藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica20023X8)44-648STUDIES ON THE THERMAL DECOMPOSITION PROCESSAND KINETICS OF PURINE DRUGSZHANG Jian, SHENG Rui-long MAI Wen-pengCollege of Chemistry and Life Sciences South-central Uniersity for Nationalities, Wuhan 430074, ChinaABSTRACT: AIM To study the thermal stability decomposition process and kinetics of such purine pharmaceuticals asaciclovir( Acv ), penciclovir( Pcv ) and their parent substance, guanine. METHoDs Using infrared technique, acceleratingtest method and thermogravimetry to investigate the thermal decomposition processes and using Coast-Redfern method, MKN methodnd Ozawa method to deal with the data to get kinetic functions. RESULTS The decomposition process and the formed productswere derived the kinetic model function was suggested by comparison of the kinetic parameters. CoNclusion Pcv and Acvsdegrading product for the first step is guanine. The sequences of their thermal stabilities is: Pcv> Acv. The two drugs kineticequation of thermal decomposition is expressed as: da/dt= Ae" aRX 1-a)KEY WORDS: aciclovir penciclovir guanine i accelerating test; thermal stability thermogravimetry non-isothermalCLC number: R912Document code: AArticle ID:0513-48702002)8-0644-05Purine drugs are a kind of low toxiciElmer Co., USA ) used under the following conditionsffective antivirus pharmaceuticals. It has inhibition effect sample mass: 3. 00 mg ; atmosphere static air heatingon the duplication of DNA in virus such as HIV-1, HIV2, VZVI21. Acyclovir( Acv )and penciclovir( Pcv )are range: 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. The were analysed on a PT-Ill computercapsule of penciclovir was prepared and theMaterials Pcy and Acy were obtained from hubeibioequivalence was studied using HPLC with fluorescence Pharmaceutical Industry Institute( Wuhan ), guanine wasmethod33. Acyclovir inhibition of induced hepes simplex purchased from Sigma Co. Purity of all raw drugs wasvirus type 1 was investigated 4I by temporal analysis better than 99.4%method.Sreis 5I studied the effect of particle sizedistribution and excipients on the dissolution of acyclovirRESULTS AND DISCUSSIONSfrom gelatin capsules tablets and powdersThermal stabilities and thermal decomposition 1 Thermal decomposition processes of Pey and Acvkinetics of purine drugs are the interesting problem in sampleslustral applications they are important in evaluatingThermogravimetric(TG)curves of Pev and Acv areand periods of validity and for controlling the qushown in figure 1the process of manufacture. In this paper, the thermalmaterials of purindloandguanine were investigated by infrared spectrometry60B=5K·min1accelerating test and thermogravimetryMATERIALS AND METHODS中國(guó)煤化工CNMHGInstruments TGS-2 model thermobalance( Perkin100200300400500600Received date: 2002-01-0402787435879, Fax: (027 37532752, Figure 1 Thermogravimetric( tG )curves of penciclovirPev ) and aciclovir( Acv藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica20023X8)44-648645As shown in Figure 1, the thermal decomposition Figure 2)nvolved two weight-loss stages. For Pev then in Figure 2 and Table 1temperature range of the first stage was 276. 45bands of remnants are almost the same as those of39820C with the mass loss being 39. 21 %( theoretical, guanine. It could be inferred that the side chain40.25 %) for Acv, the temperature range of the firstCH,CHCH,OH of Pcv and-CHOCH,CH,OHstage was 235 85-357 91C with the mass loss of of Acy were lost in the process of heating30.45%( theoretical, 32. 81%), the remainders of the processes of thermal decomposition was deduced in Figurefirst stage decomposition were analyzed by IR spectra 34040004000300040003000Figure 2 Infrared spectra of remainder and guaninea, remainder of pcy b, remainder of acy c guanineCH2 CH(CH OH)2+CO+H OGugniNHFigure 3 The reaction formulations of the first stage of thermal decompositionwasSampleWave number/ cmwhen the temperature was below 400 C and could not meltbecause of the stability of the aromatic heterocyclic33182899169513671470compound. With the bonds broken irregularly it degradeRemainder of acy33282899169513851471Remainder of pev3338289916951385147and carbonized when the temperature was above 400Ccause the experiment was carried out in air, thermaloats-Redferm method and mKn method were useddecomposition of Pev and Acv which was accompaniedwith thermal oxidation at the second stage was very中國(guó)煤化工CNMHG(1)2 Thermal decomposition kineticsaeaFrom the TG curve of pcv, the basic data(t, a的+3.7721-1.9215lmEada/dT)for stage(1)can be obtained as shown in Tableea0.12039Table r bat Standard of infrared spectroscopy藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica20023X8)44-648Table 2 Basic data at the first stage of Pev(Bmethod compared favorably with the data of Ea from N5℃min-1)19, No 20, No 21 and No 22 obtained by Coast-RedfemData a W/%o T/k da/dT Data a W/%o T/k da/dTmethod and MKn method, and kinetic model function10.10395.94582.600.0100100.54779.86608.260.0188No 20 whose Ea is 150.83 kI mol-I by Coast-Redfem20.14594,42586.260.0122110.59977.98611.010.0177method, while a value of 148.82 k mol- obtained by30.19892.52589.930.0146 12 0.651 76.10 613.760.0164 MKN method is also fairly close. It is concluded that th40.25890.34593.600.0170130.70174.28617,430.014050.30788.54596.350.0184140.74972.55621.100.0117kinetic equation of the thermal decomposition of Pcv for60.34687,15598,180.0190150.80170.66626,600.0091the first stage is da/dt= Ae- EarTx1-a)2. It showed80.45683. 15 603, 680.0197 17 0.898 67, 17 640. 35 0.0065 by simple 1. 5th order reaction mechanis/ is controlled70.40485.04600.930.0197160.85268.83633.010.007that the first stage of decomposition for Pc90.49481.79605.510.0196Table 3 The common forms of f a) and g( a)Ozawa method was also used hereltβ]=laeaR]-lng(a)-5.3305(3)19(1-a)l(1-a)1.052Ea/RT20x1-a)(1-a)12-1With the o21(1-a)fact that, with increase of heating rate, the221/x1-a)measurements were shifted to higher temperatures For the 30 6(1-ay[l-(1-ay1y2 [1-(1-ayJsame relative mass losses a, the plot of the logarithm ofthe heating rate, InB, as a function of the reciprocalTable 4 Results of kinetic analysis for pcvwhose sloproportional to the activation energy. Since the secondEa/kI mol-1 InA y Ea/kI mol-1 InA yterm on the right side of equation(3 )is a constant and72.2926.870.90the first term is small as compared with the last term, th2194.3130.870.9301194.5630.900.9234slope, l, of the resulting line is described by l3221.4735,120,9471223.1335,410.9425-1.052Ea/R4203.2431.260.9363203.9631.380.9304In the equations a is the fraction of decompos5155.1520.980.905153.3820.570.8947mperature T( K); B is the heating rate ;R is the gas6283.8348.350.9519288.7549.130.969constant i Ea is the activation energy and A is the pre-62.716.670.960756.134.430.946exponential factor and g a)is differential and integral34.13-0.280.9355expression of kinetic function. The stage(1) for Pev is0.990.9607now taken as an example to demonstrate the processll114.2315.020.9507110.3113.990.9417Thirty types of kinetic model functions 6( Table 310.73140.9471106.6413.500.937313104.0613.600.939699.6l12.390.9278were used in equations( 1)and (2), respectively.The1486.5710.680.9147values of ea and a and the linear correlation coefficients15129.85820.914126.7618.050.9024y of different model functions were calculated from a2.830.91435.68-0.200.8694390.914720.51560.83weighted least-squares plot of In Fl 9215 US 1/T and Irl g1821.64-0.750.91475.410.7840(ayre] us 1/T. The results are listed in Table 4122.1I17.900.99423.340.996648,8222.870,9932Comparing the kinetic parameters from different methods21180.1130.160.9974179.6230.040.9958he probable kinetic model functions No. 19, No 20, No22248,2745.190.9973251.3445.700.997021, and No 22 were selected whose values of correlation61.206.160.8606coefficients y obtained by Coast-Redfem method and MKN中國(guó)煤化工37.310.290.736method were all bigger than 0.99 with values of ea and 25CNMHG25.86-2.210.6506A obtained by Coast-Redfern method and MKN method54,0544.080.957627376.2668.650.960385.9769.970.9586being very close to each other also517,9395.760.9592When plotting InB us 1/T, Ea can be obtained and2952.03shown in Figure 4 and Table 5. Kinetic parameter Ea was4,660,9472.150.9246137. 78 F16.F kI mol-I as obtained by Ozawa藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica20023X8)44-648647Using the same treatment for acy it was found thatFigure 4 shows that while a changes from 0.2 toit was also controlled by a simple 1 5th order reaction 0.8, the value ranges of Ea for Pev and Acv are almostnechanism The data are shown in Table 5the same, but the values of ea for pcy increase with240increase of decomposition conversion and values of Eafor Acv decrease withof decomposition210conversion. Table 5 shows that the value of In a for acybigger than that of pey which indicates that the rate ofACYthermal decomposition Isstability of Acv is poorer than Pev. The reason is that theunpaired electrons of oxygen attached to the ether link arepushed to the methylene group connected with guanine-CH2- by which the bond Cn is weaken andthe breakage of the bond is accelerated. The fact is alsoFigure 4 The curves of conversion us Eaeflected on the lower decomposition temperature and thehigher pre-exponential factor for the decomposition ofTable 5 The activation energy of thermal decomposition and the results of accelerating test for Acv and pevOzawa methodDecrease of purity/%Ea/k moA/s-1Ea/kio d150.83137.78-166.7123.17-24.940.55154.435.22132.02-166.7734.38-41.522.423 Accelerating stability test for Pcv and Acvstability is: Pev>AevIn order to investigate the consistency of actual andtheoretical values for the drugs Pev and Acv were stored REFERENCESunder conditions of 70.C, 75 %RH, for 3 months, some [1] Gheoraert P. Efficacy and safety of famciclovir in thsamples were taken outtreatment of uncomplicated herpes zoster[ A ].Intersciencedetermine theConference on Antimicrobiol Agents and Chemotherapy[ CIpharmacopeia method and compare these with the dataAnaheim USA, 1992obtained from thermogravimetry, the results are shown in [2] Tyring S, Nahlik J, Cummingham A. Efficacy and safety ofTable 5famciclovir in the treatment of patients with herpes zosterThe data indicated that the concentrations of the twoResults of the first placebo controlled study[ A ]. Abstracts ofdrugs decreased with the increase of accelerating testthe Interscience Conference on Antimicrobiol Agents andChemotherapy[ C ]. Vol 33. No 5. Anaheim: USA, 1993time but the decomposition of Acv was quicker than that400-406of Pcv this fact was identical with that the pre- [3] Li K, Zhang J, Hu X. Study on bioequivalence of famciclovirexponential factor of Aev was bigger than that of Pev andcapsules in human[J. Chin Pharm J(中國(guó)藥學(xué)雜志)the decomposition temperature of Acv was lower than that2000357)63-4of Pcv. It accounted for the fact that the stability of Pev4] Sawtell NM, Berstein DI, Stanberry LR. A temporal analysisto acyof acyclovir inhibition of herpes simplex virus type I in vivoThe results showed that pcv and acy began toreactivation in the mouse trigeminal ganglia J ]. J InfectDis,199918(3)821-823ompose at276℃and235℃ respectively.Thedecomposition of Pcv and Acv at the first stage had the[5] Scis S, Kere J. Modification of acycloir dissolution from+「J]. Farm vesta,199950sameby which the中國(guó)煤化工CH,CH CH,OH b andCH,OCH,CH,OHC N MH GI decomposition of oxalatesgroups were lost and the same kinetic model function asPA kinetic study of thermal decomposition ofboth of them are simple 1 5th order reaction. Accordinmanganese( Il), oxalate dihydrate[ J ] Thermochim Actato the result of accelerating test, kinetic parameters and19932151)47-6decompo丹毀據(jù)rature for the first stage the therma648藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica20023X8)44-648嘌呤藥物的熱解過程及其熱分解動(dòng)力學(xué)張健”,盛瑞隆,買文鵬〔中南民族大學(xué)化學(xué)與生命科學(xué)學(xué)院湖北武漢43074)摘要∶目旳研究嘌呤類藥物的熱解過程及非等溫動(dòng)力學(xué)。方法用紅外光譜技術(shù)、加速穩(wěn)定性試驗(yàn)方法和熱重儀分析方法測(cè)定分解過程用ωαawa法以及 Coast- Redfern法和MKN法處理數(shù)據(jù)確定熱分解函數(shù)。結(jié)果確定了阿昔洛韋 aciclovirΔcwλ噴昔洛韋 penciclovir Pcv熱解過程和中間產(chǎn)物得到熱解動(dòng)力學(xué)參數(shù)活化能E指前因子A。結(jié)論加速穩(wěn)定性試驗(yàn)與熱重法的計(jì)算結(jié)果一致噴昔洛韋的熱穩(wěn)定性大于阿昔洛韋兩者熱解第一步具有相同的中間產(chǎn)物鳥嘌呤且動(dòng)力學(xué)方程相同d/dt=Aeˉux(1-α)2均為1.5級(jí)反應(yīng)過程。關(guān)鍵詞∶噴昔洛韋;阿昔洛韋;鳥嘌呤;加速試驗(yàn);熱穩(wěn)定性;熱重法;非等溫動(dòng)力學(xué)《中國(guó)優(yōu)秀博碩士學(xué)位論文全文數(shù)據(jù)庫(kù) X CDMD介紹CDⅦD由中國(guó)學(xué)術(shù)期刊光盤版連子雜志社與清華同方光盤股份有限公司共同研制得到了國(guó)務(wù)院學(xué)位辦與全國(guó)近300家博士培養(yǎng)單位的大力支持與協(xié)助。CDMD具有覆蓋學(xué)科廣、文獻(xiàn)量大、收錄質(zhì)量高、全文收錄、毎日更新、使用方式靈活等特點(diǎn)是我國(guó)最具權(quán)威的優(yōu)秀博碩士學(xué)位論文全文數(shù)據(jù)庫(kù)。1簡(jiǎn)介CD覆蓋理工、農(nóng)林、醫(yī)衛(wèi)、社會(huì)科學(xué)各學(xué)科精選收錄全國(guó)近300家博土授予單位,200~2001年的論文全文近30∞0)其中211工程高校的收錄率達(dá)80%。CDMD按學(xué)科劃分為9大專輯出版今后每年增加博碩土論文20000。2檢索系統(tǒng)①提供CNK知識(shí)倉(cāng)厙分類導(dǎo)航與學(xué)科專業(yè)導(dǎo)航兩套導(dǎo)航檢索系統(tǒng);提供關(guān)鍵詞、中文題名、副題名、中文摘要、作者姓名、導(dǎo)師、全文、引文等基本檢索功能;③提供初級(jí)檢索與髙級(jí)檢索兩套檢索界面攴持二次檢索、多種邏輯組合檢索等專業(yè)檢索功能;④提供中文簡(jiǎn)體、中文繁體和英文檢索三種檢索界面攴持中英文對(duì)照和中文簡(jiǎn)繁對(duì)照檢索⑤提供論文全文的在線瀏覽、全文下載、保存、打印等功能提供摘錄功能。3使用方式①網(wǎng)上包庫(kù)服氛WEB方式)瀆讀者直接登錄CNK數(shù)據(jù)庫(kù)交換服務(wù)中心網(wǎng)站全國(guó)共有10個(gè)進(jìn)行檢索;②鏡像站點(diǎn)方式將CDMD數(shù)據(jù)庫(kù)系統(tǒng)安裝到用戶單位的內(nèi)部網(wǎng)絡(luò)服務(wù)器上瀆者在內(nèi)部網(wǎng)上進(jìn)行檢索;③全文光盤方式將CDMD全文光盤DVD格式皮裝在本單位的計(jì)算機(jī)或局域網(wǎng)上使用更新周期CNK數(shù)據(jù)庫(kù)交換服務(wù)中心網(wǎng)站數(shù)據(jù)每日更新鏡像站點(diǎn)通過互聯(lián)網(wǎng)或衛(wèi)星每日更新光盤每半年出版一期5軟件環(huán)境用戶端 WIndow95/98/ME/20NT/XP;服務(wù)器端 Window200NT/XP地址:北京清華大學(xué)華業(yè)大廈1300室通信地址:北京清華大學(xué)84-48信箱郵編:100084聯(lián)系人:張莉聯(lián)系電話:(010)2791829/3031Fmil:qklw@cnki.,met全國(guó)免費(fèi)咨詢熱線:800810046詳情請(qǐng)?jiān)L問:CNKI電信全國(guó)中心htp/ww.cnki.ne)CNK教育全國(guó)中心htp!/ww.edhu.cmki,net)中國(guó)學(xué)術(shù)期刊光盤版電子雜志社清華同方光盤陽(yáng)H中國(guó)煤化工CNMHGI程研究中心