CN103536633B - A kind of hydrophily indigo naturalis and preparation method thereof - Google Patents
A kind of hydrophily indigo naturalis and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of hydrophily indigo naturalis, in this hydrophily indigo naturalis, contain activator more than 0.3%w/w; In described activator, contain lipophilic group alkyl and hydrophilic radical simultaneously. The present invention also provides the preparation method of hydrophily indigo naturalis. Hydrophily indigo naturalis of the present invention, has significantly reduced the contact angle of indigo naturalis, can effectively improve the dispersiveness of indigo naturalis in water, having overcome common indigo naturalis floats on liquid level, is difficult to disperse to enter the problem in water, the patient that is more convenient for uses, and improved the utilization rate of medicinal material, and security is good; The preparation method of hydrophily indigo naturalis of the present invention is easy, with low cost, is conducive to large-scale production, has a good application prospect.
Description
Technical field
The present invention relates to a kind of hydrophily indigo naturalis (medicine materical crude slice) and preparation method thereof.
Background technology
Indigo naturalis be the leaf of Acanthaceae acanthaceous indigo, polygonaceae plant indigo plant, cruciferae isatis or cauline leaf through fermentation, beat indigo,Water flies dried powder, agglomerate or the particle that processing makes. Effect is clearing heat and detoxicating, cooling blood and hemostasis, clearing liver-fire, for warm disease heatThe illnesss such as Sheng, macula, haematemesis, spitting of blood, pediatric epilepsy scared, sore swell, erysipelas, eczema have good effect. Along with to indigo naturalis researchDeeply, its therapeutic domain constantly expands, and is widely used in inside and outside, woman, youngster, contagious department illness. The clinical practice of indigo naturalis is used at presentMethod is mainly by several below: Chinese patent drug, external application, enter that decoction is taken after mixing it with water and decoct altogether with his medicine after take, wherein clinician's prescriptionIn be mostly the latter.
Investigate by TCM Document, the clinical usage of indigo naturalis in ancient times mostly is into the loose use of ball, as " health letter treasured side " DAIHESAN," medical science comform record " indigo naturalis clam meal ball, " Prescriptions for Universal Relief " blue or green gold are loose, Golden Mirror of Medicine is invincible loose etc. By to Compendium of Material Medica, " inMedicine voluminous dictionary " and clear " application at all times of indigo naturalis " of Huahai in the prescription of 58 indigo naturalis, find by statistics, indigo naturalis enters decoction and decoctsClothes have 8, account for totally 13.79%, what enter that decoction takes after mixing it with water has 2, accounts for totally 3.45%, in 48 remaining sides, is all ballLoose, account for totally 82.76%, visible indigo naturalis is clinical in ancient times enters with fado that ball is loose to be used.
In contemporary TCM Pediatrics and other clinical departments, indigo naturalis heavy dose enters decoction treatment infantile hyperpyrexia coma, lung heat is coughedCough, the disease such as spot poison mumps, tumour, see repeatly special effect. Because the above-mentioned symptoms of child disease are all acute disease, and pill has the spy of " ball person delays also "Point, prolonged disintegration, is unwell to first aid, and in the time that patient goes into a coma administration difficulty. Powder is unsuitable for children's's administration, and powder is easily inhaledInvest oral cavity, be inhaled in bronchus and lung, cause reflex cough. Decoction can overcome the deficiency of above-mentioned ball powder. CauseThis, contemporary clinical traditional Chinese medical science more options indigo naturalis enters decoction. In addition the authority " Chinese medicine voluminous dictionary " in present age meaning indigo naturalis " for oral administration decoctingSoup or to enter ball loose; External application is dry to be spread or dresses ". Visible, the usage of tcm clinical practice indigo naturalis is just occurring quietly to change at all times.
Indigo naturalis " body lightweight pine ", particle is less, and proportion is lighter, and specific area is larger; In microstructure, hydrophobicity is strongThe indigo CaCO that waits organic matter to be adsorbed in a large number porosity and looseness3Surface, makes indigo naturalis float on the water surface, is difficult for soaking, entering waterIn. In decoction, the hydrophobicity of indigo naturalis makes it float in a large number liquid surface, loss in a large number in filter process, serious shadowRing actual intake, thereby reduced bioavilability, caused the waste of herb resource. Therefore, need a kind of new technology badlyOvercome the deficiency of indigo naturalis, strengthen its hydrophily, save medicinal material, serve better tcm clinical practice.
Summary of the invention
The object of the present invention is to provide the novel indigo naturalis that a kind of hydrophily is strong. The present invention also provides hydrophily indigo naturalisPreparation method.
The invention provides a kind of hydrophily indigo naturalis, described hydrophily indigo naturalis contains activator more than 0.3%w/w; DescribedIn activator, contain lipophilic group alkyl and hydrophilic radical simultaneously.
Further, described activator is that alcohols solvent is or/and surfactant.
Further, described alcohols solvent is the alcohols solvent containing C1-10 straight or branched, be preferably methyl alcohol, ethanol,The aqueous solvent of absolute ethyl alcohol, propyl alcohol, n-butanol, ethylene glycol, glycerine, above-mentioned alcohols solvent or the mixture of multiple alcohols, moreBe preferably 95%v/v ethanol; Described surfactant is anion surfactant, cationic surfactant, amphion tableSurface-active agent or non-ionic surface active agent, be preferably lauryl sodium sulfate, benzalkonium bromide, tween, sapn, quaternary ammonium compound,Lecithin or amino acid.
The present invention also provides the preparation method of above-mentioned hydrophily indigo naturalis, and operating procedure is as follows: get indigo naturalis, at crushing processIn, pulverize with activator simultaneously, remove residue activator, obtain hydrophily indigo naturalis.
" residue activator " of the present invention refers to and also can be described as trip by the activator of not being combined with indigo naturalis in crushing processFrom activator, removal means can adopt conventional solid-liquid isolation method.
The present invention studies and shows, activator can mutually combine with indigo naturalis under the mechanical force such as pulverizing, effectively improvesThe wetability of indigo naturalis, thus its dispersiveness in water improved.
Further, described activator is that alcohols solvent is or/and surfactant.
Further, described alcohols solvent is the alcohols solvent containing C1-10 straight or branched, be preferably methyl alcohol, ethanol,The aqueous solvent of absolute ethyl alcohol, propyl alcohol, n-butanol, ethylene glycol, glycerine, above-mentioned alcohols solvent or the mixture of multiple alcohols, moreBe preferably 95%v/v ethanol; Described surfactant is anion surfactant, cationic surfactant, amphion tableSurface-active agent or non-ionic surface active agent, be preferably lauryl sodium sulfate, benzalkonium bromide, tween, sapn, quaternary ammonium compound,Lecithin or amino acid.
Wherein, described pulverizing adopts vibromill, ball mill or rod formula grinder to carry out.
Further, the addition of described activator is the more than 3% of indigo naturalis weight, is preferably 10～19%.
Further, the time that adopts vibromill to pulverize is 1-60min; Be preferably 20-40min; More preferably 23min.
Further, in vibromill crushing process, charge ratio of media 30-95%, medium material be stainless steel, special type notRust steel or pottery, shape of medium is cylindrical, spherical; Amplitude 2-6mm; Operating temperature-160～80 DEG C; Preferably, Filled DielectricsRate is 80%, column stainless steel medium, amplitude 4mm, operating temperature-20 DEG C.
Further, in ball mill crushing process, rotating speed is 100～300 turn/min, and charge ratio of media is 30～50%, ballMaterial is than 10～14:1, and milling time is 80～100min; Preferably, rotating speed is 300 turn/min, and charge ratio of media is 30%, ball materialThan 12:1, milling time is 90min.
Further, remove residue activator after, by gained solid at 50 DEG C with inner drying. This drying steps can be removedThe part activator of being combined with indigo naturalis is dried under said temperature condition, not only can ensure the dispersiveness of indigo naturalis, can also fallThe content of low auxiliary material activator, reduces dosage.
Hydrophily indigo naturalis of the present invention, has significantly reduced the contact angle of indigo naturalis, can effectively improve the dispersion of indigo naturalis in waterProperty, overcoming common indigo naturalis to float on liquid level, be difficult to disperse to enter the problem in water, the patient that is more convenient for uses, and has improved medicinal materialUtilization rate, and security is good; The preparation method of hydrophily indigo naturalis of the present invention is easy, with low cost, is conducive to extensive lifeProduce, have a good application prospect.
Brief description of the drawings
Fig. 1 X diffracting spectrum, wherein, A-hydrophily indigo naturalis of the present invention, B-indigo naturalis micro mist
Fig. 2 tradition natural indigo decoction piece infrared spectrogram
Fig. 3 indigo naturalis micro mist medicine materical crude slice infrared spectrogram
Fig. 4 hydrophily indigo naturalis infrared spectrogram
Fig. 5 red line is indigo naturalis micro mist medicine materical crude slice infrared spectrogram, and blue line is hydrophily indigo naturalis infrared spectrogram
The chromatogram of Fig. 6 absolute ethyl alcohol reference substance solution
The chromatogram of Fig. 7 hydrophily indigo naturalis need testing solution
The chromatogram of Fig. 8 negative control solution (common natural indigo decoction piece)
The impact of the different activators of Fig. 9 on contact angle
Detailed description of the invention
The preparation of embodiment 1 hydrophily indigo naturalis of the present invention (medicine materical crude slice)
Before indigo naturalis is pulverized, moisture control is in 8% left and right. In vibromill crushing process, in indigo naturalis, add 19% indigo naturalis95% ethanolic solution of amount grinds, charge ratio of media 80%, column stainless steel medium; Amplitude 4mm; Time 23min; Operating temperature-20 DEG C. After grinding finishes, remove unnecessary alcohol, obtain hydrophily indigo naturalis.
The property research of embodiment 2 hydrophily indigo naturalis (medicine materical crude slice)
(1) preparation of various natural indigo decoction pieces
Prepared by the preparation of hydrophily natural indigo decoction piece: embodiment 1.
The preparation of indigo naturalis micro mist medicine materical crude slice: before indigo naturalis is pulverized, moisture control is in 8% left and right. In vibromill, pulverize 23min,Vibromill charge ratio of media 80%, column stainless steel medium; Amplitude 4mm; Time 23min; Operating temperature-20 DEG C.
(2) measure indigo in traditional natural indigo decoction piece, indigo naturalis micro mist medicine materical crude slice and hydrophily indigo naturalis of the present invention, containing of indigo redFixed
Chromatographic condition:
Chromatographic column: global C18; Mobile phase: methyl alcohol: water (70:30); Detect wavelength: 289nm; Column temperature: 30 DEG C; Sample size:10μl。
Reference substance solution preparation:
Precision takes indigo reference substance (D-035-110323, Rui Fensi bio tech ltd, Chengdu) 4.24mg, indigoRubine reference substance (D-025-110622, Rui Fensi bio tech ltd, Chengdu) 2.17mg, adds respectively N, N-dimethylFormamide 100ml, ultrasonic 30min, is cooled to room temperature, as stock solution.
The accurate stock solution 12.5ml that draws puts in 25ml brown bottle, with DMF dilution constant volume, shakesEven, cross 0.22 μ m miillpore filter and get final product.
Need testing solution preparation:
Precision takes indigo naturalis powder (particle porphyrize) 0.20160g, indigo naturalis micro mist 0.20185g, indigo naturalis modification micro mist0.20133g, adds respectively DMF 100ml, and ultrasonic 30min, is cooled to room temperature, crosses 0.22 μ m miillpore filterObtain.
In the traditional natural indigo decoction piece of table 1, hydrophily natural indigo decoction piece and indigo naturalis micro mist medicine materical crude slice, result is surveyed in indigo containing
More than experiment shows, traditional natural indigo decoction piece is pulverizing and adding in ethanol grinding thinning process, indigo and indigo redThere is not marked change in content, can preliminary judgement, and the process of indigo naturalis hydrophily medicine materical crude slice, the organic matter in indigo naturalis does not occurChemical change significantly.
(3) mensuration that particle diameter distributes
Adopt Ma Erwen laser particle distribution instrument to measure the size distribution of indigo naturalis micro mist and hydrophily indigo naturalis. Instrument model:MalvernAPA2000, analyzer: HYDRO2000MU, software: Mastersizer2000; Measurement model: GeneralPurpose, range of results: 0.0200 μ m-2000 μ m, sample determination time: 15s, replication 3 times, the background correction time:8s; When mensuration, adopt wet method mode determination, open paddle, turn/min of oar number 2400, ultrasonic power 20MHz, ultrasonic time30s. The automatic dual pure water distiller of SZ-93A, Shanghai Yarong Biochemical Instrument Plant.
Before experiment, prepare distilled water, ultrasonic degas 20min. Because indigo naturalis is not easy to be distributed in water, therefore, measuringFront first that indigo naturalis is wetting with a small amount of absolute ethyl alcohol, then measure. When each measurement, take indigo naturalis sample 0.2g, add pure water 7mL, shakeShake and be uniformly dispersed. Each sample sampling 3 times, generates average result automatically. Experimental result is as table 2.
The particle diameter distribution table of table 2 indigo naturalis micro mist and hydrophily indigo naturalis
Use the Student-t inspection of SPSS17.0 statistical software, the grain of indigo naturalis micro mist medicine materical crude slice and hydrophily natural indigo decoction pieceFootpath is substantially suitable, and the d0.5 of hydrophily natural indigo decoction piece and d0.9 are slightly larger than indigo naturalis micro mist, but there is no significant difference significantly, canTo think that both particle diameters are suitable. Both hydrophilic differences are because particle diameter difference causes.
(4) mensuration of specific area and porosity
Use the full-automatic specific area of TriStar3000 and porosity measuring instrument (Merck & Co., Inc of the U.S.) to measure traditional indigo naturalisSpecific area and the porosity of medicine materical crude slice, indigo naturalis micro mist medicine materical crude slice and hydrophily natural indigo decoction piece. Before mensuration, material is placed in surface plate or titleIn measuring bottle, drying under reduced pressure is removed most of moisture, then blows to sample constant weight by ordinary nitrogen.
Table 3 indigo naturalis micro mist medicine materical crude slice and hydrophily natural indigo decoction piece specific area and voidage measurement result table
Use the Student-t inspection of SPSS17.0 statistical software, although, the specific area (Lang Ge of indigo naturalis micro mist medicine materical crude sliceMiao's specific area and BET specific surface) be slightly larger than hydrophily natural indigo decoction piece, but both do not have significant difference. Can not think twoThe hydrophilic difference of person is because the difference of specific area causes.
(5) XRD collection of illustrative plates is measured
For whether the crystalline structure of investigating indigo naturalis calcium carbonate in two kinds of process of lapping changes, measure respectively indigo naturalisThe X-ray diffractogram of micro mist medicine materical crude slice and hydrophily indigo naturalis of the present invention. More than be determined at the building by province and ministry Ministry of Education of Nanchang University of aviationInstitute of Analysis of key lab completes. Beuker-axs company of instrument model: D8ADVANCE(Germany produces), 5 ° of wide-angles-160 ° of scannings. Measurement result is in table 4 and Fig. 1.
Table 4 indigo naturalis micro mist and indigo naturalis activation micro mist qualification result
Utilizing XRD to detect, inspect out three kinds of inorganic matters from indigo naturalis, is respectively CaCO3、Ca(OH)2With SiO2. BothDiffraction maximum is basically identical, but the proportion of composing of three kinds of inorganic matters is variant. CaCO after indigo naturalis modification3Content risen 4.8%,Ca(OH)2Content 5.1%, the SiO that declined2Content is little. Its reason of changes is that 95% ethanol easily has good profitMoist, can spread over indigo naturalis powder surface, make it in process of lapping, indigo naturalis surface is wetting state, is connecing subsequently with airTouch or dry and dispel in the process of ethanol, Ca (OH)2With airborne a small amount of CO2React, generate CaCO3, quality slightly increasesAdd. But conspicuousness does not occur the content and component proportion of inorganic matter changes, it not the main cause that indigo naturalis wetability strengthens.
(6) infrared spectrum of ethanol qualification in hydrophily natural indigo decoction piece
The spectroscopic pure KBr of drying is blank, prepares the sample of infrared analysis. Every middle KBr content is 60mg, sample sizeBe about 0.8mg, with FTIR-650 Fourier infrared spectrum measurement instrument, spectrogram is in table 5 and Fig. 2～5:
Table 5
Can clearly see from infrared spectrogram, indigo naturalis micro mist and indigo naturalis raw material are basically identical, and all groups substantially canCoincideing, there is not significant chemical change in the micronizing of indigo naturalis. But hydrophily indigo naturalis is 3500cm in wave number-1Near hydroxylPeak intensity significantly strengthens compared with indigo naturalis micro mist medicine materical crude slice, illustrates in indigo naturalis lyophilic powder medicine materical crude slice and has newborn great amount of hydroxy group (-OH) to deposit; At 1460cm-1Peak intensity also strengthens, and illustrates and in indigo naturalis lyophilic powder medicine materical crude slice, has newborn methyl (-CH3), methylene (-CH2-) exist; This is the key evidence that in indigo naturalis lyophilic powder medicine materical crude slice, ethanol exists.
(7) mensuration of ethanol content in hydrophily medicine materical crude slice
The preparation of reference substance solution: get chromatographic grade absolute ethyl alcohol 0.2636g, be transferred to 50ml volumetric flask, add N, N-diformazanBase formamide, to scale, shakes up, and ultrasonic 20 minutes, be cooled to room temperature, obtain the reference substance solution that concentration is 5.272mg/ml.
The preparation of need testing solution: get the test sample 0.5g of hydrophily natural indigo decoction piece, to 25ml volumetric flask, add N, N-diformazanBase formamide, to scale, shakes up, and ultrasonic 20 minutes, be cooled to room temperature, cross 0.45 μ m miillpore filter, to obtain final product.
The preparation of negative solution: get the test sample 0.5g of common natural indigo decoction piece, to 25ml volumetric flask, add N, N-dimethyl methylAcid amides, to scale, shakes up, and ultrasonic 20 minutes, be cooled to room temperature, cross 0.45 μ m miillpore filter, to obtain final product.
Chromatographic condition: Agilent7890AGCSystem, AgilentChemstation work station; Knitting wool tubing string:HP-FFAP30m*0.25mm0.25 μ mfilm; Column oven: 50 DEG C of initial temperatures, retention time 2min, 15 DEG C/min program literWarm to 180 DEG C, retention time 10min; 240 DEG C of fid detector temperature, 180 DEG C of injector temperatures; Hydrogen flow rate: 40ml/min,Nitrogen flow rate 30ml/min, air velocity 300ml/min; Sample size: reference substance, need testing solution are 2 μ L.
Chromatogram specificity is investigated:
From Fig. 6-8, the retention time of absolute ethyl alcohol is 4.08min, and the method specificity is good, common natural indigo decoction pieceDo not comprise ethanol, the method can be used as the method for measuring of indigo naturalis ethanol content.
Result is measured: adopt the content of ethanol in external standard method hydrophily natural indigo decoction piece, record hydrophily natural indigo decoction piece(before dry) ethanol content is 4.68%, and hydrophily natural indigo decoction piece (after dry) ethanol content is 0.79%.
Because novel natural indigo decoction piece product need be dried rear packaging, difference between considering batch, contains the ethanol in finished productWeight range is decided to be 0.3%-5.0%.
(9) mensuration of critical relative moisture
By preceding method, drying under reduced pressure to indigo naturalis routine and the ultra-micro powder of constant weight put into the flat title that is dried to constant weightIn measuring bottle (the about 3mm of powder thickness), accurately weigh, be then placed in and fill respectively 7 kinds of listed different salt supersaturated solutions of following tableDrier in, in constant incubator, preserve 7 days for 25 DEG C, timing weighs, and calculates the moisture absorption hundred of various powder when moisture equilibrium at dry sideDivide rate.
The saturated aqueous solution of the different salt of table 6 is the relative humidity of 25 DEG C
| Saturated solution | 54%H2SO4 | 48%H2SO4 | 44%H2SO4 | NaBr | NaCl | KCl | KNO3 |
| Relative humidity (%) | 30.5 | 41.2 | 49.8 | 57.7 | 75.4 | 84.4 | 92.9 |
Draw the moisture equilibrium at dry side curve of indigo naturalis micro mist and hydrophily natural indigo decoction piece. Taking relative humidity as abscissa (RH%), inhaleWet percentage is ordinate (%) mapping, and application OriginPro8.5 software is made the tangent line at two curve two ends, when two points of intersection of tangents pairThe abscissa of answering is critical relative moisture, and the critical relative moisture of indigo naturalis micro mist medicine materical crude slice and indigo naturalis hydrophily medicine materical crude slice is respectively63.43% and 61.94%. After hydrophilically modified, critical relative moisture slightly reduces.
Embodiment 3 preparation technologies' of the present invention screening
The hydrophilic relation of contact angle and material:
When drop is freely when the space in the impact that do not stress, because the existence of interfacial tension is spherical shape. ButThat, in the time that drop contacts with surface, its net shape depends on sticky between the cohesive force of drop inside and drop and solidThe relative size of attached power. In the time that a drop is placed on surface, drop can automatically be sprawled and come at the surface of solids, or withBecome the drop of certain contact angle to exist with the surface of solids.
Suppose that the interfacial tension that power between different interfaces can be used as being used in interface direction represents, when drop is flat at solidOn face, in the time of equilbrium position, these interfacial tensions component sum in the horizontal direction should equal zero,
γS/A=γS/L+γL/Acosθ
In formula, γ S/A, γ L/A, γ S/L are respectively solid-gas, liquid-gas and solid-liquid interface tension force; θ is between liquid and solidInterface and the angle of the tangent line folded (comprising liquid) of liquid surface, be called contact angle (contactangle), θ 0 °-Between 180 °. Contact angle is the key criteria of reactive material and liquid wetability relation, and θ=90 ° can be used as wetting and nonwettingBoundary, wettable, θ when the θ<90 °>nonwetting 90 ° times. As from the foregoing, contact angle is that reflected appraisal medicine is hydrophilic importantIndex. The present invention investigates indigo naturalis method of modifying taking contact angle as index.
1, the screening test of activator
Choose that in pharmaceuticals industry, widely used alcohol reagent and surfactant are as indigo naturalis activator, such material containsHave lipophilic group alkyl and hydrophilic radical, this well meets activation indigo naturalis material property,, lives using water as modification meanwhileChanging contrast, is evaluation index by investigating contact angle, screening modifier kind.
(1) experiment medicinal material and reagent
Indigo naturalis particle, the permanent source of Sichuan medicine company provides; Methyl alcohol, ethanol, propyl alcohol, n-butanol, ethylene glycol, glycerine etc.,More than be analysis pure, be purchased from Sichuan Ke Long chemical reagent Co., Ltd.
(2) laboratory apparatus
Pine high mountain board vibromill; OCA20 video optics contact angle instrument (German Dataphysics company); SartoriusElectronic balance (Beijing Sai Duolisi instrument system Co., Ltd) etc.
(3) preparation of different activator indigo naturalis activation micro mists
Alcohols material is selected monohydric alcohol: methyl alcohol, 95% ethanol, propyl alcohol, n-butanol; Dihydroxylic alcohols: ethylene glycol; Trihydroxylic alcohol: sweetOil. Surfactant-based selection anion surfactant: lauryl sodium sulfate (NaLS); Cationic surface is livedProperty agent: bromogeramine (benzalkonium bromide); Non-ionic surface active agent: Tween 80.
Before indigo naturalis is pulverized, moisture control is in 8%. In crushing process, in indigo naturalis, add 19% above-mentioned indigo naturalis to pulverizeThe modifier of amount grinds. Technological parameter: charge ratio of media 80%, column stainless steel medium, amplitude 4mm, time 23min, work temperatureSpend-20 DEG C. Prepare finished product and be placed in sealing bag and deposit in 25 DEG C of driers, for subsequent use.
(4) the contact angle evaluation of different activator hydrophily indigo naturalis under different baking temperatures
Adopt video optics contact angle instrument (OCA20 video optics contact angle instrument, German Dataphysics public affairsDepartment) measure indigo naturalis activation micro mist at not dry, 40 DEG C, 60 DEG C, 80 DEG C, 100 DEG C dried contact angles, judge powder table with thisThe wetability of face. Utilize the full pressed powder of single-punch tablet press, above-mentioned powder is pressed into respectively to heavy 0.3g, the sheet that diameter is 12mmSon, hardness requirement is not less than 60N. Tablet hardness is surveyed with YD-20 tablet hardness instrument (Tianda Tianfa Technology Co., Ltd.)Fixed.
When mensuration, test fluid is selected distilled water, and each test fluid volume is 60 μ L, and speed is 0.5 μ L/s. Under fixing needle pointEnd is 2.0mm with the distance on slice, thin piece top. When mensuration, select the lower surface of tablet to do test surfaces (upper surface is not very as far as possibleFlat). The water is just on the boil begins and slice, thin piece upper surface Contact for record, and the picture that captures of shooting function, calculates initial (initial CA), treatsWater droplet is in the time that sheet sub-surface forms more fixing contact angle, then record, is equilibrium contact angle (balance CA) that every kind of powder is at least surveyed3 times, average. The results are shown in Table 7 and Fig. 9.
Table 7: the contact angle of different activator activation indigo naturalis changes
Known by the above results, utilize different modified active agent to activate indigo naturalis, improvement that can be in various degreeThe characteristic that indigo naturalis hydrophily is poor, illustrates and adopts a kind of solvent simultaneously with lipophilic group and hydrophilic radical can activate indigo naturalis tableFace, urgees to make it have good hydrophily, and this process (possibility) is by the lipophilic group (hydrophilic radical) and green grass or young crops of modified active agentBetween black pigment used by women in ancient times to paint their eyebrows component molecules interact and produce.
2, hydroxyl, the impact research of alkyl on indigo naturalis activation effect
Consider popularity, security that solvent borne is used, and the feasibility of suitability for industrialized production, in conjunction with above-mentioned test knotReally, select activation effect still good, the good ethanol of stability is further studied. Above-mentioned test knows, ethanol can be used as workAgent activation indigo naturalis, this activation results is in mechanical force by Related Component molecule in the alkyl in ethanol molecule or hydroxyl and indigo naturalisParticipation under interact and produce effect. The research hydrophilic variation of indigo naturalis that has been which kind of group major effect on earth, rightIn large Manufacturing science, reasonably select modifier most important.
(1) hydrophily indigo naturalis wetability preliminary test
Ethanol is mixed with to not isocyatic ethanol water, measures the impact that ethanol changes the surface tension of water. ?Whether indigo naturalis is scattered in respectively in water and 50% ethanol water with activation indigo naturalis, observe both indigo naturalis and dispersible in two kinds of solutionIn, then, the centrifugal 10min(4000r/min of indigo naturalis being scattered in water-alcohol solution), discard brown color supernatant, it is heavy to collectForm sediment, dry to constant weight for 50 DEG C, then be scattered in water, observe dispersion effect. The results are shown in Table 8.
Table 8 ethanol changes indigo naturalis-wettability
Can be found out by table 8 result, ethanol can improve the wetability of indigo naturalis in water under the effect of mechanical force. ExperimentIn, after 50 DEG C of oven dry of hydrophily indigo naturalis, still can be dispersed in water, between surperficial ethanol and indigo naturalis, there is stronger adhesion.By interpretation, indigo naturalis powder and indigo naturalis micro mist can not be scattered in water, when both dispersions are entered to 50% ethanol waterIn, particle surface contacts with ethanol molecule, and intermolecular force has increased particle wetability in ethanolic solution, and then is scattered inIn ethanolic solution, after oven dry, particle surface ethanol volatilization, not activating indigo naturalis can not be scattered in water, and hydrophily after activationMedicine materical crude slice can be scattered in water again. Based on this, there is following supposition particle to pulverize in activation process, utilize mechanical stress to particleSurface is activated, to change particle surface structure and physical arrangement, and because inside particles breaks, interior can increase, outsideUnder power effect, ethanol activation rear portion ethanol enters in the space of indigo naturalis particle, and another part is wrapped in indigo naturalis particle weekEnclose, after oven dry, surface ethanol molecule wave away, but the ethanol molecule in molecule gap may with some molecule in indigo naturalis compositionInteract and have compared with strong adhesion and be difficult to be pulled away. Inventor thinks, 1. hydrophilic radical-OH and indigo naturalis composition in ethanolThe result of interaction of molecules. In the structure of the organic principle molecule in indigo naturalis, generally contain C-O bonding C-N part, electronegativityLarge O and N in molecule or the existence of intermolecular hydrogen bonding prerequisite is provided, meanwhile, have document also to intramolecular hydrogen bond in indigo naturalisMake sufficient analysis. Under mechanical force, ethanol enters in indigo naturalis particle, and intramolecular hydrogen bond is activated simultaneously, entersAnd form alternately new hydrogen bond with the hydrophilic radical-OH of ethanol, make dry after hydrophily natural indigo decoction piece still hydrophily is goodGood. 2. lipophilic group-CH in ethanol2CH3With the interactional result of indigo naturalis component molecules. At present, people generally believe indigo naturalisIn except containing above-mentioned active ingredient, also contain a large amount of lime, still, have scholar to grind by ESEM, X-diffractionStudy carefully discovery, the inorganic constituents in indigo naturalis is mainly CaCO3And SiO2, and indigo be to depend on CaCO3Plane of crystal exists.This explanation indigo naturalis particle is that the organic molecules such as activated Calcium carbonate absorption is indigo, indigo red form, and these organic molecules have obviouslyLipophilicity, show that they and shipwreck are in affine. The existing lipophilicity alkyl-CH of ethanol2CH3There is again hydrophily-OH, whereinThe lipophilic group of alkyl in indigo naturalis carries out physical chemistry is combined, and forms unimolecule active layer, and its hydrophilic-OH just exposesIn particle periphery, good with regard to energy like this and hydrone interacts, and increases the hydrophily of indigo naturalis particle.
(2) impact of hydroxyl quantity on indigo naturalis activation effect
Choose monohydric alcohol: 95% ethanol; Dihydroxylic alcohols: ethylene glycol; Trihydroxylic alcohol: glycerine contrasts as activator, using water as ginsengAccording to activator. Described in the preparation of activation indigo naturalis micro mist and assay method photograph are front. Containing different hydroxyl alcohols to indigo naturalis modification micro mistThe impact of contact angle, the results are shown in Table 9.
Table 9 is containing the impact of the contact angle of different hydroxyl alcohols on indigo naturalis modification micro mist
Found out by experimental result, on each temperature spot, under the identical condition of alkyl, hydroxyl is more, indigo naturalis modification micro mist withoutOpinion is initial or equilibrium contact angle is just less, and this is that hydroxyl is polar group, and water is had because the more hydrophilies of hydroxyl are strongerLarge affinity, can attract hydrone, shows that alcoholic extract hydroxyl group has certain contribution function to indigo naturalis micro mist wettability simultaneously,But ethylene glycol and glycerine is initial suitable with equilibrium contact angle numerical value, prompting, and more indigo naturalis of non-hydroxyl micro mist is wettingProperty just better, this may with alcohols in alkyl quantity and space conformation also have relation.
(3) impact of alkyl length on indigo naturalis activation effect in alcoholic solution
Choose monohydric alcohol: methyl alcohol, 95% ethanol, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol contrast as activator, withWater is as with reference to activator. Described in the preparation of activation indigo naturalis micro mist and assay method photograph are front. Containing different alkyl alcohols, indigo naturalis is changedThe impact of the contact angle of property micro mist, the results are shown in Table 10.
Table 10 is containing the impact of the contact angle of different alkyl alcohols on indigo naturalis modification micro mist
Found out by experimental result, on each temperature spot, under the identical condition of hydroxyl, alkyl is longer, indigo naturalis modification micro mist withoutOpinion is initial or equilibrium contact angle is just less, and this shows that alkyl has certain contribution function to indigo naturalis micro mist wettability.
The wetability difference of each hydrophily natural indigo decoction piece in experiment, also has relation with the stability of activator, methyl alcohol, secondThe stability of alcohol, propyl alcohol, n-butanol, ethylene glycol and glycerine strengthens successively, and ethylene glycol is suitable with glycerine, six boiling pointAlso increase successively, particularly the effumability of methyl alcohol and ethanol causes both hydrophily natural indigo decoction piece wetabilitys not as other alcoholClass, but the airtight placement of room temperature is after two months, and the hydrophilicity of propyl alcohol and n-butanol reduces, and approaches with methyl alcohol, ethanol. ComprehensivelyAbove-mentioned research, considers the factor such as security, cost, selects ethanol to be advisable as modifier.
3, ethanol modified technique research
In conjunction with above-mentioned result of the test, consider the popularity of solvent use and the feasibility of industrialized production, select secondAlcohol is studied indigo naturalis active artistic condition as activator.
(1) single factor is investigated amount of alcohol added to the hydrophilic impact of indigo naturalis
Fixing milling time (23min), vibromill amplitude 4mm, charge ratio of media 80%, operating temperature-20 DEG C, with indigo naturalisMeal feeds intake, and material water ratio is controlled in 8%, investigates the impact of amount of alcohol added on indigo naturalis activation effect, the results are shown in Table11。
The impact of table 11 amount of alcohol added on indigo naturalis Powder Contact Angle and size distribution
From result, the contact angle of hydrophily natural indigo decoction piece reduces with the increase of amount of alcohol added, and particle diameter distributes（D0.9) increase, and the variation of contact angle and obviously correlation of particle diameter distribution size nothing. Along with the increase of amount of alcohol, in systemAlkyl and hydroxyl quantity increase, increased the combination chance of indigo naturalis particle and alkyl, finally make connecing of indigo naturalis modification micro mistFeeler constantly reduces. Along with adding of amount of alcohol, Ethanol Adsorption, at indigo naturalis particle surface, obtains the valence link power on the plane of disruptionSaturated, the agglomeration power between particle is shielded, and suppresses the cohesiveness of particle, promotes the crushibility of particle, but amount of alcoholConstantly increase progressively and make to form multilayer molecular absorption in system, impel particle diameter to become gradually large. Know from above, when amount of alcohol added 17%, connectFeeler minimum.
(2) impact of vibromill technique (amplitude) parameter on indigo naturalis modified effect
Get dry rear common medicine materical crude slice 400g in vibromill, add 95% ethanolic solution mixed grinding of 19% indigo naturalis crushing quantityPulverize 23min, vibromill charge ratio of media 80%, column stainless steel medium; Investigate amplitude (4mm, 5mm, 6mm) hydrophilic to indigo naturalisThe impact of property. Take out rear 50 DEG C of forced air drying 20min, to without alcohol taste, seal and preserve, measure its contact angle.
The impact of table 12 amplitude on wetability
As can be seen from the above table, amplitude has certain influence to experimental result, and along with the increase of amplitude, contact angle has increaseTrend. Therefore, the preferred best amplitude of the present invention is 4mm.
(3) single factor is investigated the vibro-grinding time
Fixing activator addition is 17%, vibromill amplitude 4mm, and charge ratio of media 80%, operating temperature-20 DEG C, with green grass or young cropsBlack pigment used by women in ancient times to paint their eyebrows meal feeds intake, and material water ratio is controlled at 8% left and right, investigates the impact of milling time on indigo naturalis activation effect, the results are shown in downTable.
The impact of table 13 milling time on indigo naturalis Powder Contact Angle and size distribution
From experimental result, the equilibrium contact angle of hydrophily natural indigo decoction piece and particle diameter distribution (D0.9) with milling timeIncrease and without significant change, initial contact angle has the trend reducing, show that milling time has initial contact angle certain relevantProperty. Milling time increases the action time that extends ethanol molecule and indigo naturalis particle, impels mechanical energy to be converted into physical chemistry bond energy,The combination of ethanol molecule and indigo naturalis particle is more firm, dissociate-OH trends towards aligning, made indigo naturalis particle just withWhen water contact, more easily sprawled by water liquid.
(3) uniform Design optimizing factors level
Adopt U5（52) uniform designs table, arrange X1(ethanol consumption) and X2(milling time), each 5 levels that arrange of every factor,Specific design is as table 14, with equilibrium contact angle and particle diameter distribution D0.9For evaluation index, screening optimum process condition, experimental resultIn table 15.
Table 14U5（52) uniform designs table
Table 15 level is replaced and result of the test
Adopt SPSS17.0 statistical software to analyze result of the test, the general introduction of ModelSummary(model) show and selectEnter X1(ethanol consumption), proofreaies and correct coefficient of determination R2=0.904, ANOVA(variance analysis) show F=28.173, P=0.013, progressively returnsReturn equation to have statistical significance.
Table 16 variable analysis
| Variable | Partial regression coefficient t | P |
| (constant) | 20.163 | 0.000 13 --> |
| X1 | -5.301 | 0.013 |
| X2 | -2.396 | 0.139 |
Known X by upper table1Should bring equation into, X2Should reject, obtaining regression equation is Y1=54.513-X1×2.443；X2=3，The approximate evaluation of optimum point is:
X1=19，X2=23
Therefore the approximate evaluation of optimal case is: activator level is 19%, grind 23min.
Embodiment 4 is dried or the impact of storage temperature on hydrophily indigo naturalis of the present invention
(1) determining of the impact of drying time on Residual ethanol in hydrophily medicine materical crude slice and drying time
Get hydrophily indigo naturalis prepared by embodiment 1 some, sealing is stored in sealing bag, gets and is laid in right amount in square plateDry placement under 50 DEG C of conditions, respectively at the the 10th, 20,30,40min sampling, according to (7), a lower test sample preparation method is prepared for examinationProduct, parallel 3 parts, measure the wherein content of alcohol residue, experimental result sees the following form.
The assay result of table 17 different time points Residual ethanol
As can be seen from the above table, after dry 20min, ethanol content changes not quite, therefore, determines that be 20min drying time.Now, in 1g hydrophily medicine materical crude slice, the average content of ethanol is 6.66mg, and mean concentration is 0.67 ± 0.02%.
(2) heat treated is on the hydrophilic impact of hydrophily medicine materical crude slice (preliminarily stabilised Journal of Sex Research)
Take the about 3g of hydrophily medicine materical crude slice prepared by embodiment 1, be laid in measuring cup, parallelly take 27 parts, 40,60,Respectively in the baking oven of 80 DEG C place 9 parts, open wide and place, respectively at 1,2,3h respectively takes out 3 parts, measures its contact angle and alcohol residue,Experimental result sees the following form.
Table 18 heats the impact on contact angle and ethanol content
As can be seen from the above table, different heating-up temperatures affects difference, heat treatment temperature to hydrophily medicine materical crude slice stabilityHigher, affect more obvious. After 40 DEG C of heat treated 3h, contact angle and the alcohol residue of hydrophily medicine materical crude slice slightly change, but change notStill have good wetability greatly; 60 DEG C with 80 DEG C of heat treated after, initial contact angle and equilibrium contact angle obviously raise, ethanolResidual quantity obviously reduces, but still has certain wetability. As can be seen here, the hydrophily natural indigo decoction piece that prepared by the present invention is at 80 DEG CAll can keep certain wetability with interior storage 3h, especially better 40 DEG C of following wetabilitys.
Embodiment 5 planetary ball mill preparation technologies
Whether the ball mill that the present embodiment has been investigated taking planetary ball mill as representative can prepare hydrophily natural indigo decoction piece.
Selecting ND8 type adjustable swing-type planetary ball mill (Nanda Tianzun Electronics Co., Ltd., Nanjing) is milling apparatus, willDried natural indigo decoction piece drops in agate tank, adds 95% ethanol that accounts for indigo naturalis weight 19%, in swing type planetary ball millCarry out solid-liquid grinding. Because revolution is the key factor that determines grinding efficiency, therefore, the present invention has mainly investigated revolution to experimentThe impact of result.
Setting ball mill running parameter is respectively: globe mill medium filling rate is 30%, ratio of grinding media to material 12:1, and milling time is90min, adopts single factor method to investigate the impact of rotating speed (100,200,300r/min) on indigo naturalis wetability. Ground medicine materical crude slice is putEnter 40 DEG C of dry 20min in air dry oven, carry out contact angle determination, experimental result sees the following form.
The impact of table 19 revolution on wetability
As can be seen from the above table, adopt planetary ball mill function to improve the surface wettability of indigo naturalis, its contact angle is reduced, andAlong with the quickening of revolution, hydrophilically modified effect is more obvious. This may can improve globe mill medium and material with raising rotating speedBetween frequency of impact relevant with number of shocks.
By following test example, beneficial effect of the present invention is described
The acute toxicity test of test example 1 indigo naturalis lyophilic powder medicine materical crude slice
With traditional natural indigo decoction piece comparison, be prepared into after lyophilic powder medicine materical crude slice, hydrophily strengthens, and has also introduced a small amount of simultaneouslyEthanol, for ensureing the security of clinical use, according to " Chinese medicine, natural drug studies on acute toxicity technological guidance principle " to indigo naturalisLyophilic powder medicine materical crude slice has carried out studies on acute toxicity.
Tested medicine: indigo naturalis lyophilic powder medicine materical crude slice (self-control). KM mouse, regular grade, body weight 18-22g, male and female half and half,By Chengdu, Da Shuo bio tech ltd provides.
Sample preparation: take a certain amount of modification indigo naturalis powder as test sample, be made into suspension with physiological saline, concentrationFor 0.4g/mL, jolting is evenly used before use.
Prerun test: get KM mouse, body weight 18-22g, male and female half and half, are divided into five groups at random, i.e. 1 group of (0.2ml/ of medicine20g), medicine 2 groups of (0.4ml/20g), medicine 3 groups of (0.6ml/20g), medicine 4 groups of (0.8ml/20g) and blank group of (physiology saltWater group) (in table 1). Before administration, fasting 12 hours, can't help water, oral administration gavage administration, the spirit of 7 days mouse of Continuous Observation after administrationState, diet situation, poisoning time etc., after test, mouse is performed an autopsy on sb．. Because administration volume is very large, be mouseWhen large administration capacity, there is not death in mouse, and also without obviously toxic reaction, prompting this product is difficult to measure LD50Therefore, carry out maximum and giveDose determination test. Grouping and administration situation are in table 20.
Table 20 divides into groups and administration situation
Maximum dosage-feeding test: get KM mouse, female half and half, body weight 18～22g, is divided into two groups at random. Fasting before administration12 hours, can't help water, point 3 oral administration gavage administrations in 24 hours, i.e. 34.29g/kg body weight, blank group gives same dosage with methodPhysiological saline, Continuous Observation 7 days. Record in detail mouse behavioral activity, state, diet, stool and urine and hair color, secretion etc.,After test, mouse is dissected to inspection.
Prerun result of the test: mouse, in 7 days that gavage medicine, has of short duration discomfort on the 1st day, movable minimizing, stool colorFor blue black look, within the 2nd day, recover normal, freely, normally, stool is wet particle shape for feed, drinking-water in mouse activity, for dark brown,Have no during this time poisoning symptom and death. After dissection, visually observe finding: thoracic cavity, abdominal cavity no abnormality seen liquid, intestinal tube has no flatulence,The important organs such as the heart, liver, spleen, lung, kidney have no color, paramophia, there is no blutpunkte or other pathological change, gastric mucosa colorRuddy, without blutpunkte or ulcer, with blank group indifference, postmortem is without extremely.
Maximum dosage-feeding result of the test: mouse is in 7 days that gavage medicine, and activity in the 1st, 2 days reduces, food, amount of drinking waterRelatively reduce, within the 3rd day, recover normal; After mouse administration, the stool color of the 1st day is blue black look, within the 2nd day, recovers normal; Outward appearance bodyLevy no abnormality seen, freely, feed, drinking-water, ight soil are all normal in activity, and fur is bright and clean, and mouth, nose, eye and Anal cleaning be without secretion,Continuous Observation 7 days, 40 mouse all survive, and body weight increases, and changes no significant difference (P > 0.05, in table 16) between group; During this timeHave no poisoning symptom and death; After dissection, visually observe finding: thoracic cavity, abdominal cavity no abnormality seen liquid, intestinal tube has no flatulence, the heart,The important organs such as liver, spleen, lung, kidney have no color, paramophia, there is no blutpunkte or other pathological change, the heart between group, liver, spleen,Lung, renal index no significant difference (P > 0.05, in table 21,22), gastric mucosa color is ruddy, and without blutpunkte or ulcer, postmortem is as good asOften.
Changes of weight situation after the administration of table 21 mouse maximum
Note: with the comparison of blank group, after administration 7 days, 1. represent P > 0.05
The heart, liver, spleen, lung, renal index situation of change after the administration of table 22 mouse maximum
Note: with the comparison of blank group, after administration 7 days, 1. represent P > 0.05
This liquor strength is 0.4g/ml, mouse administration every day 2.4ml, and mouse is taken medicine and be equivalent to indigo naturalis 0.96g/ every day20g, its tolerance multiple is 342.9 times of people, so, can think this medicine nontoxicity.
In sum, hydrophily indigo naturalis of the present invention, has significantly reduced the contact angle of indigo naturalis, can effectively improve indigo naturalis at waterIn dispersiveness, overcome common indigo naturalis and floated on liquid level, be difficult to disperse the problem in water of entering, the patient that is more convenient for uses, and carriesThe high utilization rate of medicinal material, and security is good; The preparation method of hydrophily indigo naturalis of the present invention is easy, with low cost, is conducive toLarge-scale production, has a good application prospect.
Claims (10)
1. a preparation method for hydrophily indigo naturalis, is characterized in that: get indigo naturalis, in crushing process, with activator powder simultaneouslyBroken, remove residue activator, obtain hydrophily natural indigo decoction piece, wherein, the addition of described activator be 10 of indigo naturalis weight ~19%；
Described activator is 95%v/v ethanol; Remove residue activator after, by gained solid at 50 DEG C with inner drying.
2. preparation method according to claim 1, is characterized in that: described pulverizing is to adopt vibromill, ball mill or rodFormula grinder carries out.
3. preparation method according to claim 2, is characterized in that: the time that adopts vibromill to pulverize is 1-60min.
4. preparation method according to claim 3, is characterized in that: described grinding time is 20-40min.
5. preparation method according to claim 4, is characterized in that: described grinding time is 23min.
6. according to the preparation method described in claim 2 or 3, it is characterized in that: in vibromill crushing process, charge ratio of media30-95%, medium material is stainless steel or pottery, shape of medium is cylindrical, spherical; Amplitude 2-6mm; Operating temperature-160 ~ 80℃。
7. preparation method according to claim 6, is characterized in that: described stainless steel is special stainless steel.
8. preparation method according to claim 6, is characterized in that: described charge ratio of media is 80%, column stainless steelMedium, amplitude 4mm, operating temperature-20 DEG C.
9. preparation method according to claim 2, is characterized in that: in ball mill crushing process, rotating speed is 100 ~ 300Turn/min, charge ratio of media is 30 ~ 50%, ratio of grinding media to material 10 ~ 14:1, and milling time is 80 ~ 100min.
10. preparation method according to claim 9, is characterized in that: described rotating speed is 300 turn/min, Filled DielectricsRate is 30%, ratio of grinding media to material 12:1, and milling time is 90min.
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