指数程序升温药物稳定性试验

介绍了一种新的程序升温(指数程序升温)药物稳定性预测加速试验方法及计算方法。在这一新的程序升温方法中,温度每升高10℃,升温速率将增大2～4倍:dT/dt=a^(T-T₀)/10·(dT/dt)₀,使药物在高温和低温范围内的降解程度尽可能一致,提高了试验准确度。采用单因素优选法和数值积分法处理试验数据,避免了任何近似处理,使计算结果准确可靠。与线性升温、倒数升温和对数升温加速试验进行了对比,结果表明,指数程序升温法的准确性优于其它3种升温法。     

程序变温法确定药物降解反应级数

通过电子计算机模拟程序升温加速试验,从理论上阐明了常规的程序升温法不能确定药物降解反应级数的原因是因为同一组数据可由不同的反应级数和活化能的组合所拟合;解决这一问题的关键是在一个变温程序中包含升温和降温部分;据此提出了一种新的程序变温方法(程序升降温法)。利用这种方法,可以真正做到只通过一次程序变温加速试验,就获得包括反应级数在内的药物降解的动力学参数,且确定反应级数的能力与恒温法相近似。     

程序变湿变温药物稳定性试验

目的建立一种研究湿度对药物稳定性影响的简便实验方法。方法用程序变湿和程序变温加速试验方法,以青霉素钾为例进行药物稳定性试验。结果程序变湿和程序变温加速试验与恒温恒湿对照试验得到的青霉素钾的降解动力学参数基本一致。结论程序变湿变温加速试验可以应用于药物稳定性研究。     

倒数程序升温加速试验数据处理新方法

本文介绍了一种用优迁法处理倒数升温加速试验数据的新算法。作者用ＰＣ－１５００型电子计算机与普通恒温溶联用实现倒数程序升温；用漫反射光谱光测定固体药物表面反射率，研究了维生素Ｃ片的稳定性。结果表明，新算法克服了常规算法的不足之处，使实验结果更为精确可靠。     

线性降解程序变湿法研究青霉素钾的稳定性

报道了一种新的研究湿度对固体药物稳定性影响的试验方法——线性降解程序变湿法。按照这一变湿规律进行程序变湿药物稳定性试验能最大限度地使药物在高湿和低湿范围内降解程度一致，提高了试验的精密度。作者以青霉素钾为模型药物，采用线性降解程序变湿法和指数程序变温法进行试验，求得了E_a，m，A和t_0.9等动力学参数。结果表明，新方法测定结果的精密度明显优于文献报道的程序变湿变温法。     

电子计算机控制程序升温装置

为推广电子计算机在药物稳定性研究中的应用,本文介绍了一种以廉价的PC-1500型袖珍电子计算机为核心,与普通恒温水浴联用,实现各种类型程序升温的实用控制装置及其控制程序简图。该装置简单可靠,成本低,温度控制准确度和重现性≤±0.2℃,温程分辨值和波动范围±0.05℃,计时精度<±5秒/月。     

平面单点测定法研究温度和湿度对阿司匹林稳定性的影响

目的 建立一种研究湿度与温度同时影响药物稳定性的新方法.方法 以阿司匹林为模型药物,利用均匀优化设计分散原理组合所选的温度与湿度水平,以单测点法在组合点下进行稳定性加速试验,从而获得药物与湿度、温度有关的全部动力学参数.结果 所建立的方法与恒温恒湿法和程序变温变湿法得到的降解动力学参数基本一致.与程序变温变湿法相比,其准确度及精密度均高,且只需使用普通的恒温恒湿控制装置;与经典恒温恒湿法比较,能节约时间和样品.结论 平面单点测定法可应用于湿度和温度对药物稳定性的研究.     

经典恒温法药物稳定性试验数据的电子表格处理程序

目的：建立经典恒温法药物稳定性试验数据的快速处理方法。方法：根据一级分解动力学方程和Arrhenius指数定律，采用电子表格(Excel)软件编写程序，并以实例说明。结果：获得了实例所示的4个温度4个取样时间的药物稳定性试验数据的Excel处理程序，对试验温度、取样时间不同的数据处理，稍加修改程序即可。结论：Excel处理程序编程简单、结果可靠、使用方便，是药物稳定性试验理想的数据处理程序。     

程序升温气相色谱法测定肌醇的含量

目的：建立程序升温气相色谱法测定肌醇的含量。方法：将肌醇进行硅烷化处理，正己烷提取后，以程序升温气相色谱法测定肌醇的含量。结果：肌醇的重复性试验ＲｓＤ为２．０％；平均回收率为９９．４％。结果：该方法操作简便，易行，线性关系良好。     

复方金线莲口服液的有效期测定

目的:用恒温加速试验法对复方金线莲口服液进行稳定性试验,以此测其有效期。方法:采用紫外分光光度法测定复方金线莲口服液主要有效成分牛磺酸的含量变化。结果:在恒温条件下加热时间与含量变化呈线 性关系,符合一般降解反应。结论:复方金线莲口服液有效期为460天(25℃)。     

Statistical evaluation of nonisothermal prediction of drug stability

Nonisothermal prediction of drug stability based on direct nonlinear estimation of the shelf-life was compared with the isothermal approach. The reliability of the statistics for the estimates of the shelf-life (the time period required for a drug to degrade to 90% remaining at 25 degrees C) and activation energy obtained by the two methods was evaluated by the Monte Carlo method of computer simulations. The accuracy and precision of the estimates obtained by the nonisothermal method depended largely on the experimental conditions, such as experimental periods, sampling time, and temperature rise programs. The uncertainty of the estimates was determined mainly by the extents of drug degradation and temperature change achieved during the experiment. The nonisothermal method needed suitable experimental designs and precise assay methods of drug contents to provide reliable parameter estimates.     

光和热对呋喃西林水溶液稳定性的影响

目的探讨呋喃西林水溶液对光和热的稳定性，并考察在高温光照试验中用变温法代替恒温法的可能性。方法用恒温加速试验和变温加速试验的方法。结果该药物在恒温避光加速试验和恒温光照加速试验中的降解均遵从零级动力学规律。在高温和光照同时作用下的降解速率常数k由两部分构成:k=k_dark+k_light,k_dark和k_light分别为避光时热反应的降解速率常数及光化反应的降解速率常数,且k_light=A_light·exp(-E_a,light/RT)·E。其中E为光源的照度,A_light和E_a,light为试验常数。变温法所求得的参数值与恒温法一致。结论在研究光和热对药物稳定性影响的试验中,可以采用变温法代替恒温法,以节省时间和样品,减少工作量。     

Isothermal and Nonisothermal Kinetics in the Stability Prediction of Vitamin A Preparations

A nonisothermal method was applied to shelf-life estimation of commercial vitamin A preparations. The usefulness and limitations of the nonisothermal method, as predicted by computer simulation, were validated. Degradation of vitamin A palmitate followed zero-order kinetics, and non-Arrhenius behavior was suggested for the rate constant. The nonisothermal method predicted a higher shelf-life value than the isothermal method for a syrup preparation, and vice versa, for an injection preparation. Analysis of the results suggested that the nonisothermal method provides better estimates of shelf lives than the isothermal method when drug degradation does not follow the Arrhenius equation near ambient conditions.     

Nonisothermal Stability Assessment of Stable Pharmaceuticals: Testing of a Clindamycin Phosphate Formulation

The stability of an antibiotic formulation (clindamycin phosphate in dextrose), which is stable at room temperature, was assessed by nonisothermal kinetic analysis at elevated temperatures. A preliminary study, conducted to establish apparent rate order, verified the appropriateness of a first-order kinetic model. The test formulation was then heated linearly from 70 to 90°C over 12 hr. Data (drug concentration, temperature, and time) were fitted to the first-order model using nonlinear least-squares regression. Arrhenius parameter estimates obtained from three nonisothermal trials, and rate constants at 25°C derived by extrapolation, demonstrated acceptable reproducibility and were in agreement with values derived from isothermal experiments at 30, 45, 55, 65, and 75°C. First-order rate constants obtained from studies conducted for 20 months at 25°C were in accord with isothermal and nonisothermal results.     

Data Analysis of Kinetic Modelling Used in Drug Stability Studies: Isothermal Versus Nonisothermal Assays

Purpose Kinetic modelling was applied to predict the stability of cholecystokinin fragment CCK-4 in aqueous solution, which was analyzed by isothermal and nonisothermal methods using a validated stability indicating HPLC method.Methods The isothermal studies were performed in the temperature range 40 to 80°C at pH 12 and ionic strength 0.01 M as constants, whereas nonisothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25°C/h and a temperature interval 40–82°C. The isothermal studies require two-step linear regression to estimate the parameters, resulting in a well-defined confidence interval. Nonisothermal kinetic studies require nonlinear or linear regression by previous transformation of data to estimate the parameters. In this case, the two most popular approaches, derivative and integral, were used and compared.Results Under isothermal conditions, an apparent first-order degradation process was observed at all temperatures. The linear Arrhenius plot suggested that the CCK-4 degradation mechanism was the same within the studied temperature range, with quite large uncertainties due to the small number of degrees of freedom based only on the scatter in the plot, and giving an estimated shelf life at 25°C of 35.2 days. The derivative approach yields high variability in the Arrhenius parameters, since they are dependent on the number of polynomial terms chosen, so several statistical criteria were applied to select the best model. The integral approach allows activation parameters to be calculated directly from experimental data, and provides results in good agreement with those of the traditional method, but have the advantage that the uncertainty in the final result directly reflects the goodness of fit of the experimental data to the chosen kinetic model. The application of the bootstrap technique to estimating confidence limits for the Arrhenius parameters and shelf life is also illustrated, and shows there is no difference between the asymptotic and bootstrap confidence intervals.Conclusions Nonisothermal studies give us fast and valuable information about drug stability, although their potential for predicting isothermal behaviour is conditioned by the data analysis method applied.     

Nonisothermal stability tests of famotidine and nizatidine

Nonisothermal stability tests have been proposed as an attractive and alternative method to the conventional isothermal stability tests. The stability and the degradation properties of famotidine and nizatidine were investigated using both isothermal and nonisothermal stability test techniques. Linear and logarithmic temperature programs were used and the degradation rate constant and activation energies were calculated using a computer program, which was written in BASIC. Also the advantages and disadvantages of these temperature programs are compared. The method to estimate parameters is based on nonlinear curve fitting the nonisothermal concentration-time-temperature curve equation. The nonisothermal stability test results were compared with the results of isothermal stability tests and similar results were obtained.     

Dehydration kinetics of piroxicam monohydrate and relationship to lattice energy and structure

The dehydration kinetics of piroxicam monohydrate (PM) is analyzed by both model-free and model-fitting approaches. The conventional model-fitting approach assuming a fixed mechanism throughout the reaction is found to be too simplistic. The model-free approach allows for a change of mechanism and activation energy, Ea, during the course of a reaction and is therefore more realistic. The complexity of the dehydration of PM is illustrated by the dependence of Ea on both the heating conditions, isothermal or nonisothermal, and on the fraction of conversion, alpha (0 < or = alpha < or = 1). Under both isothermal and nonisothermal conditions, Ea increases with alpha for 0 < or = alpha < or = 0.25, followed by an approximately constant value of Ea during further dehydration. In the constant-Ea region, isothermal dehydration follows the two-dimensional phase boundary model (R2), whereas nonisothermal dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. Structural studies suggest that the complex hydrogen-bond pattern in PM is responsible for the observed dehydration behavior. Ab initio calculations provide an explanation for the changes in the molecular and crystal structures accompanying the reversible change in hydration state between anhydrous piroxicam Form I and PM. This work also demonstrates the utility of model-free analysis in describing complex dehydration kinetics.