嘌呤药物的热解过程及其热分解动力学

药学学报 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中国煤化工CNMHGInstruments TGS-2 model thermobalance( Perkin100200300400500600Received date: 2002-01-0402787435879, Fax: (027 37532752, Figure 1 Thermogravimetric( tG )curves of penciclovirPev ) and aciclovir( Acv药学学报 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中国煤化工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药学学报 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中国煤化工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药学学报 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(中国药学杂志)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中国煤化工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丹毁据rature for the first stage the therma648药学学报 Acta Pharmaceutica Sinica20023X8)44-648嘌呤药物的热解过程及其热分解动力学张健”,盛瑞隆,买文鹏〔中南民族大学化学与生命科学学院湖北武汉43074)摘要∶目旳研究嘌呤类药物的热解过程及非等温动力学。方法用红外光谱技术、加速稳定性试验方法和热重仪分析方法测定分解过程用ωαawa法以及 Coast- Redfern法和MKN法处理数据确定热分解函数。结果确定了阿昔洛韦 aciclovirΔcwλ喷昔洛韦 penciclovir Pcv热解过程和中间产物得到热解动力学参数活化能E指前因子A。结论加速稳定性试验与热重法的计算结果一致喷昔洛韦的热稳定性大于阿昔洛韦两者热解第一步具有相同的中间产物鸟嘌呤且动力学方程相同d/dt=Aeˉux(1-α)2均为1.5级反应过程。关键词∶喷昔洛韦;阿昔洛韦;鸟嘌呤;加速试验;热稳定性;热重法;非等温动力学《中国优秀博硕士学位论文全文数据库 X CDMD介绍CDⅦD由中国学术期刊光盘版連子杂志社与清华同方光盘股份有限公司共同研制得到了国务院学位办与全国近300家博士培养单位的大力支持与协助。CDMD具有覆盖学科广、文献量大、收录质量高、全文收录、毎日更新、使用方式灵活等特点是我国最具权威的优秀博硕士学位论文全文数据库。1简介CD覆盖理工、农林、医卫、社会科学各学科精选收录全国近300家博土授予单位,200~2001年的论文全文近30∞0)其中211工程高校的收录率达80%。CDMD按学科划分为9大专辑出版今后每年增加博硕土论文20000。2检索系统①提供CNK知识仓厍分类导航与学科专业导航两套导航检索系统;提供关键词、中文题名、副题名、中文摘要、作者姓名、导师、全文、引文等基本检索功能;③提供初级检索与髙级检索两套检索界面攴持二次检索、多种逻辑组合检索等专业检索功能;④提供中文简体、中文繁体和英文检索三种检索界面攴持中英文对照和中文简繁对照检索⑤提供论文全文的在线浏览、全文下载、保存、打印等功能提供摘录功能。3使用方式①网上包库服氛WEB方式)渎读者直接登录CNK数据库交换服务中心网站全国共有10个进行检索;②镜像站点方式将CDMD数据库系统安装到用户单位的内部网络服务器上渎者在内部网上进行检索;③全文光盘方式将CDMD全文光盘DVD格式皮装在本单位的计算机或局域网上使用更新周期CNK数据库交换服务中心网站数据每日更新镜像站点通过互联网或卫星每日更新光盘每半年出版一期5软件环境用户端 WIndow95/98/ME/20NT/XP;服务器端 Window200NT/XP地址:北京清华大学华业大厦1300室通信地址:北京清华大学84-48信箱邮编:100084联系人:张莉联系电话:(010)2791829/3031Fmil:qklw@cnki.,met全国免费咨询热线:800810046详情请访问:CNKI电信全国中心htp/ww.cnki.ne)CNK教育全国中心htp!/ww.edhu.cmki,net)中国学术期刊光盘版电子杂志社清华同方光盘阳H中国煤化工CNMHGI程研究中心