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

合作研究：了解粉末特性和加工条件对药片性能的影响

• 批准号: 1538380
• 负责人: German Drazer
• 金额: $ 20万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1538380&HistoricalAwards=false
• 关键词: Collaborative; Research; Understanding; Effect; Powder

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.

药物片剂占当今分配的口服固体剂型的大部分。它们传统上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。然而，尽管产品质量控制有着悠久的历史，但它在很大程度上依赖于经验方法。例如，评估赋形剂可变性对药物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制造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，了解原材料特性和生产工艺参数对产品质量和性能的相互关系具有重要的战略意义。普渡大学和罗格斯大学的研究人员的合作研究工作将结合联合收割机实验，模拟和建模，以解决这一重要问题的情况下，通过直接压缩粉末制造的药片。合作的广泛性质也提供了一个很好的机会，培养研究生和本科生在工程和制药科学在广泛的实验和计算技术。调查人员还将通过不同的本科研究项目在两所大学进行协调的外展工作。此外，该项目产生的数值方法将通过NSF支持的开放访问HUBzero平台广泛提供给制药和工艺工程界和教育工作者，如pharmaHUB.org。研究工作的智力价值在于开发一种预测性的多功能一种基于对单个粉末颗粒水平的机械理解的比例模型，粉末性质（例如，润湿）和处理参数（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）。研究的变革性质包括：（i）在大变形和高约束下压缩粉末的新的机械模型，以预测详细结构和材料强度，以及多尺度方法，以描述溶剂吸收，并结合特设实验，使主要的渗透机制脱钩（毛细管吸胀和Case-II扩散），并且能够描述崩解行为; ㈡一套广泛的专门实验（片剂硬度、自由和限制性肿胀，具有多种流体的柱吸液），这将允许用于日益复杂的系统的迭代实验-模型协同作用。然后，将利用该模型和一组特设实验来揭示和理解原材料性质和生产工艺参数与片剂质量和性能之间的相互关系。