CN1096466C - New physical form of artemisinin and its use in production of pharmaceuticals - Google Patents
New physical form of artemisinin and its use in production of pharmaceuticals Download PDFInfo
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Abstract
The invention relates to a new physical form of triclinic Artemisinin. The Artemisinin has a good water-solubility, a high solution velocity and improved bioavailability. Also, the triclinic Artemisinin can be prepared to an oral solid antimalarial pharmaceutical.
Description
The present invention relates to a kind of new physical form of artemisinin and its application in medicine preparation.It is more particularly related to the preparation method of the oblique crystal form crystal of qinghaosu three, and its preparing the application in a kind of Solid oral pharmaceutical dosage form that patient's body bioavilability can be improved.
The calibration for being often the purity and its ultimate density of raw material with the key of administered in solid dosage forms drug is made.In addition, the physicochemical properties of solid drugs are also to be worth an important factor for drawing attention, because its any variation all will affect its absorption and therapeutic efficiency.
As the antimalarial obtained is separated from plant ginghao annua, qinghaosu is a kind of Sesquiterpene with endoperoxides function, has been recommended for multiple anti-medicine acute malaria caused by treatment plasmodium falciparum at present.Qinghaosu is its high relapse rate as a kind of major defect of effective antimalarial.Qinghaosu is not soluble in water and oily in previous report, but it is dissolved in most of aprotic organic solvent (Klayman, 1985), its absolute configuration is to utilize X-ray diffraction analytic approach by Chinese Scientists, obtained from the crystal being recrystallized to give in 50% hydrous ethanol is measured, unit structure cell is the p2 of rhombic form 1212 spatial groups (Qinghaosu ResearchGroup, 1980).So far, it is obtained although qinghaosu can be recrystallized as drug from different solvents, its other polymorphic configurations or crystal have not been reported.We have now found that the qinghaosu being recrystallized to give from hexamethylene can have (Chan et al., 1996) with three oblique crystal form crystal.As different polymorphic configuration or crystal, qinghaosu shows the different physicochemical properties including solubility.Since when PH is less than 7, water solubility is lower than 1% or 1mg ml to the other compounds of qinghaosu-1, cause bioavilability differ greatly from or problem (Kaplan, 1972；Halebian, 1975), to cause the extreme loss of therapeutic efficiency.The low aqueous solubility and its short-half-life and first-pass metabolism of qinghaosu result in its high relapse rate.It is therefore important that selecting the qinghaosu crystal form appropriate with good aqueous solubility to prepare oral drugs.
In saying this bright book, we will be sometimes referring to following journal articles, and attached bright literature author:
Citation
1984/1 Crystallography of Beurskens, P.T (1984) Technical Report
Laboratory, Toernooiveld, 6525 ed.Nijmegan, Netherlands.
Brossi, A., Venugopalan, B., Dominguez Gerpe, L., Yeh, H.J.C.,
Flippen-Anderson, J.L., Buchs, P., Luo, X.D., Milhous, W.and
Peters, W. (1988) J.Med.Chem.31,645-650.
Chan, K.L., Yuen, K.H., Takayanag i, H., Janadasa, S., Peh, K.K.and Lim, L.Y. (1997) Submitted to Phytochemistry.
Cromer, D.T. (1974) International Tables for X-rayCrystallography, Vol.IV, The Kynoch press, Birmingham, England, Table 2.3.1.
Cromer, D.T.and Waber, J.T. (1974) International Tables forX-ray Crystallography, Vol.IV, The Kynoch Press, Birmingham, England, Table
2.2A.
Gilmore, C.J. (1 984) J.Appl.Cryst.17,42-46
Halebian, J.K. (1975) J.Pharm.Sci.64,1269-1288.
Ibers, J.A.and Hamilton, W.C. (1964) Acta Crystallogr.17,781.
Kaplan, S.A. (1972) Drug Metab.Rev.1,15.
Klayman, D.L. (1985) Science 228,1049-1055.
Peh, K.K.and Yuen, K.H. (1996) Int.J.Pharm.139,95-103.
Qinghaosu Research Group (1980) Scientia Sinica 23,380-396.
TEXSAN (1985) TEXRAY Structure Analysis Package, Molecular
Structure Corporation.
Titulaer, H.A.C., Zuidema, J., Kager, P.A., Wetsteyn, J.C.F.M., Lugt, C.H.B.and Merkus, F.W.H.M. (1990) J.Pharm.Pharmacol., 43,810-813.
Wagner, J.G. (1975) Bioavailability.In Fundamentals ofClinical Pharmacokinetics, Illinois:Drug IntelligencePublications, p.337-358.
Yuen, K.H., Peh, K.k., Quah, Y.L.and Chan, K.L. (1997)
Drug Develop.Indust.Pharm.23 (2), 231-234.
Zhao, S.S.and Zeng, M.Y. (1985) .Planta Medica 51,233-237.
According to the first aspect of the invention, the present invention provides a kind of new physical form of artemisinin, i.e., three oblique crystal form sweet wormwood cellulose crystals.
The oblique orthogonal to that crystal form of crystal form sweet wormwood cellulose crystal of of the invention three, which is compared, has preferably water-soluble, faster rate of dissolution, and higher bioavilability.
The third aspect of the invention is the application for having three oblique crystal form sweet wormwood cellulose crystals of good biological availability in medicine preparation.
Finally, the three oblique crystal form sweet wormwood cellulose crystals with preferable bioavilability are used as antimalarial, therapeutic efficiency will be improved and recurrence rate may be lowered.
Qinghaosu is obtained using continuous pillar layer separation extract liquor then according to the method for previous Klayman (1985) description with the dried powder of n-hexane or (40-60 DEG C) of petroleum ether extraction annua sweet wormwood leaf.
According to the present invention, 25g qinghaosu is dissolved completely in the hexamethylene (700ml) of heat, and clarification hot solution is slowly cooled to room temperature, three oblique crystal form crystal are gradually precipitated at this time.Crystal, which is stood overnight, makes its sufficient crystallising, is then filtered under diminished pressure and is washed with cold hexamethylene.Repeated recrystallization is twice up to obtaining determining the crystal that fusing point is 156-157 DEG C, yield 93.5% from hexamethylene.
The method that thus obtained three oblique crystal form crystal is described according to the such as Chan (1996), pass through microscopic examination, density measurement, differential scanning calorimetry (dsc), Infrared Analysis (ir), it identifies with crystallography X-ray diffraction method, and is compared with rhombic form crystal.
Fig. 1 is shown, the microscopic observation of three oblique crystal form qinghaosus (A) and rhombic form qinghaosu (B), and magnifying power is 10 × 40, and the microscope detection of two kinds of qinghaosu samples shows significant morphological differences.Three oblique crystal form crystal (A) are thin and transparent, and rhombic form crystal (B) is close and thick.
Sweet wormwood cellulose crystal is precisely weighed in the compound specific gravity bottle of nitrogen protection, and relative volume calculate and calculate density result is as shown in table 1.The statistics averag density of rhombic form crystal is apparently higher than the averag density of three oblique crystal form crystal, the former is 1.300 ± 0.001SD g cm-3, the latter is 1.293 ± 0.003SD g cm-3。
Fig. 2 is the differential thermogram of three oblique crystal forms (A) and two kinds of crystal habit standard differential scanning calorimetries of rhombic form (B), shows that they are two kinds of polymorphics.Three oblique crystal forms (A) only generate a TmFor 155.00 ± 0.03 DEG C of molten decalescence point, and there are two molten decalescence point, T for rhombic form (B)mFor 154.88 ± 0.2 DEG C (tables 2).The Δ H value of two kinds of samples shows their crystallinity having the same.Differential thermogram melts the oblique gradient expression qinghaosu melting degradation after decalescence point.Instrument is in standardization when analysis, and scanning speed is 10.00 degree mins, and three oblique crystal form (A) crystal weight used is 2.00 milligrams, and rhombic form (B) crystal weight is 2.30 milligrams.
Fig. 3 indicates the infrared spectroscopy of three oblique crystal forms (A) and rhombic form (B) two kinds of qinghaosu crystal prototypes.As the difference existing for the crystal structure it is anticipated that as, in 2845-3000cm-1And 1300-1500cm-1Region, the infrared spectroscopy of three oblique crystal form crystal (A) show obviously absorption more broader than rhombic form crystal (B), this is as caused by the flexible and bending vibration of saturation CH atom respectively.In 1738cm-1, the stretching vibration of the C=0 of three oblique crystal form (A) lactones shows it than broader absorption in rhombic form (B) lactone.
Fig. 4 is the three-dimensional view for the three oblique crystal forms (A) and rhombic form (B) qinghaosu molecules align observed along z axis.
Fig. 4 shows three oblique crystal form crystal (A) and rhombic form crystal (B) in morphologic difference with X-ray diffraction analytic approach.The former has in a unit structure cell there are four independent compact arranged molecule, and equal number of molecule contained by the latter is upper further discrete from one another in arrangement.The oblique corresponding lattice constant of crystal form spatial group of the three of one P1 is a=9.891 (4) A；B=15.343 (2) A；C=9.881 (2) A；V=1458 (1) A3；α=90.92 (1) °；β=102.99 (2) ° and γ=93.28 (2) °.For other crystal forms, the P2 of rhombic form crystal 121The corresponding size of 2 spatial groups is a=9.450 (3) A；B=24.090
(3)A；C=6.364 (2) A；V=1449 (1) A3, this point is identical as described in previous open source literature (Qinghaosu Research Group, 1980)
Due to z=4 and F.W.=282.34, the calculating density of three oblique crystal forms is 1.286g cm-3, and the density of rhombic form is then higher, is 1.294g cm-1.This two kinds calculating density are compared with the density of the two kinds of crystal measured with compound specific gravity bottle method, it is found that their result is almost the same (table 1).The density of calculating and the measurement of the rhombic form crystal being previously reported is respectively 1.296gcm-3With 1.30g cm-3(Qinghaosu Research Group, 1980) is also consistent with our result now.
Fig. 5 is the ORTEP view for the three oblique crystal forms (A) and rhombic form (B) crystal observed along Z axis.Fig. 6 is that the atom of qinghaosu indicates.The comparison of two kinds of crystal molecule conformations shows that they are almost the same in Fig. 5.The bond distance of three oblique crystal forms (A) is almost similar (table 3-4) with rhombic form (B's).However, two kinds of polymorphous bond angles and torsional angle difference, are indicated in table 5-7 with asterik value.
Our research also shows that three selected oblique crystal form qinghaosus have water solubility more better than rhombic form qinghaosu.Under study for action, it is precisely weighed 30mg sweet wormwood cellulose crystal, is added in the water of 100ml, and sonication 6 hours at 24 DEG C.High performance liquid chromatography (hplc) with reduction Electrochemical Detection carrys out the drug concentration in analytical solution.Acquired results show three oblique crystal form crystal (44.3 μ g ml of qinghaosu-1± 1.2SD) than rhombic form crystal (17.7 μ g ml-1± 1.0SD) there is higher solubility in water.
The dissolution in vitro curve of sweet wormwood cellulose crystal is to be measured under non-setting condition by the wheeled paddling process of USP dissolution experiment instrument (AT7 type, Sotax CH-4008, Basel, Switzerland).Sweet wormwood cellulose crystal is sieved to obtain particle of the size at 300-710 μm with testing sieve (Endecotts Ltd., England).If particle, less than 250 μm, crystal meeting agglomeration simultaneously is difficult to disperse in dissolving medium, lead to the reduction of rate of dissolution.It is 100rpm in wheeled stirring rate, under conditions of temperature is 24 DEG C (room temperature), by 150mg qinghaosu dissolution of crystals in the solvent medium of 900ml distilled water in experiment.1ml sample is taken out with automatic fraction collector (Model CY7-50, Sotax, Switzerland) at different intervals in 24 hours.It is used in the electrochemical detector of reduction-mode, the concentration of the drug suitably diluted is measured by hplc.Each detection is repeated four times, and obtains the mean intensity value of qinghaosu in the solution, concentration value relative time is calculated and marks curve.
Fig. 7 represents dissolution in vitro curve of the sweet wormwood cellulose crystal of three oblique crystal forms (A) and two kinds of forms of rhombic form (B) under non-setting condition.Three oblique crystal form curves (A) show cracking rate of dissolution, and saturated concentration can be reached in 3 hours, and another curve (B) just reaches saturation after 10-14 hours.Moreover, the saturated concentration of the former (A) is significantly higher than rhombic form (B), they are 48.0 and 18.0 μ g ml respectively-1。
The oblique crystal form crystal of qinghaosu three is mixed with pharmaceutical carrier appropriate, different pharmaceutical dosage forms is made.A preferred embodiment of the present invention is the preparation of three oblique crystal form qinghaosu tablets.The composition of qinghaosu tablet is as follows:
| Qinghaosu (three oblique crystal forms) | 250mg |
| Lactose-hydrate | 45mg |
| Microcrystalline cellulose | 45mg |
| Crosslinked polyvinylpyrrolidone | 19mg |
| Magnesium stearate | 0.25% |
Microcrystalline cellulose and crosslinked polyvinylpyrrolidone are mixed in planetary stirrer first, lactose and qinghaosu is then added.Mixing 5 minutes.Enough distilled water is added in mixture of powders and is granulated.Wet granular is sieved with the screen of aperture 1.00mm, then drying 1 hour at 60 DEG C.Particle is sieved with 710 μm of aperture screens again.Before carrying out tabletting, it is added magnesium stearate as lubricant to wherein.It is 7kg (Erweka tablet hardness tester) and the tablet with a thickness of 3.8mm that average hardness is suppressed with the rotary tablet machine of diameter 8mm flat faced punches.
The dissolution in vitro degree research of sweet wormwood cellulose crystal is completed by the wheeled paddling process of 23 dissolving test instrument of USP.Test is carried out in the 900ml distilled water that temperature is 37.0 ± 0.5 DEG C of revolving speed 100rpm.2ml sample, at 3,6,10,15,20,25,30 minutes, is taken out for 1,2,3,4,12 hour by preset time interval.Drug concentration is detected with the reverse phase hplc method that Zhao and Zeng (1985) is discussed.Mobile phase is the 0.01M Phosphoric acid disodium dodecahydrate buffer containing 50% methanol, and PH is adjusted to 6.5 with glacial acetic acid.Flow velocity is 0.8ml min-1, detected at 260nm with UV detector.Before analysis, accurate measuring 1ml sample dilutes in teat glass and with 4ml distilled water.Then 1ml solution is transferred in reaction flask, and 10% NaOH of 200 μ l is added thereto, after vortex mixed 1 minute, in the heater, heated 30 minutes at 45 DEG C.Add vortex mixed after 150ml glacial acetic acid.100 μ l sample injections are taken to enter chromatographic column.The solubility curve of three oblique crystal form tablets is as shown in table 8.
Drug is measured in the intracorporal bioavilability of people by the comparison of the oblique crystal form of qinghaosu three and rhombic form bioavilability assessed value in vivo.In experiment, 8 healthy male volunteers are given into the oral aqueous suspension for being sieved into the qinghaosu crystal grain of 300-710 μ size administration, their age was at 30-43 years old (average 35.6 years old ± 4.4SD), weight 50-71kg (average 62.3kg ± 7.5SD), and written agreement book is signed, experimental protocol is by Joint Review Boardon Bioavailability Studies of the Penang General Hospital and theSchool of Pharmaceutical Sciences, Univercity Sains Malay What sia was proved.According to cross-random programming, two interim intervals 1 week.Volunteer is randomly divided into two groups of every group of four people, and is administered according to following timetable:
| Group | First week |
|
| 1 | Rhombic form and salicylazosulfapyridine |
Three |
| 2 | Three oblique crystal forms and salicylazosulfapyridine | Rhombic form |
The qinghaosu single oral dose that each volunteer gives is 10mg kg-1, i.e., in the form of the aqueous suspension of the water containing 150ml, it is administered after the fasting of (12 hours) overnight.The coecum mouth conduction time of suspension is by first group and second group of two groups of volunteer at first week while (Peh and Yuen, 1996) that the 1g salicylazosulfapyridine taken is determined.Diet is unable at least two hours after the tablet has been ingested.Volunteer used walking movement in an experiment, forbids strenuous exercise and No alcoholic beverages.Forearm vein inner catheter through being inserted into takes 8ml volume blood samples in 0.25,0.5,1,2,3,4,6,8,10,14,18 and 24 hour after 0 (before medication), and medication from each volunteer.Blood sample collection used (Becton, Dickinson, NewJersey, USA) in the vacuum tank of test tube of hepari is centrifugated 1 minute at revolving speed 3500rpm.Plasma sample stored frozen is until analysis.Salicylazosulfapyridine is hydrolyzed into sulfapryidine in large intestine group.The indicant that the sulfapryidine absorbed in blood will be reached as coecum.It is horizontal that serum sulfapryidine is measured according to hplc method used in Yuan etc. (1997).
It is horizontal using the qinghaosu in hplc-ecd technology analysis plasma sample.Before being analyzed with hplc-ecd, sample preparation is as follows: the 200ng ml of 100 μ l being accurately added in the plasma sample of 1.00ml equal portions-1The acetonitrile solution of dihydroartemisinine (internal standard).With 3 × 3ml methyl tertiary butyl ether(MTBE) (Merck, USA) rotation extraction mixture 30 minutes on test tube whirler (Model34528 Sinjders), then it is centrifugated 15 minutes at revolving speed 3500rpm again.With the dry combined extract liquor of nitrogen at 45 DEG C, then plus 100 μ l mobile phases, be then centrifugated 10 minutes at revolving speed 12800rpm.Supernatant collection enters in the reaction tube of 0.1ml (PierceReactivialTM, USA), sample injection after ten minutes is being washed with the argon gas purging being saturated by deionized-distilled water.
After sample preparation is described more fully below, the specific analytical method of qinghaosu is detected.Jasco Pu-960 solution delivery system is all connected to a digital electrochemical source of current detector (DECADE) with stainless steel adapter tube.The latter includes the high shielded chamber adjusted by air pulse adjuster, one has 7161 sample injector of Rheodyne of 20 μ l sample loops, one Upchurch that refills being connected with the 5 μ column of Supelcosil LC-CN that an internal diameter is 250 × 4.6mm protects chromatographic column, one equipped with glassy carbon working electrode and Ag/AgCl reference electrode (the R&M Marketing being saturated with KCl, Essex, UK) flow cell.Mobile phase is made of the acetonitrile buffer of the PH 75%0.10M ammonium acetate (Merk, Darmstadt) for being adjusted to 5.5, and flow velocity is maintained at 1.5ml min-1.In entire analytic process, while being continuously passed through argon gas, is heated 2 hours by elder generation at 50 DEG C, be then maintained at 30 DEG C and carry out violent deoxidation so that heat phase will be flowed.Detector is operated under the reduction-mode that sensitivity is 10nA fs. in being -10V using current potential.Signal reaches record output end after 0.1s is filtered out.The standard reserving solution (100 μ g ml) of all qinghaosus (Aldrich Chemical Co..USA), it (is synthesized according to method described in Brossi et al. (1984) with dihydroartemisinine, its purity is suitable with standard sample provided by the Dr.Simone C.Vonwiller of University of Sydney) (Labscan limited, Ireland) is handled in hplc grades of pure acetonitriles.
Artemislnin content is measured by the peak height ratios of measurement drug and internal standard compound.Daily analysis test will make standard curve, and Specification Curve of Increasing is by by the qinghaosu of various concentration and constant internal standard compound (200ng ml-1) be added in the blank plasma of people and complete.Qinghaosu concentration range is in 12.5-800ng ml-1.The accuracy on the same day and precision are by concentration repeated measurement 6 times each in one day.Adjacent two days numerical value is measured by continuous research in 6 days simultaneously.Accuracy is expressed as the percentage that surveyed mean concentration determines value relatively, and precision is indicated with the coefficient of variation (CV).The percentage for the drug peak value that gained peak value does not extract relative to equivalent after extraction is the rate of recovery of extraction process.
Pharmacokinetic analysis carries out as follows: drug plasma Cmax (Cmax) and plasma drug level relative to the time make curve, (AUC under curve0-∞) the gross area be converted into logarithm before analysis.AUC is calculated using linear trapozoidal rule0-∞It is worth and is extrapolated to infinitely.CmaxAnd AUC0-∞Value is statistically calculated using method of analysis of variance (ANOVA) described in Wagner (1975).TmaxValue is compared according to Wilcoxon signed-rank experimental method with control sample.
The detection method of accuracy and precision on the day of and between two days adjacent has been given in Table 9 it, while the rate of recovery of dihydroartemisinine and qinghaosu is respectively as shown in table 10 and 11.In addition, it is 12.5ng ml under the conditions of 5: 1 that the detection limit of test method, which is signal-to-noise ratio,-1。
The mean plasma concentration level curve of three oblique crystal forms (A) and two kinds of crystal habits of rhombic form (B) is as shown in figure 8, each data point in blood plasma is listed in table 12 simultaneously.The mean plasma concentration curve of three oblique crystal forms (A) is significantly higher than rhombic form (B).In addition, the former Cmax average out to 580.89ng ml-1, it is 3.35 times of the latter, the latter is only approximately 173.65ngml-1。
It is estimated suspension coecum mouth conduction time (time for reaching colon) according to the method for Peh and Yuen (1996) according to the data of the blood plasma level of surveyed sulfapryidine.The average value of acquisition is 2.7 ± 0.6 hours, it indicates that preparation reaches the beginning of colon.Fig. 9 indicates the curve of the percent absorbent value relative time of three oblique crystal forms (A) and two kinds of preparations of rhombic form (B).There is dotted line to indicate that suspension reaches coecum.There is no increases for curve absorption value after it shows this time point.Thus absorption of the qinghaosu in colon can be ignored.The trap that rhombic form crystal (B) is observed is low, mainly due to reach colon before its drug dissolve and absorb it is less.
Each numerical value C of pharmacokinetic parametermax, Tmax, AUC0-∞All as shown in table 13.TmaxAnd AUC0-∞It respectively indicates absorption rate and absorbs numerical value, and CmaxTo it is both related.The T of two kinds of crystal habitsmaxIt is worth no statistical significant difference, but CmaxAnd AUC0-∞Logarithm have statistical conspicuousness, showing two kinds, crystal habit absorption rate is similar but trap is different.The AUC of the oblique crystal form form of the three of 90%0-∞Logarithm conversion value is 3.1-3.7 relative to the confidence interval of rhombic form form.So the oblique crystal form absorption of crystal amount of qinghaosu three is 3.4 times of rhombic form or improves 340%.
Pharmacokinetic parameter the numerical value Ke, t of two kinds of crystal configurations are given in table 141/2, Vd.All three parameter values of two kinds of crystal are all much like and without statistical significant difference.These numerical value are similar with described in existing literature (Titulaer etc., 1990).Density value (the g cm for the sweet wormwood cellulose crystal that table 1 is recrystallized from hexamethylene (Artecyclohex) and 50% hydrous ethanol (Artaquenol)-3)
*Statistical significant difference: the main endothermic temperature peak (Tm) of 2 Artecyclohex and Artaquenol crystal melt of (P=0.0018, P < 0.01) table and total enthalpy (Δ H)
*Intramolecular spacing (A ± (SD)) between the non-hydrogen atom of 3 Artecyclohex and Artaquenol of average value ± SD (n=3) table
Intramolecular spacing between the hydrogen atoms of table 4 Artecyclohex and Artaquenol
Intramolecular bond angle (° ± (SD)) between the non-hydrogen atom of table 5 Artecyclohex and Artaquenol
*Intramolecular bond angle (°) between Artaquenol type and the different 6 Artecyclohex and Artaquenol hydrogen atoms of value table of Artecyclohex type
*The twist angle of distinguishing value table 7 Artecyclohex and Artaquenol of Artaquenol and Artecyclohex or configuration angle
* the distinguishing value # of Artaquenol and Artecyclohex is clockwise movement from relative atom 2 to 3 and the atom 1 Chong Die with atom 4 is observed, and is labeled as positive number.The solubility curve of the oblique crystal form qinghaosu tablet of table 8 three
The accuracy and precision of 9 qinghaosu of table detection
The rate of recovery of 10 dihydroartemisinine of table
The 11 qinghaosu rate of recovery of table
Value of each blood plasma qinghaosu concentration of table 12 in different time
ND: undetectable 13 C of tablemax, TmaxAnd each numerical value of AUCo- ∞
Cmax: maximum concentration Tmax: reaching the time AUC of maximum concentrationo-∞: each numerical value of area under the curve table 14 Ke, t1/2 and Kd
Ke: elimination rate constant t1/2: eliminating half-life period Vd: volume of distribution
| No of measurements(n) | Artecyclohex | Artaquenol |
| 12345 average value variances | 1.290 1.289 1.295 1.295 1.296 1.293* 0.003 | 1.299 1.301 1.300 1.301 1.299 1.300* 0.001 |
| Sweet wormwood cellulose crystal | Tm *(℃) | ΔH*(J g-1) |
| Artecyclohex Artaquenol | 155.00±0.03 154.88±0.20 | 80.76±2.37 82.43±4.57 |
| Atom | Atom | Artecyclohex | Artaquenol |
| O1 O1 O2 O3 O3 O4 O5 O5 C1 C2 C2 C3 C3 C4 C4 C6 C6 C7 C8 C9 C10 C10 C11 | C1 C5 C1 O4 C6 C4 C5 C6 C2 C3 C13 C4 C12 C5 C9 C7 C14 C8 C9 C10 C11 C15 C12 | 1.34(3) 1.42(3) 1.21(3) 1.48(2) 1.41(3) 1.44(3) 1.41(3) 1.49(3) 1.55(3) 1.48(3) 1.57(3) 1.47(3) 1.52(4) 1.52(3) 1.57(3) 1.60(4) 1.47(3) 1.47(4) 1.59(4) 1.52(3) 1.51(4) 1.55(3) 1.55(4) | 1.33(5) 1.47(4) 1.17(5) 1.47(3) 1.42(5) 1.45(4) 1.38(4) 1.43(4) 1.57(5) 1.56(4) 1.51(4) 1.47(4) 1.50(5) 1.63(4) 1.55(4) 1.57(5) 1.45(4) 1.56(4) 1.52(4) 1.58(4) 1.54(5) 1.51(5) 1.51(5) |
| Atom | Atom | Artecyclohex | Artaquenol |
| C2 C3 C5 C7 C7 C8 C8 C9 C10 C11 C11 C12 C12 C13 C13 C13 C14 C14 C14 C15 C15 C15 | H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 H17 H18 H19 H20 H21 H22 | 1.041 1.024 0.974 1.023 0.912 0.973 0.963 0.968 0.958 0.941 0.998 0.955 0.981 0.992 1.009 0.977 0.961 0.933 0.967 0.903 1.053 0.957 | 0.921 0.977 1.016 1.005 0.921 1.033 1.004 0.978 0.987 0.922 1.067 0.955 1.068 0.999 1.031 0.923 1.029 0.963 1.003 0.940 1.016 0.980 |
| Atom | Atom | Atom | Artecyclohex | Artaquenol |
| O3 O3 O3 O5 O5 C7 C6 C7 C8 C8 C10 C9 C9 C11 C10 C11 C12 C12 C4 O4 O4 O4 C9 C9 C3 O5 O5 O1 C3 C3 C1 O1 O1 O2 | C6 C6 C6 C6 C6 C6 C7 C8 C9 C9 C9 C10 C10 C10 C11 C12 C3 C3 C3 C4 C4 C4 C4 C4 C4 C5 C5 C5 C2 C2 C2 C1 C1 C1 | O5 C7 C14 C7 C14 C14 C8 C9 C10 C4 C4 C11 C15 C15 C12 C3 C4 C2 C2 C9 C3 C5 C3 C5 C5 O1 C4 C4 C1 C13 C13 O2 C2 C2 | 106(2) 110(2) 107(2) 106(2) 107(2) 120(3) 119(3) 114(2) 109(2) 112(2) 112(2) 110(2) 111(2) 112(3) 114(3) 113(3) 112(2) 111(3) 112(3) 105(2) 104(2) 113(2) 112(2) 109(2) 113(2) 104(2) 116(2) 113(2) 112(2) 116(3) 113(3) 122(3) 118(3) 119(3) | 107(3) 115(3)* 105(4) 108(4) 112(3)* 110(4)* 112(3)* 116(3) 110(4) 115(4) 110(4) 117(3)* 109(4) 109(4) 111(3) 114(4) 116(4) 117(4)* 111(4) 106(3) 110(4)* 111(3) 115(4) 108(4) 107(3)* 111(4)* 109(3)* 110(4) 109(3) 117(4) 108(4)* 117(6) 118(4) 125(5)* |
| Atom | Atom | Atom | Artecyclohex | Artaquenol |
| C6 C6 C8 C8 C6 C7 C7 C9 C9 H6 C8 C10 C4 C9 C11 C15 C10 C10 C12 C12 H10 C11 C11 C3 C3 H12 C12 C4 C2 O5 O1 C4 C3 C1 C13 C2 C2 C2 H14 H14 H15 C10 C10 C10 H20 H20 H21 C6 C6 C6 H17 H17 H18 | C7 C7 C7 C7 C7 C8 C8 C8 C8 C8 C9 C9 C9 C10 C10 C10 C11 C11 C11 C11 C11 C12 C12 C12 C12 C12 C3 C3 C3 C5 C5 C5 C2 C2 C2 C13 C13 C13 C13 C13 C13 C15 C15 C15 C15 C15 C15 C14 C14 C14 C14 C14 C14 | H4 H5 H4 H5 H5 H6 H7 H6 H7 H7 H8 H8 H8 H9 H9 H9 H10 H11 H10 H11 H11 H12 H13 H12 H13 H13 H2 H2 H2 H3 H3 H3 H1 H1 H1 H14 H15 H16 H15 H16 H16 H20 H21 H22 H21 H22 H22 H17 H18 H19 H18 H19 H19 | 111.69 107.68 109.62 101.13 106.46 109.62 104.72 111.78 110.07 106.52 108.61 104.83 109.99 109.66 107.66 107.11 107.98 112.83 105.77 109.21 106.24 111.06 109.40 110.57 106.39 106.49 104.82 109.15 106.86 105.46 109.30 108.81 100.42 114.15 99.48 121.98 110.77 113.41 102.73 103.94 101.69 116.51 107.70 112.22 104.71 113.06 100.96 111.48 106.79 111.81 107.13 109.97 109.49 | 111.20 108.40 108.89 109.22* 108.40 110.86 112.17* 107.08* 110.28 99.21* 110.33 97.54* 112.07 113.75 101.16 106.31 119.32* 105.17* 114.18* 102.07* 102.26* 105.41* 106.46* 118.32* 110.30* 100.01* 89.98* 110.89 116.65* 102.89 116.65* 107.26 99.11 117.91 106.10* 113.50* 108.02 120.70* 99.64 107.61 104.97 114.35 114.90* 111.95 104.87 107.74* 102.00 111.36 118.07* 118.73* 104.92 99.92* 102.44* |
| atom |
| 1 |
|
|
| Artecyclohex | Artaquenol |
| O4 O4 O4 O4 O4 O4 O4 O4 O4 O3 O3 O3 O3 O3 O5 O5 O5 O5 O1 O1 O1 O1 O1 O2 O2 O2 C6 C6 C6 C7 C7 C7 C8 C8 C8 C8 C8 C9 C9 C9 C10 C10 C10 C11 C11 C11 C12 C12 C12 C12 C4 C4 C4 C4 C5 C5 C5 | O3 O3 O3 C4 C4 C4 C4 C4 C4 O4 O4 O4 C6 C6 C6 C5 C5 C5 C5 C5 C5 C1 C1 C1 C1 C1 O3 O5 C7 C6 C8 C8 C7 C9 C9 C9 C9 C10 C4 C4 C9 C9 C11 C10 C12 C12 C11 C3 C3 C3 C9 C3 C3 C5 O5 O1 C4 | C6 C6 C6 C9 C9 C3 C3 C5 C5 C4 C4 C4 O5 C7 C7 O1 C4 C4 O5 C4 C4 C2 C2 O1 C2 C2 O4 C5 C8 C8 C9 C9 C6 C10 C10 C4 C4 C11 C3 C3 C4 C4 C12 C9 C3 C3 C10 C4 C2 C2 C10 C2 C2 O1 C6 C1 C3 | O5 O5 C14 C8 C10 C12 C2 O5 O1 C9 C3 C5 C5 C8 C8 C1 C9 C3 C6 C9 C3 C3 C13 C5 C3 C13 C4 C4 C9 C9 C10 C4 C14 C11 C15 C3 C5 C12 C12 C2 C3 C5 C3 C4 C4 C2 C15 C5 C1 C13 C15 C1 C13 C1 C14 C2 C2 | -74(2) 41(3) 172(2) 69(2) -168(2) 166(2) -68(2) -47(3) 73(3) -110(2) 132(2) 10(3) 34(3) -94(3) 20(3) 158(2) 70(3) -164(2) -101(2) -170(2) -44(3) 34(3) 168(2) 165(2) -158(3) -24(4) 50(3) 23(3) 60(3) -83(3) -161(2) -36(3) 141(3) 179(2) -58(3) -179(2) -53(3) -52(3) 53(3) 179(2) -56(3) 70(3) 50(4) 54(3) -50(3) -177(3) -175(3) -71(3) 79(3) -54(3) 178(2) -48(3) 180(2) 32(3) 148(2) -27(3) 55(3) | -74(3) 46(4) 167(3)* 69(4) -166(3) 170(3) -53(4)* -50(6) 72(5) -106(3) 129(3) 11(5) 32(5) -94(4) 26(4)* 145(5)* 66(4) -170(5) -94(4)* -172(3) -48(4) 29(7) 157(5)* 166(4) -153(6) -24(7) 49(4) 27(5) 57(4) -92(4)* -165(2) -39(5) 148(4)* 171(3)* -65(4)* -169(4)* -50(5) -46(4) 50(4) 173(3)* -44(4)* 75(4) 48(4) 43(4)* -53(4) -174(3) -170(3) -70(4) 79(5) -44(5)* 167(3)* -57(5)* 180(3) 24(6) 147(4) -15(8)* 67(4)* |
| Time (min) | Concentration (mg ml-1) (n=6) |
|
| 3 6 10 15 20 25 30 60 120 180 240 720 | 16.38 18.84 23.04 29.01 35.49 39.71 45.54 55.26 70.11 72.04 76.82 83.14 | 2.09 1.53 2.22 1.81 2.86 2.04 1.37 3.68 2.86 3.15 2.44 2.81 |
| The same day | Adjacent two days | |||||||
| Concentration (ng mL-1) | Average recovery rate (ng mL-1) | SD | CV (%) | % error | Average recovery rate (ng mL-1) | SD | CV (%) | % error |
| 25 50 200 800 | 23.43 48.06 199.53 781.78 | 1.25 1.86 1.97 11.25 | 5.33 3.87 0.99 1.44 | 7.34 6.07 0.77 2.28 | 24.58 48.91 199.60 792.59 | 2.48 5.00 6.13 11.83 | 10.08 2.05 3.07 1.49 | 7.84 6.77 2.45 1.36 |
| Concentration (ng mL-1) | Average recovery rate (%) | SD | CV (%) |
| 200 | 94.93 | 4.82 | 5.08 |
| Concentration (ng mL-1) | Average recovery rate (%) | SD | CV (%) |
| 25 | 88.86 | 2.95 | 3.32 |
| 50 | 87.60 | 8.15 | 9.31 |
| 200 | 87.53 | 3.67 | 4.20 |
| 800 | 97.68 | 1.54 | 1.57 |
| Three oblique crystal form (ng mL-1) | ||||||||||
| time (hr.) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | mean | SD |
| 0.00 0.25 0.50 1.00 2.00 3.00 4.00 5.00 6.00 8.00 10.00 12.00 14.00 | 0.00 38.36 177.20 299.54 692.36 566.42 478.95 332.66 234.52 176.95 122.11 89.73 19.00 | 0.00 34.51 191.10 325.47 548.31 466.29 323.61 253.26 145.06 91.09 58.09 31.16 ND | 0.00 47.29 94.44 124.09 254.99 475.60 212.93 174.22 94.32 77.19 67.99 26.11 ND | 0.00 29.43 74.47 197.80 543.71 710.10 404.26 302.64 154.37 95.93 72.36 30.00 ND | 0.00 18.76 58.71 90.47 286.14 507.61 187.12 126.45 70.74 52.26 45.68 34.51 ND | 0.00 32.53 77.82 171.24 526.84 364.05 231.67 188.98 134.39 70.62 67.27 20.00 ND | 0.00 12.92 66.28 118.39 318.52 643.86 322.24 113.42 67.77 59.70 48.29 39.72 ND | 0.00 11.19 51.76 129.80 542.47 419.39 297.05 114.67 69.01 38.86 14.04 ND ND | 0.00 28.12 98.97 182.10 464.17 519.17 307.23 200.79 121.27 82.83 61.98 33.90 3.63 | 0.00 12.76 54.24 87.23 156.84 115.31 98.94 86.14 57.98 42.56 30.60 25.57 7.13 |
| Rhombic form (ng mL-1) | ||||||||||
| 0.00 0.25 0.50 1.00 2.00 3.00 4.00 5.00 6.00 8.00 10.00 12.00 14.00 | 0.00 ND 10.94 67.64 114.67 191.96 135.00 100.40 85.76 72.11 21.24 ND ND | 0.00 ND 39.10 56.97 196.43 125.96 94.07 53.99 49.40 35.88 21.73 ND ND | 0.00 ND 30.67 63.55 96.67 151.76 87.24 68.76 49.65 22.60 ND ND ND | 0.00 ND 9.33 30.17 -88.86 202.88 185.64 70.37 53.87 23.35 17.14 ND ND | 0.00 ND 5.11 29.80 65.90 130.05 56.85 40.72 33.40 15.78 11.93 ND ND | 0.00 ND 36.13 76.08 149.28 93.94 89.23 72.60 61.44 35.00 15.00 ND ND | 0.00 ND 31.41 54.86 73.35 212.06 110.82 75.71 67.64 34.76 8.58 ND ND | 0.00 ND 10.69 49.90 154.74 98.78 63.05 38.46 25.00 16.52 ND ND ND | 0.00 ND 21.67 53.62 117.49 150.92 102.74 65.13 53.27 32.00 11.95 ND ND | 0.00 ND 13.89 16.66 45.51 46.52 41.67 20.30 19.09 18.15 8.58 ND ND |
| Three oblique crystal forms | Rhombic form | ||||||
| Project | Cmax (ng mL-1) | Tmax (hr.) | AUCo-∞ (hr ng mL-1) | Cmax (ng mL-1) | Tmax (hr.) | AUCo-∞ (hr ng mL-1) |
AUCo-∞Ratio of the three oblique crystal forms relative to |
| 1 2 3 4 5 6 7 8 | 692.36 548.31 475.60 710.10 507.61 526.84 643.86 542.47 | 2 2 3 3 3 2 3 2 | 355.47 2494.13 1741.68 2802.50 1615.64 1994.67 1912.01 1702.46 | 191.96 196.43 151.76 202.88 130.05 149.28 212.06 154.74 | 3 2 3 3 3 2 3 2 | 912.21 717.18 583.28 735.68 423.32 667.83 713.03 467.02 | 3.90 3.48 2.99 3.81 3.82 2.99 2.68 3.65 |
| Average value | 580.89 | 2.50 | 2227.57 | 173.65 | 2.63 | 652.44 | 3.42 |
| SD | 88.64 | 0.53 | 677.22 | 30.51 | 0.52 | 157.74 | 0.47 |
| CV (%) | 15.26 | 21.20 | 30.40 | 17.57 | 19.77 | 24.18 | 13.74 |
| Three oblique crystal forms | Rhombic form | |||||
| Subject | Ke (hr-1) | t1/2 (hr) | Vd (liter kg-1) | Ke (hr-1) | t1/2 (hr) | Vd (liter kg-1) |
| 1 2 3 4 5 6 7 8 | 0.22 0.25 0.27 0.29 0.43 0.32 0.32 0.27 | 3.16 2.74 2.56 2.42 1.60 2.15 2.19 2.53 | 12.82 15.82 21.19 12.44 14.26 15.56 16.53 21.47 | 0.31 0.30 0.38 0.38 0.42 0.24 0.24 0.33 | 2.22 2.32 1.84 1.82 1.64 2.92 2.85 2.21 | 35.11 46.68 45.51 35.73 55.78 63.15 57.57 50.51 |
| Average value | 0.30 | 2.42 | 16.26 | 0.33 | 2.21 | 50.51 |
| SD | 0.06 | 0.46 | 3.44 | 0.07 | 0.47 | 11.53 |
| CV (%) | 21.68 | 19.01 | 21.16 | 20.34 | 21.27 | 22.83 |
Claims (10)
1. a kind of physical aspect of qinghaosu, which is characterized in that the qinghaosu is three oblique crystal form crystal.
2. application of the three oblique crystal form crystal qinghaosus in pharmaceutical composition preparation.
3. a kind of pharmaceutical preparation comprising three oblique product type crystal qinghaosu described in claim 1.
4. pharmaceutical preparation according to claim 3, wherein qinghaosu exists in a manner of chemical combination or combination with a kind of pharmaceutically acceptable carrier.
5. pharmaceutical preparation according to claim 3 or 4 is used as a kind of oral drugs.
6. pharmaceutical preparation according to claim 3 or 4 is used as a kind of anti-malaria medicaments.
7. pharmaceutical preparation according to claim 3 or 4, which is characterized in that the pharmaceutical preparation is solid dosage forms.
8. pharmaceutical preparation according to claim 5, which is characterized in that the pharmaceutical preparation is solid dosage forms.
9. pharmaceutical preparation according to claim 6, which is characterized in that the pharmaceutical preparation is solid dosage forms.
10. a kind of method for preparing three oblique crystal form crystal qinghaosus comprising following step:
A) qinghaosu is dissolved in several alkane of hot ring；
B) solution is slowly cooled to room temperature, three oblique crystal form crystal are gradually precipitated at this time；
C) make crystal growth；
D) crystal is collected under reduced pressure；
E) crystal collected is washed with several alkane of cold ring；And
Recrystallize crystal from several alkane of ring, to obtain the crystal that precise melting point is 156-157 DEG C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MYP19604715 | 1996-11-14 | ||
| MYPI96004715A MY129255A (en) | 1996-11-14 | 1996-11-14 | A new physical form of artemisinin and its use in the production of pharmaceuticals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1189496A CN1189496A (en) | 1998-08-05 |
| CN1096466C true CN1096466C (en) | 2002-12-18 |
Family
ID=19749764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97120284A Expired - Fee Related CN1096466C (en) | 1996-11-14 | 1997-11-12 | New physical form of artemisinin and its use in production of pharmaceuticals |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1096466C (en) |
| MY (1) | MY129255A (en) |
| PE (1) | PE20000016A1 (en) |
| ZA (1) | ZA9710178B (en) |
-
1996
- 1996-11-14 MY MYPI96004715A patent/MY129255A/en unknown
-
1997
- 1997-11-12 ZA ZA9710178A patent/ZA9710178B/en unknown
- 1997-11-12 CN CN97120284A patent/CN1096466C/en not_active Expired - Fee Related
- 1997-11-13 PE PE1997001019A patent/PE20000016A1/en not_active Application Discontinuation
Non-Patent Citations (3)
| Title |
|---|
| J.APPL.CRYST.17:42-46 1984.1.1 GILMORE,C.J. * |
| J.APPL.CRYST.17:42-46 1984.1.1 GILMORE,C.J.;J.MED,CHEM 31:645-650 1988.1.1 MILHOUS,W.;PETERS,W. * |
| J.MED,CHEM 31:645-650 1988.1.1 MILHOUS,W.;PETERS,W. * |
Also Published As
| Publication number | Publication date |
|---|---|
| MY129255A (en) | 2007-03-30 |
| PE20000016A1 (en) | 2000-02-06 |
| ZA9710178B (en) | 1998-05-28 |
| CN1189496A (en) | 1998-08-05 |
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