Gatlin L A, Nail S L
Glaxo Research Institute, Research Triangle Park, North Carolina.
Bioprocess Technol. 1994;18:317-67.
Freeze drying provides a valuable tool to the formulation scientist by permitting dehydration of heat-sensitive drugs and biologicals at low temperature. The final product is quickly and easily reconstituted, and the process is compatible with aseptic operations. Freezing is a critical step, since the microstructure established by the freezing process usually represents the microstructure of the dried product. The product must be frozen to a low enough temperature to be completely solidified. If the solute crystallizes during freezing, this temperature is the eutectic temperature. If the solute remains substantially amorphous with freezing, the relevant temperature is the collapse temperature. Understanding the physical form of the solute--crystalline or amorphous--after freezing can be important from the standpoint of drying characteristics, appearance of the final product, and even product stability during storage. Supercooling is a significant factor in freezing of formulations intended for freeze drying--prior to both primary and secondary (eutectic) crystallization. The driving force for freeze drying is the difference in vapor pressure of ice between the sublimation zone and the condenser. Because the vapor pressure of ice increases sharply with increased product temperature, it is important from the standpoint of process efficiency to maintain product temperature as high as possible during primary drying without damaging the product. The upper limit of product temperature during primary drying again depends on the physical form of the solute. Exceeding either the eutectic temperature (crystalline solute) or the collapse temperature (amorphous solute) results in loss of the desirable properties of a freeze dried product. Freeze drying is a coupled heat and mass transfer process, where either heat transfer or mass transfer may be rate limiting with respect to the overall drying rate. Heat transfer is often the rate-limiting transfer operation because of the high heat of sublimation of ice and the inefficiency of heat transfer. Conduction is the primary mechanism of heat transfer, as opposed to convection or thermal radiation. The rate-limiting resistance to heat transfer is usually the interfacial, or contact, resistance caused by poor contact between materials--the heated shelf, metal trays, and the bottom surface of glass vials. Since the thermal conductivity of a gas is directly proportional to pressure in the free molecular flow regime, the chamber pressure during primary drying is an important determinant of the overall heat transfer rate. As a result, the drying rate for a heat transfer-limited process increases sharply with chamber pressure up to a pressure where free molecular flow conditions no longer apply.(ABSTRACT TRUNCATED AT 400 WORDS)
冷冻干燥为制剂科学家提供了一种有价值的工具，它能在低温下使热敏性药物和生物制品脱水。最终产品能快速且容易地复溶，并且该过程与无菌操作兼容。冷冻是一个关键步骤，因为冷冻过程中形成的微观结构通常代表了干燥产品的微观结构。产品必须冷冻到足够低的温度以完全固化。如果溶质在冷冻过程中结晶，这个温度就是共晶温度。如果溶质在冷冻时基本保持非晶态，相关温度就是塌陷温度。从干燥特性、最终产品外观以及储存期间的产品稳定性等角度来看，了解冷冻后溶质的物理形态（结晶态或非晶态）可能很重要。过冷是冷冻干燥制剂冷冻过程中的一个重要因素——在一次结晶和二次（共晶）结晶之前。冷冻干燥的驱动力是升华区和冷凝器之间冰的蒸气压差。由于冰的蒸气压随产品温度升高而急剧增加，从工艺效率的角度来看，在一次干燥过程中尽可能保持产品温度高而又不损坏产品很重要。一次干燥过程中产品温度的上限再次取决于溶质的物理形态。超过共晶温度（结晶溶质）或塌陷温度（非晶溶质）会导致冷冻干燥产品失去理想特性。冷冻干燥是一个传热和传质耦合的过程，其中传热或传质可能相对于整体干燥速率而言是限速的。由于冰的升华热高且传热效率低，传热通常是限速的传递操作。传导是主要的传热机制，与对流或热辐射不同。限速的传热阻力通常是由材料（加热搁板、金属托盘和玻璃小瓶底面）之间接触不良引起的界面或接触阻力。由于在自由分子流态下气体的热导率与压力成正比，一次干燥过程中的腔室压力是整体传热速率的重要决定因素。因此，对于传热受限的过程，干燥速率会随着腔室压力急剧增加，直至达到自由分子流条件不再适用的压力。（摘要截选至400字）
