-1、1308cm-1、
1221cm-1、1188cm-1、918cm-1、756cm-1、706cm-1、600cm-1、544cm-1And 515cm-1Place shows characteristic absorption
Peak.
The Raman spectrum of described crystal formation is about at 3096cm-1、3081cm-1、3071cm-1、3063cm-1、2945cm-1、
1754cm-1、1640cm-1、1631cm-1、1624cm-1、1609cm-1、1444cm-1、1431cm-1、1429cm-1、1376cm-1、
1373cm-1、1370cm-1、1296cm-1、1271cm-1、1262cm-1、1227cm-1、1194cm-1、1165cm-1、1049cm-1、
1036cm-1、1018cm-1、788cm-1、754cm-1、708cm-1、644cm-1、641cm-1、554cm-1、428cm-1、326cm-1、
294cm-1、264cm-1、268cm-1、173cm-1Place is with the presence of absworption peak, wherein at 3096cm-1、3081cm-1、2945cm-1、
1754cm-1、1640cm-1、1631cm-1、1624cm-1、1609cm-1、1296cm-1、1262cm-1、1194cm-1、1049cm-1、
788cm-1、754cm-1、554cm-1And 428cm-1Place shows characteristic absorption peak.
Described crystal formation dissolution is characterised by: in vitro in dissolution test, in same dissolution medium, compared with crude drug,
Crystal formation III has faster dissolution rate, higher stripping quantity, and in multiple dissolution medium, crystal formation III reaches 65 at the dissolution of 60min
～100%.
After described crystal formation oral medication 1 hour starts onset, within after oral medication 2 hours, reaches maximum drug effect, and drug effect maintains
Time is 1～4h, has obvious drug effect advantage in 1～4h compared with aspirin crude drug after oral medication.
The method preparing the crystal formation (crystal formation III) of above-mentioned aspirin, comprises the following steps:
10g aspirin crude drug is added in 30～80mL dehydrated alcohol, then reflux in 75～85 DEG C of water-baths 2～
3h obtains backflow, adds 4 DEG C of distilled water of 1～3 times of backflow volume, then stand crystallization in 0～15 DEG C in backflow, logical
Cross the solid matter separation that crystallization is obtained by sucking filtration, then described solid matter vacuum under room temperature (is less than or equal to
0.02Mpa) it is dried 7～9h.
The crystal formation of above-mentioned aspirin is being prepared in the medicine of antipyretic, analgesia, antiinflammatory or prevention cardiovascular and cerebrovascular disease
Application.In above-mentioned aspirin crystal formation (crystal formation III) antiinflammatory, analgesic experiment in vivo, with crystalline substance compared with the crude drug of dosage
Type III onset time is fast, drug effect is high, action time is lasting, is suitable to prepare aspirin novel crystal forms pharmaceutical preparation and combinations thereof thing.
Beneficial effects of the present invention is embodied in:
The present invention has prepared a kind of purity height, the aspirin novel crystal forms (crystal formation III) of good stability, its crystal formation system
Preparation Method is simple, environmental protection, and especially selecting ethanol is recrystallisation solvent, safe and easily separated, it is adaptable to industrialized great production.At body
In outer dissolution experiment, crystal formation III dissolution rate is faster, and accumulative release concentration is significantly higher than crude drug；Effect experiment in animal body
The drug effect of middle crystal formation III is significantly better than crude drug, can be used for preparing the novel crystal forms preparation of aspirin and pharmaceutical composition thereof.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of the aspirin crystal formation III of the present invention；
Fig. 2 is the DSC collection of illustrative plates of the aspirin crystal formation III of the present invention；
Fig. 3 is the Fourier-infared spectrum of the aspirin crystal formation III of the present invention；
Fig. 4 is the Raman spectrogram of the aspirin crystal formation III of the present invention；
Fig. 5 is the aspirin crystal formation III of present invention Cumulative release profile figure in the hydrochloric acid of pH1.2；
Fig. 6 is the aspirin crystal formation III of present invention Cumulative release profile in the acetate buffer solution of pH4.5
Figure；
Fig. 7 is the aspirin crystal formation III of present invention Cumulative release profile in the phosphate buffered solution of pH6.8
Figure；
Fig. 8 is the aspirin crystal formation III of present invention Cumulative release profile figure in water；
Fig. 9 is the aspirin crystal formation III analgesia drug effect at mouse hot-plate model of the present invention；
Figure 10 is the X-ray powder diffraction pattern of aspirin crude drug of the present invention (crystal formation I).
Detailed description of the invention
With embodiment, the present invention is elaborated below in conjunction with the accompanying drawings.
The present invention provides a kind of aspirin novel crystal forms being named as aspirin crystal formation III, aspirin crystal formation III
Different from the solid existence of two kinds of aspirin crystal formations that current document is reported；The aspirin that the present invention provides simultaneously is brilliant
The preparation method of type III, has environmental protection, simple, and the advantage being suitable for industrialized large-scaled production；Experiment shows, aspirin crystal formation
III has the advantages characteristic that release in vitro is quick, drug effect is high and action time is lasting.
1. the specific features of aspirin crystal formation III is described as follows:
DSC characterizes: heating rate is 10 DEG C/min, and temperature range is 25～170 DEG C, and endothermic transition is at 139～141 DEG C；
XRD characterize: Cu-K α radiates (40kV, 40mA), sweep limits 10～50 °, diffraction pattern about in 2 θ=15.54 °, 23.35 °,
Characteristic peak is shown at 23.42 °, 27.09 ° and 31.40 °；Infrared absorption spectroscopy characterizes: KBr tabletting, about at 3421cm-1、
3020cm-1、2999cm-1、2962cm-1、2871cm-1、1753cm-1、1693cm-1、1604cm-1、1576cm-1、1458cm-1、
1420cm-1、1371cm-1、1308cm-1、1221cm-1、1188cm-1、918cm-1、756cm-1、706cm-1、600cm-1、544cm-1
And 515cm-1Place shows the characteristic absorption peak of crystal formation III；Raman Characterization: optical maser wavelength is 633nm, scans wave-number range
It is 100～4000cm-1, about at 3096cm-1、3081cm-1、2945cm-1、1754cm-1、1640cm-1、1631cm-1、1624cm-1、1609cm-1、1296cm-1、1262cm-1、1194cm-1、1049cm-1、788cm-1、754cm-1、554cm-1And 428cm-1Place's table
Reveal characteristic peak.
2. the concrete preparation method of aspirin crystal formation III is as follows:
Aspirin crude drug is dissolved in dehydrated alcohol (i.e. aspirin crude drug and the dehydrated alcohol of about 3～8 times of volumes
W/v be 1g/ (3～8mL)) in, be placed in water bath with thermostatic control, at temperature is 75～85 DEG C reflux 2～3h, the coldest
But (prevent container from meeting cold explosion) after and add 1～4 DEG C of distilled water of 3 times of volumes, then stand crystallization, sucking filtration, crystallization in 0～15 DEG C
Thing is placed in vacuum drying oven, in room temperature, less than or equal to 0.02Mpa under be vacuum dried 7～9h, remove residual solvents and moisture,
Collect gained crystal formation.Crystal formation III prepared by the present invention, dissolution rate is fast, and drug effect is higher, good stability, is that preferable pharmacy is former
Material, and preparation method is simple and environmentally-friendly, is suitable for industrialized large-scaled production.
3. the preparation performance evaluation of aspirin crystal formation III is as follows:
(1) vitro cumulative drug release determination
Aspirin crude drug and crystal formation III cross No. 4-6 sieve respectively, take powder appropriate, molten according to 2010 editions Chinese Pharmacopoeias
Out-degree measure correlation technique, in four kinds of dissolution mediums (water, the hydrochloric acid solution of pH1.2, the acetate buffer of pH4.5,
The phosphate buffer of pH6.8) in, use the accumulative release concentration of both white oil by dual-wavelength methods, draw Dissolution profiles.Record
Aspirin crystal formation III has dissolution rate and higher accumulative releasing degree faster compared with crude drug.
(2) the internal evaluation of pesticide effectiveness
Use antiinflammatory (mice ear, Rat Carrageenan are tested) and analgesia (mouse hot-plate experiment, acetic acid twisting experiment)
Aspirin crude drug and the drug effect of crystal formation III under model determination Isodose.Internal pharmacodynamic results shows aspirin crystal formation
III is superior to crude drug at aspects such as onset time, duration of efficacy, ceiling effects.
Embodiment:
The preparation of aspirin crystal formation III
Take 10g aspirin crude drug to be dissolved in the dehydrated alcohol of 50mL, make the ethanol solution of aspirin, then put
Reflux in 80 DEG C of water-baths 2h, slightly adds 4 DEG C of distilled water of 2 times of backflow volumes after cooling, and stands crystallization 2h, crystallization in 4 DEG C
Rear decompression sucking filtration, the filtering residue that sucking filtration obtains is transferred in culture dish, then in vacuum drying oven, true under room temperature, 0.02Mpa
The empty 8h that is dried, collection gained crystal, weigh (9.0g), seals up for safekeeping.
The physical characterization analysis of aspirin crystal formation III
By X-ray powder diffraction (XRD) analyze aspirin crystal formation III Powder samples (condition determination: Cu-K α radiate,
Graphite monochromatic diffraction, 40kV, 40mA, sweep limits is 10～50 °；Test instrunment: Germany Bruker-axs company d8advance
Type X-ray diffractometer).Measurement result shows, aspirin crystal formation III about in 2 θ=15.54 °, 23.35 °, 23.42 °,
Characteristic peak is shown at 27.09 ° and 31.40 °.The representative X-ray powder diffraction figure of aspirin crystal formation III is shown in Fig. 1.
Endothermic transition characteristic (the condition determination: rise of aspirin crystal formation III is analyzed by differential scanning calorimetry (DSC)
Beginning temperature is 25 DEG C, and final temperature is 170 DEG C, and heating rate is 10 DEG C/min；Test instrunment: Switzerland METTLER TOLEDO is public
Department's DSC822 type differential scanning calorimeter).Test result shows, the characteristic endothermic transition of aspirin crystal formation III is about 139
～141 DEG C.The representative DSC figure of aspirin crystal formation III is shown in Fig. 2.
By infrared (IR) absorption spectroanalysis aspirin crystal formation III (method of testing: KBr pressed disc method；Test instrunment:
Shimadzu, Japan FTIR-8400S type Fourier transform infrared spectrometer).Test result shows, aspirin crystal formation
The characteristic absorption peak of III is about at 3421cm-1、3020cm-1、2999cm-1、2962cm-1、2871cm-1、1753cm-1、1693cm-1、
1604cm-1、1576cm-1、1458cm-1、1420cm-1、1371cm-1、1308cm-1、1221cm-1、1188cm-1、918cm-1、
756cm-1、706cm-1、600cm-1、544cm-1And 515cm-1.The representative infrared spectrogram of aspirin crystal formation III is shown in Fig. 3.
By Raman spectrum analysis aspirin crystal formation III, (test condition: optical maser wavelength 633nm, scanning wave-number range is
100～4000cm-1, 17mW；Test instrunment: France's HORIBA JOBIN YVON company HR800 type laser Raman spectrometer).Survey
Test result shows, the characteristic absorption peak of aspirin crystal formation III is about at 3096cm-1、3081cm-1、2945cm-1、1754cm-1、
1640cm-1、1631cm-1、1624cm-1、1609cm-1、1296cm-1、1262cm-1、1194cm-1、1049cm-1、788cm-1、
754cm-1、554cm-1And 428cm-1.The representative Raman spectrogram of aspirin crystal formation III is shown in Fig. 4.
The vitro release of aspirin crystal formation III measures
The aspirin crystal formation III prepared by embodiment and aspirin crude drug cross No. 4, No. 6 sieves the most successively, take
The sample of No. 4-6 sieve, according to the method (Rotating shaker) of the dissolution determination of 2010 editions " Chinese Pharmacopoeias " four kinds of dissolution systems
(pH1.2 hydrochloric acid, pH4.5 acetate buffer, pH6.8 phosphate buffer and water) is measured.
1) experimental condition
Method: Rotating shaker
Temperature: 37 ± 0.5 DEG C；
Rotating speed: controlling slurry rotating speed is 100 ± 1r/min；
Granularity: crude drug and crystal formation III all cross No. 4-6 sieve；
Dissolution medium: pH1.2 hydrochloric acid, pH4.5 acetate buffer, pH6.8 phosphate buffer and water；
2) collection of sample and mensuration
Measure the hydrochloric acid 500mL (as a example by the hydrochloric acid of pH1.2, other three kinds of media all with) of pH1.2, inject stripping rotor,
Heating keeps the temperature at 37 ± 0.5 DEG C；Adjustment rotating speed is 100r/min, by aspirin crude drug or the crystalline substance of precision weighing
Type III8g is placed in and turns in basket, starts immediately and rotates and start timing；Respectively 1min, 5min, 15min, 30min, 45min,
Sampling when 60min, 90min, 120min, 150min, 180min, 240min, every sub-sampling 1mL, through the microporous filter membrane of 0.45 μm
Filter, take subsequent filtrate 0.5mL, after each sampling, in stripping rotor, replenish the corresponding dissolution medium of 1mL immediately.Every kind of crystal formation
Parallel assay three times in every kind of dissolution medium.Use white oil by dual-wavelength method aspirin and salicylic absorption value, calculate
ADifference, get rid of salicylic interference, calculate the concentration of different time points aspirin according to standard curve, draw aspirin former
Material medicine and the vitro cumulative releasing curve diagram of crystal formation III, result is shown in Fig. 5-Fig. 8, it can be seen that crystal formation in four kinds of dissolution mediums
III shows higher dissolution (dissolution of crystal formation III is 65～100%) than crude drug in 60min；Crystal formation III exists
In four kinds of dissolution mediums, the accumulative release concentration in 15～60min is significantly higher than crude drug (P < 0.05)；I.e. crystal formation III ratio is former
Material medical instrument has dissolution rate and higher dissolution faster.
The internal evaluation of pesticide effectiveness of aspirin crystal formation III
Laboratory animal: Kunming mouse, body weight 18～22g；SD rat, male and female half and half, body weight 130～150g.By Xi'an
University of communications's medical college Experimental Animal Center provides.
(1) antiinflammatory experiment
Aspirin crystal formation III suppression mice caused by dimethylbenzene xylene ear swelling experiment
1) take 40 male mice in kunming, be randomly divided into 4 groups (matched group, group of solvents, crude drug group, crystal formation III groups),
Often group 10.
2) before use, with 0.4% xanthan gum solution, medicine being prepared as suspension, dosage is 100mg/kg, according to
Liquor strength is converted into 0.2mL/10g and carries out gastric infusion: matched group is not administered；Group of solvents: give 0.4% xanthan gum solution；
Crude drug group: give the suspension of aspirin crude drug；Crystal formation III group: the aspirin crystal formation III giving corresponding dosage mixes
Suspension.
3) after being administered 1h, it is scorching that each group mouse right ear is coated with 20 μ L caused by dimethylbenzene xylene, and after 1h, the most de-cervical vertebra is put to death, along auricle limit
Edge cuts ears, with the card punch of diameter 9mm, sweeps away auricle in same area, weighs with analytical balance, the weight of record auricle
Amount.
4) swelling is calculated, by swelling as evaluation index: swelling=auris dextra weight-left ear weight.
5) result is painted table and carries out statistical analysis, is shown in Table 2, it can be seen that aspirin crystal formation III can significantly inhibit two
The mouse ear swelling (P < 0.01 compared with matched group) that toluene causes；And the effect of aspirin crystal formation III is better than Ah Si
Woods crude drug (P < 0.01)；I.e. in terms for the treatment of mice caused by dimethylbenzene xylene ear inflammation, aspirin crystal formation III curative effect is better than former
Material medicine.
Table 2 aspirin crystal formation III suppression mice caused by dimethylbenzene xylene ear swelling effect (N=10)
Compare with matched group,*P < 0.05,**P<0.01；Compare with crude drug group#P < 0.05,##P<0.01
Aspirin crystal formation III suppression chondrus ocellatus Holmes causes rat paw edema experiment
1) take 32 SD rats, male and female half and half, be randomly divided into 4 groups of (matched group, group of solvents, crude drug group, crystal formation III
Group), often group 8, measure the original volume of Rat Right metapedes, i.e. rat sufficient volume in normal state.
2) before use, with 0.4% xanthan gum solution, medicine being prepared as suspension, dosage is 100mg/kg, according to
Liquor strength is converted into 2mL/100g and carries out gastric infusion: matched group is not administered；Group of solvents: give 0.4% xanthan gum solution；Former
Material medicine group: give the suspension of aspirin crude drug；Crystal formation III group: give the aspirin crystal formation III suspendible of corresponding dosage
Liquid.
4) 0.5h after being administered, each group Rat Right hindpaw injection 1% carrageenin causes inflammation.
5) Rat Right metapedes volume is measured respectively when 0.5h, 1h, 2h, 3h, 4h, 6h after causing inflammation；
6) swelling is calculated, using swelling as evaluation index: swelling=(sufficient volume of different time points-initially sufficient
Volume)/initial foot volume × 100%.
7) result is painted table and carries out statistical analysis, is shown in Table 3, it can be seen that after administration 1～6h, aspirin crystal formation III
The rat paw edema effect (P < 0.01 compared with matched group) caused by chondrus ocellatus Holmes can be significantly inhibited；Aspirin crystal formation III is 1
～the effect of 4h is significantly better than aspirin crude drug (P < 0.01 or P < 0.05 compared with crude drug group) i.e. aspirin crystal formation
III causes the curative effect of rat foot aspect of inflammation than crude drug more preferably treatment chondrus ocellatus Holmes.
Table 3 aspirin crystal formation III suppression chondrus ocellatus Holmes cause rat paw edema effect (N=8)
Compare with matched group,*P < 0.05,**P<0.01；Compare with crude drug group#P < 0.05,##P<0.01
(2) analgesic experiment
Aspirin crystal formation III suppression hot plate causes mice pain experiment
1) arranging hot plate temperature is 55 DEG C, makes temperature constant in 55 ± 0.5 DEG C time, and test can proceed by；
2) take 80 Kunming kind female mices, first measure the normal pain reaction (lift metapedes and turn one's head or lick metapedes) of mice
Time, i.e. Basic Pain Threshold, surveying 3 times altogether, time interval is 10min, is qualified mice with the average time of mice in 5～30s,
Select 40 qualified mices, be randomly divided into 4 groups (matched group, group of solvents, crude drug group, crystal formation III groups), often group 10.
2) before use, with 0.4% xanthan gum solution, medicine being prepared as suspension, dosage is 100mg/kg, according to
Liquor strength is converted into 0.2mL/10g and carries out gastric infusion: matched group is not administered；Group of solvents: give 0.4% xanthan gum solution；
Crude drug group: give the suspension of aspirin crude drug；Crystal formation III group: the aspirin crystal formation III giving corresponding dosage mixes
Suspension.
4), after being administered, mensuration mice is in the pain response time of 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, such as mice
In beaker, 60s is reactionless, then press 60s and calculate.
5) threshold of pain increase rate is calculated, using threshold of pain increase rate as evaluation index: threshold of pain increase rate=(after administration during pain reaction
The pain response time before m-administration)/it is administered front pain response time × 100%.
6) result is drawn and carries out statistical analysis, sees Fig. 9, it can be seen that upon administration 1～4h, aspirin crystal formation
III can significantly improve hot plate and cause mice pain reaction (P < 0.01 compared with matched group)；Aspirin crystal formation III 1.5,2,
The analgesic effect of 2.5h is significantly better than crude drug (with crude drug group than P < 0.05) i.e. crystal formation III and causes mice pain at treatment hot plate
The curative effect of aspect is more preferable than crude drug.
Aspirin crystal formation III suppression acetic acid causes mouse writhing experiment
1) trial test, lumbar injection 0.6% acetum, 0.2mL/ only, observe mouse writhing in 15min (abdominal part caves in,
Trunk is upheld with hind leg) number of times, select the Kunming mouse 40 that writhing number of times is at about 30 times, male and female half and half；
2) it is randomly divided into 4 groups (matched group, group of solvents, crude drug group, crystal formation III groups), often group 10.
3) before use, with 0.4% xanthan gum solution, medicine being prepared as suspension, dosage is 100mg/kg, according to
Liquor strength is converted into 0.2mL/10g and carries out gastric infusion: matched group is not administered；Group of solvents: give 0.4% xanthan gum solution；
Crude drug group: give the suspension of aspirin crude drug；Crystal formation III group: the aspirin crystal formation III giving corresponding dosage mixes
Suspension.
4) 1h after being administered, each group mouse peritoneal is injected 0.6% acetum, 0.2mL/, is observed mouse writhing in 15min
Number of times, using writhing number of times as evaluation index.
5) result paints table, and carries out statistical analysis, is shown in Table 4, it can be seen that aspirin crystal formation III can significantly improve vinegar
The mouse web portion pain reaction (P < 0.01 compared with matched group) that acid causes；The analgesic effect of aspirin crystal formation III is the most excellent
In crude drug (P < 0.01 compared with crude drug group) i.e. aspirin crystal formation III curative effect in terms for the treatment of acetic acid causes mice pain
More preferable than crude drug.
Table 4 aspirin crystal formation III suppression acetic acid cause mouse writhing effect (N=10)
Compare with matched group,*P < 0.05,**P<0.01；Compare with crude drug group#P < 0.05,##P<0.01
Aspirin crude drug used by the present invention is the most classical medicinal aspirin crystal formation I, and powder diagram is shown in
Shown in Figure 10, show the characteristic diffraction peak of crystal formation I.
The stability of aspirin crystal formation III
After crystal formation III embodiment prepared seals half a year up for safekeeping under room temperature, again carry out physical characterization analysis, point
Analysis result keeps constant, and having good stability of aspirin crystal formation III is described.
Owing to aspirin crystal formation III has release characteristics faster in vitro, affect its absorption in vivo, point
The process such as cloth, metabolism, and then show higher drug effect and longer drug action time in vivo, therefore, utilize Ah
Department's woods crystal formation III solid matter as active component, can manufacture out medicine and combinations thereof thing and antipyretic, ease pain, anti-
The aspects such as inflammation and cardiovascular and cerebrovascular disease prevention carry out clinical practice, thus reach to improve the effect of clinical drug curative effect.
Claims (6)
1. the crystal formation of an aspirin, it is characterised in that: the X-ray powder diffraction figure of this crystal formation in 2 θ=15.54 °,
Characteristic peak is shown at 23.35 °, 23.42 °, 27.09 ° and 31.40 °；The endothermic transition temperature of described crystal formation is 139～141
℃。
A kind of crystal formation of aspirin, it is characterised in that: the infrared absorption spectroscopy of described crystal formation exists
3421cm-1、3020cm-1、2999cm-1、2962cm-1、2871cm-1、1753cm-1、1693cm-1、1604cm-1、1576cm-1、
1458cm-1、1420cm-1、1371cm-1、1308cm-1、1221cm-1、1188cm-1、918cm-1、756cm-1、706cm-1、
600cm-1、544cm-1And 515cm-1Place shows characteristic absorption peak.
A kind of crystal formation of aspirin, it is characterised in that: the Raman spectrum of described crystal formation exists
3096cm-1、3081cm-1、2945cm-1、1754cm-1、1640cm-1、1631cm-1、1624cm-1、1609cm-1、1296cm-1、
1262cm-1、1194cm-1、1049cm-1、788cm-1、754cm-1、554cm-1And 428cm-1Place shows characteristic absorption peak.
A kind of crystal formation of aspirin, it is characterised in that: in described crystal formation dissolution test in vitro
The dissolution of 60min reaches 65～100%.
A kind of crystal formation of aspirin, it is characterised in that: after described crystal formation oral medication 1 hour
Starting onset, within after oral medication 2 hours, reach maximum drug effect, duration of efficacy is 1～4h.
6. the method for the crystal formation preparing aspirin as claimed in claim 1, it is characterised in that: comprise the following steps:
Being added by 10g aspirin crude drug in 30～80mL dehydrated alcohol, then in 75～85 DEG C of water-baths, backflow 2～3h obtains
Backflow, adds 4 DEG C of distilled water of 1～3 times of backflow volume in backflow, then stands crystallization in 0～15 DEG C, by taking out
The solid matter that crystallization is obtained by filter separates, and is then vacuum dried under room temperature by described solid matter.
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