De Grandi Davide, Meghdadi Alireza, LuTheryn Gareth, Carugo Dario
Department of Drug Sciences, Faculty of Pharmacy, University of Pavia Pavia 27100 Italy.
Department of Pharmaceutics, School of Pharmacy, University College London London WC1N 1AX UK
RSC Adv. 2022 Jul 19;12(32):20696-20713. doi: 10.1039/d2ra02745c. eCollection 2022 Jul 14.
Drug nanocrystals are a delivery system comprised of an active pharmaceutical ingredient, with small amounts of a surface stabilizer. Despite offering simplicity in formulation, their manufacture can be a challenging endeavour; this is especially true when the production is performed using microfluidic devices. Although precipitation within microchannels can lead to issues such as clogging, microfluidics is an appealing manufacturing method as it provides fine control over mixing conditions. This allows production of nanoparticles with a narrower size distribution and greater reproducibility compared to batch methods. To generate microfluidic devices cost effectively, replica moulding techniques are considered the manufacturing standard. Due to its simplicity and relatively low cost, 3D printing has become prevalent at the laboratory scale, especially during iterative development of new devices. A challenge of microfluidic-based methods is that they require specialized equipment and multi-step procedures, making them less accessible to users with no previous experience. In a recent study we developed a 3D printed flow-through reactor, referred to as reactor-in-a-centrifuge (RIAC). It is a simple device designed to fit in a 50 mL tube and actuated using a laboratory centrifuge, which removes the need for specialized instrumentation. The manufacturing capabilities of the RIAC have been already proven, by reproducible production of liposomes and silver nanoparticles. The present work demonstrates the use of RIACs with a straight- and spiral-shaped channel architecture to produce quercetin nanocrystals, with therapeutically relevant size (190-302 nm) and very low size dispersity (polydispersity index, PDI < 0.1). The work focused on evaluating how changes in operational parameters (actuation speed) and formulation components (medium viscosity and stabilizer type), impacted on nanocrystal size and PDI. Under all tested conditions the obtained nanocrystals had a smaller size and narrower size distribution, when compared to those produced with alternative methods. The obtained quercetin nanosuspensions however showed limited stability, which should be addressed in future investigations. The simplicity of the RIAC makes it an appealing technology to research groups, especially in low-resource settings and without prior expertise in microfluidics.
药物纳米晶体是一种由活性药物成分和少量表面稳定剂组成的给药系统。尽管其制剂配方简单，但其制造过程可能具有挑战性；当使用微流控设备进行生产时尤其如此。尽管微通道内的沉淀可能会导致诸如堵塞等问题，但微流控技术仍是一种有吸引力的制造方法，因为它能对混合条件进行精细控制。与分批法相比，这使得能够生产尺寸分布更窄且重现性更高的纳米颗粒。为了经济高效地制造微流控设备，复制成型技术被视为制造标准。由于其简单性和相对较低的成本，3D打印在实验室规模中已变得很普遍，尤其是在新设备的迭代开发过程中。基于微流控的方法面临的一个挑战是它们需要专门的设备和多步骤程序，这使得没有经验的用户较难使用。在最近的一项研究中，我们开发了一种3D打印的流通式反应器，称为“离心式反应器”（RIAC）。它是一种简单的设备，设计用于适配50 mL试管，并使用实验室离心机驱动，从而无需专门的仪器。通过可重现地生产脂质体和银纳米颗粒，RIAC的制造能力已经得到了证明。目前的工作展示了使用具有直形和螺旋形通道结构的RIAC来生产槲皮素纳米晶体，其尺寸具有治疗相关性（190 - 302 nm）且尺寸分散性非常低（多分散指数，PDI < 0.1）。这项工作重点评估了操作参数（驱动速度）和制剂成分（介质粘度和稳定剂类型）的变化如何影响纳米晶体的尺寸和PDI。在所有测试条件下，与用其他方法生产的纳米晶体相比，所获得的纳米晶体尺寸更小且尺寸分布更窄。然而，所获得的槲皮素纳米悬浮液稳定性有限，这在未来的研究中应予以解决。RIAC的简单性使其成为研究团队有吸引力的技术，特别是在资源匮乏的环境中且没有微流控技术专业知识的情况下。
