Beirowski Jakob, Inghelbrecht Sabine, Arien Albertina, Gieseler Henning
University of Erlangen, Division of Pharmaceutics, Freeze Drying Focus Group, 91058 Erlangen, Germany.
J Pharm Sci. 2011 Oct;100(10):4471-81. doi: 10.1002/jps.22634. Epub 2011 May 23.
The present study investigates whether controlling the product temperature below the critical formulation temperature (CFT) during primary drying in a freeze drying cycle is a prerequisite for the stabilization of drug nanoparticles. For that purpose, the CFT of four drug nanosuspensions stabilized with different types (amorphous and crystalline) and concentrations of steric stabilizers and either of the disaccharides, trehalose and sucrose, was determined by differential scanning calorimetry and freeze-dry microscopy. Freeze-drying experiments were performed such that product temperatures during primary drying remained either below or well above the CFT of individual mixtures. It was found that glass formation did not influence the stability of the nanoparticles, suggesting that an adequate type of steric stabilizer and lyoprotectant concentration is present. Freeze drying could also be performed above the eutectic temperature without compromising on the final product quality profile, such as nanoparticle size and structural preservation of the lyophilized cake. The high concentration of solid drug nanoparticles provided additional cake stability. The results of this study confirm for the first time that primary drying for drug nanosuspensions can be greatly shortened because induced viscous flow or even meltback is not a limitation for nanoparticle stability and cake elegancy.
本研究调查了在冷冻干燥循环的一次干燥过程中将产品温度控制在临界制剂温度（CFT）以下是否是药物纳米颗粒稳定化的先决条件。为此，通过差示扫描量热法和冷冻干燥显微镜测定了四种用不同类型（无定形和结晶）和浓度的空间稳定剂以及两种二糖（海藻糖和蔗糖）之一稳定化的药物纳米混悬液的CFT。进行冷冻干燥实验，使一次干燥过程中的产品温度保持在低于或远高于各个混合物的CFT。结果发现，玻璃形成并不影响纳米颗粒的稳定性，这表明存在合适类型的空间稳定剂和冻干保护剂浓度。也可以在共晶温度以上进行冷冻干燥，而不会影响最终产品的质量特征，如纳米颗粒大小和冻干饼的结构保存。高浓度的固体药物纳米颗粒提供了额外的饼稳定性。本研究结果首次证实，药物纳米混悬液的一次干燥可以大大缩短，因为诱导粘性流动甚至回熔并不是纳米颗粒稳定性和饼美观度的限制因素。
