Rapid determination of dry layer mass transfer resistance for various pharmaceutical formulations during primary drying using product temperature profiles
Rapid determination of dry layer mass transfer resistance for various pharmaceutical formulations during primary drying using product temperature profiles
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DOI：
10.1016/j.ijpharm.2006.01.036
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发表时间：
2006-04-26
影响因子：
5.8
通讯作者：
Akers, MJ
中科院分区：
文献类型：
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作者：
Kuu, WY;Hardwick, LM;Akers, MJ
在冻干循环的初级干燥阶段，干燥层的传质阻力可能是影响最高产品温度和干燥时间的最重要因素。产品阻力参数应确定每种配方，因为它们依赖于配方组成和浓度。本研究的目的是确定干层传质阻力，使用一种简单而快速的方法，在实验室干燥器中的初级干燥过程中，使用监测的产品温度曲线的各种药物制剂。用于测定的数学工具是结合Powell优化算法的初级干燥模拟程序。对于所研究的每种制剂，使用-15或-20 ° C的搁板温度和控制在100 mTorr（0.1 Torr）的室压力进行初步干燥。记录初步干燥期间的产品温度曲线（T-b），并将其作为参数估计的输入数据。作为干层厚度e的函数的标准化产品电阻R-pN可以描述为：R-pN = R-0 + A（1）1（1 + A（2）1），其中常数R-0、A（1）和A（2）是水蒸气通过干层的产品电阻参数。即使当参数A（1）为负时，表明产品温度随时间推移逐渐降低，也可以使用所提出的方法快速并成功地确定各种药物制剂的干层产品电阻参数。本工作中获得的5%甘露醇的产品阻力方程，表示为R-pN = 0.0002025 + 20.23l，与Pikal [Pikal. M.J. 1985.实验室数据在冷冻干燥工艺设计中的应用：热阻和产品阻力参数以及冷冻干燥的计算机模拟。J. Parent. Sci. Technol.39，115-138.]用微量天平法测定，RpN = 1.40 + 16.0l。对于3%乳糖-LDH制剂获得的产品抗性值也非常接近于由（米尔顿，N.，Pikal，M.J.，罗伊，M. L.，Nail，S.L.，1997.评价测压温度测量作为冻干过程中监测产品温度的方法。PDA J. Pharm. Sci. Technol.51，7-16.）对于5%乳糖，使用MTM（测压温度测量）方法。利用得到的参数R-0、A（1）.和A（2），可以进行模拟以确定初级干燥期间的最高产品温度和干燥时间。因此，可以确定最佳循环参数以避免产品塌陷。所提出的方法只需要精确测量的产品温度曲线，很容易在实验室干燥器中获得。(c)2006 Elsevier B. V.保留所有权利。
Mass transfer resistance of the dry layer during the primary drying phase of a lyophilizaton cycle is probably the most important factor affecting maximum product temperature and drying time. Product resistance parameters should be determined for each formulation because of their dependence of formulation composition and concentration. The purpose of this study was to determine the dry layer mass transfer resistance, using a simple and rapid method, for various pharmaceutical formulations during primary drying in a laboratory dryer, using monitored product temperature profiles. The mathematical tools used for the determination were a primary drying simulation program in conjunction with Powell's optimization algorithm. For each formulation studied, primary drying was performed using a shelf temperature of -15 or -20 degrees C and the chamber pressure controlled at 100 mTorr (0.1 Torr). The product temperature profiles (T-b) during primary drying were recorded and became the input data for the parameter estimation. The normalized product resistance, R-pN, as a function of the dry layer thickness, e, can be described by: R-pN = R-0 + A(I)l(1 + A(2)l), where the constants R-0, A(1) and A(2) are product resistance parameters of water vapor through the dry layer. Even when the parameter A(1) was negative, indicating that product temperature atypically decreased over time, the dry layer product resistance parameters of the various pharmaceutical formulations could be rapidly and successfully determined using the proposed approach. The product resistance equation obtained in this work for 5% marmitol, expressed as R-pN = 0.0002025 + 20.23l, is similar to that obtained by Pikal [Pikal. M.J.. 1985. Use of laboratory data in freeze drying process design: heat and product resistance parameters and the compute simulation of freeze drying. J. Parent. Sci. Technol. 39, 115-138.] using the microbalance method, expressed as RpN = 1.40 + 16.0l. The product resistance values obtained for the 3% lactose-LDH formulation are also very close to those obtained by (Milton, N., Pikal, M.J., Roy, M.L., Nail, S.L., 1997. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J. Pharm. Sci. Technol. 51, 7-16.) for 5% lactose using the MTM (manometric temperature measurement) method. With the obtained values of the parameters R-0, A(1). and A(2), simulations can be performed to determine the maximum product temperature and the drying time during primary drying. As such, Optimum cycle parameters can be determined to avoid collapse of the product. The proposed approach requires only accurately measured product temperature profiles, easily obtained in a laboratory dryer. (c) 2006 Elsevier B.V. All rights reserved.