Preparation and scale up of extended-release tablets of bromopride

Reproducibility of the tablet manufacturing process and control of its pharmaceutics properties depends on the optimization of formulation aspects and process parameters. Computer simulation such as Design of Experiments (DOE) can be used to scale up the production of this formulation, in particular for obtaining sustained-release tablets. Bromopride formulations are marketed in the form of extended-release pellets, which makes the product more expensive and difficult to manufacture. The aim of this study was to formulate new bromopride sustained release formulations as tablets, and to develop mathematical models to standardize the scale up of this formulation, controlling weight and hardness of the tablets during manufacture according to the USP 34th edition. DOE studies were conducted using Minitab(tm) software. Different excipient combinations were evaluated in order to produce bromopride sustained-release matrix tablets. In the scale-up study, data were collected and variations in tableting machine parameters were measured. Data were processed by Minitab(tm) software, generating mathematical equations used for prediction of powder compaction behavior, according to the settings of the tableting machine suitable for scale-up purposes. Bromopride matrix tablets with appropriate characteristics for sustained release were developed. The scale-up of the formulation with the most suitable sustained release profile was established by using mathematical models, indicating that the formulation can be a substitute for the pellets currently marketed.

片剂生产工艺的重现性及其药剂学性质的调控，依赖于处方组成与工艺参数的优化。实验设计（Design of Experiments, DOE）这类计算机仿真方法，可用于该处方的生产放大，尤其适用于缓释片剂的制备。溴必利（Bromopride）处方目前以缓释微丸的形式上市，这不仅导致产品售价偏高，也增加了生产难度。本研究旨在开发新型溴必利缓释片剂处方，并构建数学模型以实现该处方生产放大的标准化，同时按照美国药典第34版（USP 34th edition）的要求，对生产过程中的片剂重量与硬度进行管控。本研究借助Minitab(tm)软件开展了实验设计研究，为制备溴必利缓释骨架片，对多种辅料组合进行了筛选评价。在生产放大研究中，研究人员收集了相关数据，并测定了压片机参数的波动情况。随后通过Minitab(tm)软件对数据进行处理，生成了可用于预测粉体压片行为的数学方程，所得参数设置适配于生产放大需求。本研究成功制备出具备合格缓释性能的溴必利骨架片剂。通过数学模型确定了具备最优缓释特性的处方的生产放大方案，结果表明该处方可替代当前市售的微丸制剂。