Milton N, Pikal M J, Roy M L, Nail S L
Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
PDA J Pharm Sci Technol. 1997 Jan-Feb;51(1):7-16.
The objective of this study was to evaluate manometric temperature measurement as a non-invasive method of monitoring product temperature during the primary drying phase of lyophilization. This method is based on analysis of the transient response of the chamber pressure when the flow of water vapor from the chamber to the condenser is momentarily interrupted. Manometric temperature measurements (MTM) were compared to product temperature data measured by thermocouples during the lyophilization of water, mannitol, lactose and potassium chloride solutions. The transient pressure response was mathematically modeled by assuming that four mechanisms contribute to the pressure rise: 1) direct sublimation of ice through the dried product layer at a constant temperature, 2) an increase in the temperature at the sublimation interface due to equilibration of the temperature gradient across the frozen layer, 3) an increase in the ice temperature due to continued heating of the frozen matrix during the measurement, and 4) leaks in the chamber. Experimental transient pressure response data were fitted to an equation consisting of the sum of these terms containing three variables corresponding to the vapor pressure of ice, product resistance to vapor flow, and the vial heat transfer coefficient. Excellent fit between the mathematical model and the experimental data was observed, and the value of the variables was calculated from the measured transient pressure response by a least squares method. The product temperature measured by MTM, which measures the temperature at the sublimation interface, was compared with product temperature measured by thermocouples placed in the bottom center of the vials. Manometrically measured temperatures were consistently lower than the thermocouple measurements by about 2 degrees C, this difference being largely accounted for by the temperature gradient across the frozen layer. The resistance of the dried product to mass transfer calculated from MTM was found to agree reasonably well with values measured by a direct vial technique. Product resistance was observed to increase with increasing solute concentration, and to increase continuously as the depth of the dried product layer increases for mannitol and potassium chloride. For lactose, product resistance increases continuously with thickness up to the onset of collapse, at which point the product resistance becomes essentially independent of depth. Scanning electron microscopy was used to explain this observation based on changes in morphology of the solid. The vial heat transfer coefficients obtained from regression analysis were on the order of 10(-3)-10(-4) cal.sec-1. degrees C-1; however, the scatter in the vial heat transfer coefficient data prevents the method from being used for accurate measurement of the vial heat transfer coefficient. The results of the study show that the manometric method shows promise as a process development tool and as an alternative method of in-process product temperature measurement during primary drying.
本研究的目的是评估压力温度测量作为一种在冻干一次干燥阶段监测产品温度的非侵入性方法。该方法基于分析当从腔室到冷凝器的水蒸气流动瞬间中断时腔室压力的瞬态响应。在水、甘露醇、乳糖和氯化钾溶液的冻干过程中，将压力温度测量（MTM）与通过热电偶测量的产品温度数据进行了比较。通过假设四种机制导致压力升高，对瞬态压力响应进行了数学建模：1）冰在恒定温度下通过干燥产品层直接升华；2）由于冷冻层上温度梯度的平衡，升华界面处温度升高；3）在测量过程中由于冷冻基质的持续加热，冰的温度升高；4）腔室泄漏。将实验瞬态压力响应数据拟合到一个由这些项之和组成的方程，该方程包含与冰的蒸气压、产品对蒸气流的阻力以及小瓶传热系数相对应的三个变量。观察到数学模型与实验数据之间具有良好的拟合度，并通过最小二乘法从测量的瞬态压力响应中计算出变量的值。将测量升华界面温度的MTM所测得的产品温度与放置在小瓶底部中心的热电偶所测得的产品温度进行了比较。通过压力测量的温度始终比热电偶测量的温度低约2℃，这种差异主要由冷冻层上的温度梯度造成。发现根据MTM计算的干燥产品的传质阻力与通过直接小瓶技术测量的值相当吻合。观察到产品阻力随溶质浓度的增加而增加，并且对于甘露醇和氯化钾，随着干燥产品层深度的增加而持续增加。对于乳糖，产品阻力随厚度持续增加直至坍塌开始，此时产品阻力基本上与深度无关。使用扫描电子显微镜基于固体形态的变化来解释这一观察结果。通过回归分析获得的小瓶传热系数约为10^(-3)-10^(-4) cal·sec^(-1)·℃^(-1)；然而，小瓶传热系数数据的分散性使得该方法无法用于精确测量小瓶传热系数。研究结果表明，压力测量方法作为一种过程开发工具以及在一次干燥过程中进行过程中产品温度测量的替代方法具有潜力。
