台阶变温变湿对阿司匹林稳定性的影响

目的 研究湿度和温度对固体阿司匹林稳定性的影响.方法采用台阶变温变湿加速试验法,通过两次试验获得药物相关的降解动力学参数:一次是在恒温下进行的台阶变湿加速试验,另一次是在恒湿下进行的台阶变温加速试验.结果台阶变温变湿法得到的降解动力学参数为:m=1.19±0.02,Ea= 95.1±1.5 kJ·mol-1,A= (1...     

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.     

基于台阶变温变湿法研究温度和湿度对维生素 C稳定性的影响

目的：探索台阶变温变湿加速试验法用于研究温度与湿度对药物稳定性影响的可行性。方法以维生素C为模型药物,通过恒温台阶变湿加速试验和恒湿台阶变温加速试验获得相关的降解动力学参数。结果台阶变温变湿法测得的降解动力学参数：m ＝4．5,Ea ＝111．5 kJ· mol－1,A ＝1．2×1013· h－1;经典恒温恒湿法测得：m ＝4．8,Ea ＝112．3 kJ· mol－1,A ＝8．9×1012 h－1;两者结果基本一致。结论该方法可用于维生素C稳定性的研究,且省时经济,容易操作。     

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。     

台阶型变湿变温法对固体哌拉西林钠的稳定性研究

目的建立台阶型变湿变温法对固体药物的稳定性研究方法。方法以哌拉西林钠为模型,采用台阶型变湿变温法研究哌拉西林钠的降解动力学过程。结果得到了哌拉西林钠降解过程的动力学参数A、m及Ea,与经典恒温恒湿法比较,结果一致。结论台阶法可用于哌拉西林钠的降解动力学研究,是否能用于其它固体药物还需进一步研究。     

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。     

台阶型变温加速试验——药物稳定性预测的新方法

本文提出一个药物稳定型预测的变温动力学新方法——台阶型变温法。它比其它七十年代的变温动力学方法,设备简单易行;比经典恒温动力学方法,则大大减少人力和时间。本法数据处理简单,可以计算,也可以图解,结果精度也高。文中以蔗糖酸催化水解、抗坏血酸水溶液的氧化及阿糖胞苷水解脱氨反应实验结果为例,说明在工作量大为减轻的情况下,对于活化能、指数前因子(频率因素)、以及常温速度常数或贮存期的预测,台阶法与经典法的差别无显著性意义。     

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。     

变温加速法解析阿司匹林降解反应的动力学参数

目的:采用变温加速法测定药物降解反应的动力学参数.并与等温加速法相比较,考察该方法的准确性.方法:以阿司匹林为模型药物,在设定的实验条件下,从温度变化过程中药物的残存率与时间的关系入手,根据化学动力学的原理,采用非线性最小二乘法解析其降解反应的动力学参数Ea及A.结果:阿司匹林的降解反应属准一级反应.在pH 2、pH 4和pH 6的条件下,采用变温加速法求得阿司匹林的降解反应的Ea分别是:16.13、18.19和23.87 kJ/mol(升温速率为5℃/h和10℃/h的平均值),等温加速法测得的Ea分别为16.12、18.01和23.93 kJ/mol.结论:采用变温加速法与等温加速法测得的药物降解反应的动力学参数基本一致.与等温加速法相比,变温加速法测定药物的稳定性具有迅速、可靠、简便、用样量少等特点.     

光散射法测定难溶性药物粒度

目的 研究光散射法中湿法测定难溶性药物粒度的方法及要求.方法 HT6K 通过仪器参数设定、样品的制备、分析方法验证确定原料药粒度测定的方法,根据生产工艺、体外溶出及体内吸收制定原料药粒度标准,对利伐沙班原料药进行粒度测定.结果与结论 粒度对药物的有效性、安全性、稳定性都有重要影响,湿法测定原料药的粒度方法稳定、结果准确、重现性好,在药物开发过程中应对药物粒度的测定方法进行详细研究并制定符合要求的粒度标准.     

Programmed humidifying in drug stability experiments

The stability of penicillin potassium, as a solid state model, was investigated by a programmed humidity and temperature controlled method. An optimization calculational approach to data handling is suggested. The stability of drugs which are unstable to both heat and moisture could be studied by a single pair of experiments, one with programmed humidity control and one non-isothermal, rather than many standard isothermal studies, each at constant relative humidity. The controlling system, based on a pocket computer, was found to be accurate and reliable. The results indicated that the kinetic parameters obtained were comparable to those from isothermal studies.     

青霉素钾的单点测定恒温恒湿稳定性试验

目的 建立青霉素钾的单点测定恒温恒湿稳定性试验方法.方法 在恒温和不同湿度及在恒湿和不同温度下进行加速试验,以获得青霉素钾与湿度和温度有关的动力学参数.结果 与经典恒温恒湿法相比,单点测定恒温恒湿稳定性试验大大减少了工作量;与程序变湿变温法相比,只需使用普通的恒温恒湿控制装置.结论 单点测定恒温恒湿稳定性试验可用于湿度对青霉素钾稳定性研究.     

Compatibility of chewing gum excipients with the amino acid L-cysteine and stability of the active substance in directly compressed chewing gum formulation

Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.     

Evaluation of the stability of aspirin in solid state by the programmed humidifying and non-isothermal experiments

The influence of both moisture and heat on the stability of aspirin was investigated by a single pair of experiments, one with programmed humidity control and the other non-isothermal, rather than many standard isothermal studies, each at constant relative humidity. In experiments, we adopted the acid-base back titration method to measure the content of aspirin in the presence of its degradation products. It was found that the degradation of aspirin could be expressed as ln[(c ₀−c)/c]=kt+D, where D was a lag time item not related to humidity and temperature. The relationship between the degradation rate constant k and humidity H _r and temperature T could be described as Arrhenius equation multiplied by an exponential item of relative humidity: k = A · exp(mH _r ) · exp(−(E _a /RT)), where A, E _a and m were the pre-exponential factor, observed activation energy, and a parameter related to humidity, respectively. The results obtained from the programmed humidifying and non-isothermal experiments, A=(1.09±2.04)×10¹² h⁻¹, E _a =(93.5±2.2) kJ · mol⁻¹ and m=1.18±0.19, were comparable to those from isothermal studies at constant humidity, A=(1.71±0.35)×10¹² h⁻¹, E _a =(94.9±0.7) kJ · mol⁻¹ and m=1.20±0.02. Since the programmed humidifying and non-isothermal experiments save time, labor and materials, it is suggested that the new experimental method can be used to investigate the stability of drugs unstable to both moisture and heat, instead of many classical isothermal experiments at constant humidity.     

Evaluation of non-isothermal methods in stability studies of human insulin pharmaceutical preparations

The purpose of this research was to study the thermal stability of a human insulin pharmaceutical preparation using non-isothermal conditions and comparison with classical isothermal experiments. The isothermal studies were performed in the temperature range 20–60 °C, whereas non-isothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25 °C per hour and temperature interval 30–70 °C.     

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.     

Physicochemical Stability of Phenobarbital Polymorphs at Various Levels of Humidity and Temperature

The physicochemical stability of six phenobarbital modifications [forms A, B, C (monohydrate), D (dioxane solvate), E (hemihydrate), and F] at various levels of humidity and temperature were measured using X-ray diffractometry and differential scanning calorimetry. Form D was identified as a new crystalline form (dioxane solvate). Polymorphic transformations of the modifications were investigated by the Kissinger method under nonisothermal conditions. Change of polymorphic content of phenobarbital modifications under various humidity levels at 45°C was evaluated by X-ray powder diffraction. The polymorphic stability under isothermal conditions was estimated kinetically, based upon the Jander equation. Forms A, B, and F were stable at 0 and 75% RH and 45°C for 3 months. On the contrary, forms C, D, and E transformed during storage. The transformation rates of form D were larger than that of forms C and E.