Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, United States.
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, United States; Princeton Materials Institute, Princeton University, Princeton, NJ 08544, United States.
Int J Pharm. 2023 Jun 10;640:122985. doi: 10.1016/j.ijpharm.2023.122985. Epub 2023 Apr 29.
Flash NanoPrecipitation (FNP) is a scalable, single-step process that uses rapid mixing to prepare nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Because the two steps of particle self-assembly - (1) core nucleation and growth and (2) adsorption of a stabilizing polymer onto the growing core surface - occur simultaneously during FNP, nanoparticles formulated at core loadings above approximately 70% typically exhibit poor stability or do not form at all. Additionally, a fundamental limit on the concentration of total solids that can be introduced into the FNP process has been reported previously. These limits are believed to share a common mechanism: entrainment of the stabilizing polymer into the growing particle core, leading to destabilization and aggregation. Here, we demonstrate a variation of FNP which separates the nucleation and stabilization steps of particle formation into separate sequential mixers. This scheme allows the hydrophobic core to nucleate and grow in the first mixing chamber unimpeded by adsorption of the stabilizing polymer, which is later introduced to the growing nuclei in the second mixer. Using this Sequential Flash NanoPrecipitation (SNaP) technique, we formulate stable nanoparticles with up to 90% core loading by mass and at 6-fold higher total input solids concentrations than typically reported.
闪蒸纳米沉淀(FNP)是一种可扩展的单步工艺,利用快速混合制备具有疏水性内核和两亲性稳定壳的纳米颗粒。由于在 FNP 过程中,颗粒自组装的两个步骤 - (1) 核的成核和生长和 (2) 稳定聚合物吸附到生长的核表面 - 同时发生,因此在核心负载高于约 70%时,所配制的纳米颗粒通常表现出较差的稳定性或根本无法形成。此外,先前已经报道了在 FNP 过程中可以引入的总固体浓度的基本限制。这些限制被认为具有共同的机制:将稳定聚合物夹带在生长的颗粒核心中,导致失稳和聚集。在这里,我们展示了 FNP 的一种变体,将颗粒形成的成核和稳定步骤分离到单独的顺序混合器中。该方案允许疏水性内核在第一个混合室中不受稳定聚合物吸附的阻碍而进行成核和生长,然后在第二个混合器中将稳定聚合物引入到生长的核中。使用这种顺序闪蒸纳米沉淀(SNaP)技术,我们通过质量高达 90%的核心负载和比通常报道的高 6 倍的总输入固体浓度来配制稳定的纳米颗粒。
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