Collaborative Research: Understanding the Effect of Powder Properties and Processing Conditions on the Performance of Pharmaceutical Tablets

药物片剂占今天口服固体剂型的很大一部分。它们传统上是通过直接压缩活性药物成分和赋形剂粉末的混合物来制造的。然而，尽管历史悠久，产品质量控制广泛依赖于经验方法。例如，评估赋形剂可变性对片剂性能的影响仍然是一个巨大的挑战。为了解决这些问题，美国食品和药物管理局发布了在生产过程中实施质量设计的指导方针，制造商越来越关注原材料和过程控制。因此，了解原材料特性和制造工艺参数对产品质量和性能之间的相互关系具有战略重要性。普渡大学（Purdue）和罗格斯大学（Rutgers）的研究人员将结合实验、模拟和建模，来解决直接压缩粉末生产药片的这一重要问题。合作的广泛性也提供了一个极好的机会，在广泛的实验和计算技术方面培养工程和制药科学的研究生和本科生。调查人员还将参与两所大学通过不同的本科生研究项目协调的外展工作。此外，通过美国国家科学基金会支持的开放获取HUBzero平台，如pharmaHUB.org，该项目产生的数值方法将广泛地提供给制药和工艺工程社区以及教育工作者。该研究工作的智力价值在于开发了一种预测的多尺度模型，该模型基于对单个粉末颗粒水平的机制理解，并捕获了粉末特性（例如润湿性）和加工参数（例如压缩力）与干片剂的关键质量属性（例如硬度）和片剂性能（例如与水接触的崩解行为）之间的复杂相互关系。该研究的变革性质包括：(1)在大变形和高约束下的压缩粉末的新机制模型，以预测详细的结构和材料强度，以及描述溶剂吸收的多尺度方法，结合特殊实验，解耦了主要渗透机制（毛细管吸胀和case-II扩散），并能够描述解体行为；（二）一套广泛的特别实验（片剂硬度、自由和受限溶胀、多种流体的柱吸胀），使实验模型能够对日益复杂的系统进行迭代协同。然后，该模型和一组特别实验将用于揭示和理解原料性质和制造工艺参数与片剂质量和性能之间的相互关系。

Pharmaceutical tablets account for a large fraction of oral solid dosage forms dispensed today. They are traditionally manufactured by directly compressing a blend of the active pharmaceutical ingredient and excipient powders. In spite of its long history, however, product quality control relies extensively on empirical methods. Evaluating the impact of excipient variability on the performance of pharmaceutical tablets, for example, still presents a great challenge. To address these problems, the U.S. Food and Drug Administration has released guidelines for the implementation of quality-by-design in the manufacturing process and manufacturers are increasingly focusing on raw materials and process controls. It is therefore of strategic importance to understand the interrelationship between raw material properties and manufacturing process parameters on product quality and performance. The collaborative research effort by researchers at Purdue and Rutgers will combine experiments, simulations and modeling to address this important issue in the case of pharmaceutical tablets manufactured by direct compression of powders. The broad nature of the collaboration also provides an excellent opportunity to train graduate and undergraduate students in engineering and pharmaceutical sciences in a wide range of experimental and computational techniques. The investigators will also engage in outreach efforts coordinated at both universities through different undergraduate research programs. In addition, the numerical methods resulting from the project will be broadly available to the pharmaceutical and process engineering communities and educators through NSF's supported open-access HUBzero platforms, such as pharmaHUB.org. The intellectual merit of the research work lies in developing a predictive multi-scale model that is based on a mechanistic understanding at the level of individual powder particles and captures the complex interrelationship between powder properties (e.g., wetting) and processing parameters (e.g., compression force) with critical quality attributes of dry tablets (e.g., hardness) and tablet performance (e.g., disintegration behavior in contact with water). The transformative nature of the research includes: (i) A novel mechanistic model of compressed powders under large deformations and high confinement to predict detailed structure and material strength, and a multi-scale approach to describe solvent uptake combined with ad-hoc experiments that decouple the dominant penetration mechanisms (capillary imbibition and case-II diffusion) and is able to describe disintegration behavior; (ii) A broad set of ad-hoc experiments (tablet hardness, free and constrained swelling, column imbibition with multiple fluids) that will allow iterative experiment-model synergy for increasingly complex systems. The model and the set of ad-hoc experiments will then be utilized to reveal and understand the interrelationship between the properties of the raw materials and manufacturing process parameters with the quality and performance of pharmaceutical tablets.