Narula Akshay, Yang Da Hye, Chakravarty Paroma, Li Na
Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road Unit 3092, Storrs, CT 06269, United States.
Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., San Francisco, CA 94080, United States.
J Pharm Sci. 2025 Jan;114(1):210-222. doi: 10.1016/j.xphs.2024.08.017. Epub 2024 Aug 24.
The purpose of this study was twofold: to identify the growth mechanisms of amorphous nanoparticles in solution and during the drying process at high temperatures, and to guide the process condition and stabilizer selection for amorphous nanoparticle formulations. In contrast to nanocrystals that are mostly mechanically robust, amorphous nanoparticles tend to undergo deformation under stress. As a result, development of a stable formulation and evaluation of the drying process for re-dispersible amorphous nanoparticles present considerable challenges. Although amorphous nanoparticles have stability issues, they have several pros in terms of production, high monodispersity, and diverse applications in drug delivery. In this study, amorphous nanoparticles were prepared via liquid-liquid phase separation, and their growth mechanisms were investigated both in solution and during the drying process. In solution, particles were found to be susceptible to flocculation, crystallization, coalescence, and Ostwald ripening, with coalescence being a preliminary step providing the driving force for Ostwald ripening. However, during the heat drying process, coalescence and crystallization were found to be the primary mechanisms for particle growth, with Ostwald ripening being negligible due to reduced molecular mobility. The glass transition temperature (T) of these amorphous nanoparticles was found to be a crucial factor both in solution and during the drying process. At temperatures < T, particles remained in a rigid, glassy state thereby inhibiting coalescence, whereas at or above T, particles transition from glassy to rubbery state, making them more susceptible to deformation and coalescence. The mechanistic understanding of particle growth from this study can also be extended to the stabilization of other types of soft nanoparticles.
确定无定形纳米颗粒在溶液中以及高温干燥过程中的生长机制，并指导无定形纳米颗粒制剂的工艺条件选择和稳定剂选择。与大多具有机械稳定性的纳米晶体不同，无定形纳米颗粒在应力作用下容易发生变形。因此，开发稳定的制剂以及评估可再分散无定形纳米颗粒的干燥过程面临着相当大的挑战。尽管无定形纳米颗粒存在稳定性问题，但它们在生产、高单分散性以及药物递送中的多种应用方面具有若干优势。在本研究中，通过液 - 液相分离制备了无定形纳米颗粒，并研究了它们在溶液中和干燥过程中的生长机制。在溶液中，发现颗粒易发生絮凝、结晶、聚结和奥斯特瓦尔德熟化，聚结是为奥斯特瓦尔德熟化提供驱动力的初步步骤。然而，在热干燥过程中，发现聚结和结晶是颗粒生长的主要机制，由于分子流动性降低，奥斯特瓦尔德熟化可忽略不计。这些无定形纳米颗粒的玻璃化转变温度（T）在溶液中和干燥过程中都是一个关键因素。在温度 < T 时，颗粒保持刚性的玻璃态，从而抑制聚结，而在 T 或高于 T 时，颗粒从玻璃态转变为橡胶态，使其更容易发生变形和聚结。本研究对颗粒生长的机理理解也可扩展到其他类型软纳米颗粒的稳定化。
