Text

theses

ETD doctoral

In the pharmaceutical industry, processing granular materials is inevitable when manufacturing solid dosage forms, such as tablets, capsules, dry powder inhalants, vascular stent, or injectable solid compositions. As pharmaceutical industries make products that necessitate a significant (albeit controllable) risk to human health, a systematic, proactive, scientific, and risk-based approach has been adopted by health authorities (e.g., Food and Drug Administrative) for drug safety: Quality-by-Design (QbD). The QbD-based pharmaceutical development emphasizes the mechanistic understanding of input material properties and process dynamics to recognize how the formulation and process factors affect the final product. Once we have comprehensive material and process understanding, the manufacturing process is stable and predictable, the performance and safety of the final product can be predicted and ensured, the entire drug product development can run faster with less waste and cost.
In the last decade, the pharmaceutical industries have grasped a world-wide transformation to continuous manufacturing technologies due to its capability of fast development, enhanced risk management, and improved quality control. The deep understanding of material behavior and process dynamics on the continuous manufacturing platform will be one of the primary focuses for the entire pharmaceutical industry in the next decades.

By considering all of the above regulatory requirements and state-of-the-art pharmaceutical techniques, this dissertation is constructed toward unraveling the possible correlation between material properties, process parameters, and product performance, based on continuous manufacturing platform for solid dosage development. In each chapter, attempts have been made to investigate a) how the certain properties of an input material impact its process behavior and performance of output material or final product, b) how the certain process parameters alter process dynamics which further impact the performance of output material or final product, and c) how to design formulation and production methodology to enhance drug productivity or therapeutic performance.

Four specific investigations are implemented:
(1) The effect of twin-screw feeders on material properties is investigated to understand whether the post-feeder powder has the same properties as the pre-feeder one. The flowing behavior of fourteen pharmaceutical powders is characterized before and after feeder. it has been found that powder may behave more cohesively after passing through a twin-screw feeder due to electrostatic charge acquisition. Such behavior can only be discerned by performing the appropriate characterization method, which can be correlated with the tendency of powder electrostatic charging and its particle size,
(2) API agglomeration behavior during the continuous process is investigated. A novel method for quantifying material agglomeration tendency is developed based on image analysis. It enables us to assess the risk of non-uniform products caused by ingredient agglomeration. In this work, it has been found that the powder is densified in the twin-screw feeder and then introduced as lumps to the downstream process, which generates difficulty for uniform mixing. Twenty-two pharmaceutical powders are examined and the capability is developed to assess ingredient agglomeration risk based on proper raw material characterization.
(3) The existence of API agglomerates reduces content uniformity of the final product. we also explore how to design blending processes to diminish or even eliminate API agglomerates, which are generated due to feeder passage. A case study is performed in a continuous powder blending system, which consists of two feeders, a conical mill, and a tubular blender. Multiple blending protocols are implemented, involving different impeller rotational speed of blender, multiple levels of powder holdup in blender, with/without using the conical mill at multiple impeller speeds and screen size. It has been found that the API agglomerates can be significantly reduced when powder passes through an extensive number of blades (NOB) in a blender, or a conical mill is assembled
(4) Improving the dissolution of poorly soluble drug products is a key challenge in drug product development. In this dissertation, a novel approach is invented to enhance the dissolution of poorly soluble drugs by applying the concept of the surface coating. A simple process, twin-screw extrusion at low process temperature, is performed that enables the melt-coating of API particles with a small amount of surfactant. Four case studies are conducted to evidence the practicality of the melt-coating methodology, in which the combinations of three BCS class II drugs and three surfactants are examined. Remarkably, the results support that the melt-coating technique significantly improves the dissolution of poorly soluble drugs.

ETD_11183

Ph.D.

Includes bibliographical references

doi:10.7282/t3-yyjw-p173

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