嘌呤药物的热解过程及其热分解动力学

644●药学学报Acta Pharmaceutica Sinica 2002 37 8)544 - 648STUDIES ON THE THERMAL DECOMPOSITION PROCESSAND KINETICS OF PURINE DRUGSZHANG Jian* , SHENG Rui-long , MAI Wen-peng( Cllge of Chemistry and Life Sciences , South-central Uniersity for Nationalities , Wuhan 430074 , China )ABSTRACT :AIM To study the thermal stability , decomposition process and kinetics of such purine pharmaceuticals asaciclovir( Acv ) , penciclovir( Pev ) , and their parent substance ，guanine. METHODS Using infrared technique , acceleratingtest method and thermogravimetry to investigate the thermal decomposition processes and using Coast- Redferm method , MKN methodand Ozawa method to deal with the data to get kinetic functions. RESULTS The decomposition process and the formned productswere derived , the kinetie model function was suggested by comparison of the kinetic parameters. CONCLUSION Pev and Aev' s .degrading product for the first step is guanine. The sequences of their thermal stabilities is : Pev> Acv'The two dnugs' kineticequation of themal decomposition is expressed as :da/dt= Ae~ E( 1-a)2KEY WORDS : aciclovir ; penciclovir ; guanine ; accelerating test ; thermal stability ; thermogravimetry ; non-isothermalkineticsCLC number : R912Document code :AArticle ID :0513 - 48702002 )08- 0644 - 05Purine drugs are a kind of low toxicity ，highlyElmer Co. ,USA ), used under the following conditions :effective antivirus pharmaceuticals. It has inhibition effectsample mass : 3.00 mg ; atmosphere : static air ; heatingon the duplication of DNA in virus such as HIV-1 , HIV-rate:2.5 ,4 ,5 ,8，10 and 15C min-' ; temperature2 , VZV[12]. Acyclovir( Aev ) and penciclovir( Pev )arerange: 30 ~ 630C. Infrared spectrograph FT-IR Nexustwo important members in the family of purine drugs.470( America Nicolet ). All the thermogravimetric dataSome related research work has been reported. Thewere analysed on a PT-1II computer.capsuleof penciclovir was prepared and theMaterials Pev and Acv were obtained from Hubeibioequivalence was studied using HPLC with fluorescencePharmaceutical Industry Institute ( Wuhan ) , guanine wasmethoc 31. Acyelovir inhibition of induced hepes simplexpurchased from Sigma Co. Purity of all raw drugs wasvirus type 1 was investigatet 41 by temporal analysisbetter than 99.4% .method. SreisSI studied the effect of partide sizedistribution and excipients on the dissolution of acyclovirRESULTS AND DISCUSSIONSfrom gelatin capsules , tablets and powders .Thermal stabilities and thermal decomposition1 Thermal decomposition processes of Pev and Acvkinetics of purine drugs are the interesting problem insamplesindustrial applications , they are important in evaluatingThermogravimetric( TG ) curves of Pev and Acv areand periods of validity , and for controlling the quality inshown in Figure 1.the process of manufacture. In this paper ，the thermal100}decomposition process and kinetics of 3 typical raw80Acv一-PcvGuanincmaterials of purine drugs ，penciclovir ，acyclovir andguanine 3 were investigated by infrared spectrometry ，β =SK. min-'accelerating test and thermogravimetry .E 40-MATERIALS AND METHODS2(Instruments TGS-2 model thermobalance( Perkin-0b 0 200Temperaturv°C00500 600 市Received date : 2002-01-04.Fionure1药学学报Acta Pharmaceutica Sinia 2002 37 8)644 - 648645●As shown in Figure 1 , the thermal decomposition( Figure 2).processes involved two weight-loss stages. For Pev , theAs shown in Figure 2 and Table 1 , the absorptiontemperature range of the first stage was 276.45 ~bands of remnants are almost the same as those of398. .209C with the mass loss being 39.21 % ( theoretical ,guanine. It could be infferred that the, side 。chain40.25% ); for Aev , the temperature range of the first-CH2CH( CH20H) of Pev and - CH20CH2CH2OHstage was 235.85 ~ 357.919C with the mass loss ofof Acv were lost in the process of heating. So the30.45% ( theoretical , 32.81 % ), the remainders of theprocesses of thermal decomposition was deduced in Figureirst stage decomposition were analyzed by R spectra 3.00b10012090f1108070宝970f608174050304000 3000 2000 10004000 30020010004000 30002000Wave number/cm-!Figure 2 Infrared spectra of remainder and guaninea. Remainder of Pev ib. Remainder of Acv ic. GuanineHCH,CH2CH(CH2OH)2NH+CO+HOPev°7五NNH2GuanineCH2OCH2CH2OHAcvFigure 3 The reaction formulations of the first stage of thermal decompositionFigure 1 shows that guanine was relatively stableWave number / cm-Samplewhen the temperature was below 400C and could not meltWIH2_ vaH__ Vc=0比-N 8c-H33182899I695I367I470because of the stability of the aromatic heterocyclicRemainder of Acv3328 2899 1695 1 385 1 471compound. With the bonds broken irregularly it degradedRemainder of Pev33382899169513851471and carbonized when the temperature was above 400C.Because the experiment was carried out in air , thermalCoats- Redferm method and MKN method were useddecomposition of Pev and Acv which was accompaniedhere. The equations are shown below :with thermal oxidation at the second stage was veryg(a)AREacomplicated.IrT2= lnβE- RT(1)2 Thermal decomposition kineticsAEaIn g51g15s=In+ 3.7721 - 1.9215lnEa .From the TG curve of Pev，the basic data( T,a，71.9βRda/dT ) for stage( 1 ) can be obtained as shown in Table0.12039 Ea(2)646 .药学学报Acta Pharmaceutica Sinia 2002 37 8)644 - 648Table2 Basic data at the first stage of Pev( β=method，compared favorably with the data of Ea from No.5C min-1 )19 ,No.20 ,No.21 and No.22 obtained by Coast- RedfemData a W/% T/K da/dT Data a W/% T/K da/dTmethod and MKN method ，and kinetic model function1 0.103 95.94 582.60 0.0100 10 0.547 79.86 608.26 0.0188No.20 whose Ea is 150.83 kJ mol -1 by Coast-Redfermn.2 0.145 94.42 586.26 0.0122 11 0.599 77.98 611.01 0.0177method ,while a value of 148.82 kJ mol- 1 obtained by3 0.198 92.52 589.93 0.0146 12 0.651 76.10 613.76 0.0164MKN method is also fairly close. It is concluded that the4 0.258 90.34 593.60 0.0170 13 0.701 74.28 617.43 0.0140kinetic equation of the thermal decomposition of Pev for5 0.307 88.54 596.35 0.0184 14 0.749 72.55 621.10 0.0117the first stage is da/dt= Ae- Ea/RT2( 1-a2. It showed6 0.346 87.15 598.18 0.0190 15 0.801 70.66 626.60 0.009170.404 85.04 600.93 0.0197 16 0.852 68.83 633.01 0.0072that the first stage of decomposition for Pev is controlled80.456 83.15 603.68 0.0197 17 0.898 67.17 640.35 0.0065by simple 1.5th order reaction mechanism.90.494 81.79 605.510.0196Table 3 The common forms of j( a) and g( a)Ozawa method was also used here :No.(a)g(a)l[β]= l[ A]- lng(a )-5.330519 (1-a)- lu(1-a)一1.052Ea/ RT(3)2(21-a/(1-a)14-1With the Ozawa method , advantage is taken of the21(1-a)(1-a)-1-1fact that , with increase of heating rate，thermogravimetric221/X1-a)(1-a)-2-1measurements were shifted to higher temperatures. For the36{1-a)[1-(1-a)/]}2 [1-(1-a)3 ]same relative mass losses ,a , the plot of the logarithm ofthe heating rate ，lnβ, as a function of the reciprocalTable 4 Results of kinetic analysis for Pevtemperature, is a straightline，whose slope isCoast-Redfem methodMKN methodNoproportional to the activation energy. Since the secondEa/kJ mol-! In4Ea/kJ mol-! ln4term on the right side of equation( 3 )is a constant and173.13 27.07 0.9147172. 2926.87 0.9056the first term is small as compared with the last term , the194.31 30.87 0. 9301194.5630.90 0.9234slope , l，of the resulting line is described by l =221 .4735.12 0. 9471223.1335.41 0.9425- 1.052Ea/ R.203.24 31.26 0. 9363203.9631.38 0. 9304155.1520.98 0.9057153.3820.57 0 .8947In the equations ,a is the fraction of decompostion at283.83 48.35 0. 9519288.7549.130.9699temperature T(K);β is the heating rate ; R is the gas83.6110.64 0. 960778.128.98 0.9402constant ; Ea is the activation energy and A is the pre-862.716.67 0.960756.134.43 0.9461exponential factor , and g( a ) is differential and integral41.812.83 0.960734.13 -0.28 0.9355expression of kinetic function. The stage( 1 ) for Pev is1031.360.99 0.9607 .23.15 -2.77 0. 922211114.2315.020.9507110.3113.99 0.9417now taken as an example to demonstrate the process .12110.73 14.58 0.9471106.6413.50 0.9373Thity types of kinetic model functions6k Table 3 )13104.0613.60 0.939699.6112.39 0.9278were used in equations( 1 ) and( 2 ), respectively. The1486.5710.68 0.914781.219.09 0. 8952values of Ea and A and the linear correlation coefficients15129. 8518.820.9147126.7618.050.9024γ of different model functions were calculated from a1643.282.83 0.914735.68 -0.20 0.869428.860.39 0.914720.51 -3.56 0. 8341weighted least-squares plotofln 1.9215 vs 1/T and l[ g1821 .64 .-0.75 0.914712.91-5.41 0.7840(a)T2] us 1/T. The results are listed in Table 4.1125.4218.73 0.9907122.1117.90 0, 99422150.83 23.34 0, 9966148.8222.87 0.9932Comparing the kinetic parameters from different methods ,180.11 30.16 0.9974179.6230.04 0.9958the probable kinetic model functions No. 19 ,No.20 ,No.248.2745.19 0.9973251.34 45.70 0. 997021 , and No.22 were selected whose values of correlation2361.206.16 0.860654.533.87 0.8186coefficients Y obtained by Coast- Redfem method and MKN2444.833.25 0. 809737.310.29 0.7356method were all bigger than 0.99 with values of Ea and33.941.36 0.765425.86 -2.21 0. 650620250.8443.55 0.9607254.0544.08 0.9576 .A obtained by Coast-Redferm method and MKN method376.26 68.65 0. 9607385.97 69.97 0.9586being very close to each other also.501.68 93.87 0.9607517.9395.76 0.9592When plotting ln3 us 1/T , Ea can be obtained and52.034.20 0.939644.871.560.9126药学学报Acta Pharmaceutica Sinia 2002 37 8)644 - 648647●Using the same treatment for Acv , it was found thatFigure 4 shows that while a changes from 0.2 toit was also controlled by a simple 1 .5th order reaction0.8 ,the value ranges of Ea for Pev and Acv are almostmechanism. The data are shown in Table 5.the same , but the values of Ea for Pev increase with240|increase of decomposition conversion , and values of Eafor Acv decrease withincreaseof decomposition210-conversion . Table 5 shows that the value of lnA for Acv is .180bigger than that of Pev , which indicates that the rate ofAcvthermal decomposition is quicker than that of Pev and the3150stability of Acv is poorer than Pev. The reason is that thePev120unpaired electrons of oxygen attached to the ether link arepushed to the methylene group connected with guanine ,90.6 0.7 0.8一-CH2- ,by which the bond C- -N is weaken andConversionthe breakage of the bond is accelerated. The fact is alsoFigure4 The curves of conversion us Eareflcted on the lower decomposition temperature and thehigher pre- exponential factor for the decomposition ofAcv. .Table 5 The activation energy of thermal decomposition and the results of accelerating test for Acv and PevCoast- Redfem methodOzawa methodDecrease of purity/ %DrugEa/kJ mol-1lnA/s-1ln4/s-10d30 d60d150. 8323.34137.78- 166.7123.17~24.941.622.24Aev154.44 .35.22132.02- 166.7734.38-41.5200.862.423.433 Accelerating stability test for Pev and Acvstability is : Pev> Acv.In order to investigate the consistency of actual andtheoretical values for the drugs , Pev and Acv were storedREFERENCES :under conditions of 709C , 75% RH , for 3 months , some[1] CheoraertP. Eficacy and safety of famciclovir in thesamples were taken out at intervals of 30 days ，totreatment of uncomplicated herpes zoster[ A ] Intersciencedetermine the concentrations of drugs according to theConference on Antimicrobiol Agents and Chemnotherapy[ C ]pharmacopeia method and compare these with the dataAnaheim : USA , 1992.obtained from thermogravimetry , the results are shown in[2] Tyring S , Nahlik J , Cunningham A. Efcacy and safely ofTable 5.famciclovir in the treatment of patients with herpes zoster.Results of the first placebo controlled study[ A ]. Abstracls ofThe data indicated that the concentrations of the twothe. Interscience Conference on Antimicrobiol Agents anddrugs decreased with the increase of accelerating testChenotherapy[C]. Vol 33. No 5. Anaheim: USA , 1993.time , but the decomposition of Acv was quicker than that400- 406.of Pev，this fact was identical with that the pre-[3] Li K ,ZhangJ ,Hu X. 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