Exploration Of Parameters For The Continuous Blending Of Pharmaceutical Powders

The transition from traditional batch blending to continuous blending is an opportunity for the pharmaceutical industry to reduce costs and improve quality control. This operational shift necessitates a deeper understanding of the mixing process informed by particle dynamics and variable interdependencies. The thesis aims to establish a framework for characterizing and improving continuous pharmaceutical blending using a tiered experimental methodology and multivariate analysis. This parameter space exploration attempts to reconcile previous research within the context of cohesive pharmaceutical powders and develop general design principles for maximizing blender performance. A design of experiments was conducted to determine mixing performance with respect to three factors - physical design, operating parameters, and material properties. Multivariate analysis using projections to latent structures was employed to quantify the effect of raw and intermediate variables on the variance reduction ratio. Significant parameters identified included the choice of API, fill fraction, the number of blade passes, the mean residence time, the Bodenstein number, and the period of input feed fluctuations. The results highlight the importance of shear and radial mixing for cohesive powders, which suggest that one-dimensional axial models common in blending literature may not be a sufficient theoretical framework for pharmaceutical applications. The research yielded several insights into design principles for optimizing blending performance. Increasing mean residence time and radial mixing create more robust processing by reducing the impact of material properties and fluctuations in feed consistency. The variance reduction ratio can be improved in a cost-effective manner by determining the fill fraction which maximizes intermediate metrics such as space time, mean residence time, and the number of blade passes. Multivariate analysis was demonstrated to be a practical tool for parameter space optimization and a promising technique for characterizing the effect of material properties on processing.

(Cont.) The predictive capability of the process model was found to dependent on the scale of scrutiny of the powder mixture in the blender. Choosing the correct scale of scrutiny was demonstrated to be of critical importance in determination of blend quality. Growing pressures on pharmaceutical industry due to patent expirations has forced manufacturers to look beyond the US and EU for potential manufacturing locations in addition to invest in novel manufacturing methods and technologies. The capstone work in this thesis proposes a framework that managers of pharmaceutical and biologics manufacturing can utilize to identify critical issues in globalization of manufacturing and in making strategic manufacturing location decisions.

The main focus of our research is to investigate continuous powder blending. The unit operation of powder blending is widely used to reduce the heterogeneity degree of product mixture in the manufacture of catalysts, cement, food, metal parts, and many other industrial products. Currently in pharmaceutical industry, continuous powder blending has received more attention as an efficient alternative to the traditional batch blending of powders due to its ability in handling high-flux continuous tablet manufacturing. Numerous previous approaches have been performed focusing on investigating the applicability of continuous manufacturing system. However, the development of reliable industrial system is limited by the inaccuracy of mixing index, the complicated effects of operating conditions and the black-box characterization method, all of which result from the lack of a theoretical model that can quantitatively characterize the whole continuous powder mixing process. Therefore, the overall research objective of this work is to develop a general standard method for quantitative process design and control. In this context, three different specific aims are accomplished. We analyze and distinguish different heterogeneity sources in the continuous blending process and develop a general model of continuous blending. Fourier series is applied to characterize the axial blending component, and a periodic section model is developed to capture the cross-sectional blending component. Based on the modeling work, efficient design, control, and scale-up strategies applicable for practical blending of pharmaceutical powders are determined. The effectiveness of the methodology is demonstrated in particle blending simulations and experiments using industrial mixing apparatuses to check its applicability and robustness in pharmaceutical industrial use.

Provides an extensive and up-to-date overview of the theory and application of computational pharmaceutics in the drug development process Exploring Computational Pharmaceutics - AI and Modeling in Pharma 4.0 introduces a variety of current and emerging computational techniques for pharmaceutical research. Bringing together experts from academia, industry, and regulatory agencies, this edited volume also explores the current state, key challenges, and future outlook of computational pharmaceutics while encouraging development across all sectors of the field. Throughout the text, the authors discuss a wide range of essential topics, from molecular modeling and process simulation to intelligent manufacturing and quantitative pharmacology. Building upon Exploring Computational Pharmaceutics - AI and Modeling in Pharma 4.0, this new edition provides a multi-scale perspective that reveals the physical, chemical, mathematical, and data-driven details of pre-formulation, formulation, process, and clinical studies, in addition to in vivo prediction in the human body and precision medicine in clinical settings. Detailed chapters address both conventional dosage forms and the application of computational technologies in advanced pharmaceutical research, such as dendrimer-based delivery systems, liposome and lipid membrane research, and inorganic nanoparticles. A major contribution to the development and promotion of computational pharmaceutics, this important resource: Discusses the development track, achievements, and prospects of computational pharmaceutics Presents multidisciplinary research to help physicists, chemists, mathematicians, and computer scientists locate problems in the field of drug delivery Covers a wide range of technologies, including complex formulations for water-insoluble drugs, protein/peptide formulations, nanomedicine, and gene delivery systems Focuses on the application of cutting-edge computational technologies and intelligent manufacturing of emerging pharmaceutical technologies Includes a systematic overview of computational pharmaceutics and Pharma 4.0 to assist non-specialist readers Covering introductory, advanced, and specialist topics, Exploring Computational Pharmaceutics - AI and Modeling in Pharma 4.0 is an invaluable resource for computational chemists, computational analysts, pharmaceutical chemists, process engineers, process managers, and pharmacologists, as well as computer scientists, medicinal chemists, clinical pharmacists, material scientists, and nanotechnology specialists working in the field.

This book covers the theoretical and practical aspects of the mixing of solids and presents an overview as well as detailed know-how and experience. The book demonstrates the state of the art of mixing and segregation technology, quality control, design of mixers, design scale-up and engineering of complete processes. Includes checklists, criteria for choosing batch or continuous process, and practical examples of installed systems.

Simulations in Bulk Solids Handling Valuable resource for engineers and professionals dealing with bulk granular or powdered materials across industries using Discrete Element Methods (DEM) In many traditional university engineering programmes, no matter whether undergraduate or postgraduate, the behavior of granular materials is not covered in depth or at all. This omission leaves recent engineering graduates with little formal education in the major industrial area of bulk solids handling. This book teaches young professionals and engineers to find appropriate solutions for handling granular and powdered materials. It also provides valuable information for experienced engineers to gain an understanding and appreciation of the most significant simulation methods–DEM chief amongst them. For any student or professional involved with bulk solids handling, this book is a key resource to understand the most efficient and effective stimulation methods that are available today. Its comprehensive overview of the topic allows for upcoming professionals to ensure they have adequate knowledge in the field and for experienced professionals to improve their skills and processes.

Continuous processing is an advantageous alternative for the current methods used in the pharmaceutical manufacturing. Important advantages that it offers include smaller equipment footprint, reduced efforts in the scale-up work, and the potential to utilize already continuous processes to make the entire manufacturing more efficient. In the current pharmaceutical manufacturing environment, powder mixing process is carried out in the batch mode. The necessary methods and guidelines to design an equivalent continuous process are not well established. The work presented in this dissertation focuses on the characterization, design and optimization of a continuous powder mixing process for pharmaceutical powders. A systematic study was performed of the effects of process and design variables, and material properties involved in the continuous powder mixing process. The bulk powder flow behavior was characterized using the residence time distribution (RTD) measurement approach. Impeller speed, material bulk density and impeller design greatly influenced the mean residence time. With increasing impeller speed, mechanical fluidization was observed, which significantly affected axial dispersion coefficients. Intermediate rotation rates exerted maximum strain on the material, which leads to maximum homogenization. The strain measurements correlated well with the properties of tablets including content uniformity and tablet hardness. Mixing performance was largely dominated by the material properties of the mixture, and the blend uniformity measurement was affected by the sample size analyzed. An experimental protocol was developed to measure the blend uniformity in the in-line mode, and a methodology was further built to quantitatively relate the in-line NIR measurements with the off-line wet chemistry measurements. Considering the shear limitations of the continuous bladed mixer, alternative blending strategies, suitable for blending of cohesive materials were also demonstrated. A combination of a high-shear mixing followed by a low-shear mixing process provided the optimal mixing performance. The predictive understanding of the continuous powder mixing process developed in this dissertation can assist towards the design and development of a fully controlled continuous manufacturing process.

A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency. This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles. Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.

Dosage Form Design Parameters, Volume II, examines the history and current state of the field within the pharmaceutical sciences, presenting key developments. Content includes drug development issues, the scale up of formulations, regulatory issues, intellectual property, solid state properties and polymorphism. Written by experts in the field, this volume in the Advances in Pharmaceutical Product Development and Research series deepens our understanding of dosage form design parameters. Chapters delve into a particular aspect of this fundamental field, covering principles, methodologies and the technologies employed by pharmaceutical scientists. In addition, the book contains a comprehensive examination suitable for researchers and advanced students working in pharmaceuticals, cosmetics, biotechnology and related industries. Examines the history and recent developments in drug dosage forms for pharmaceutical sciences Focuses on physicochemical aspects, prefomulation solid state properties and polymorphism Contains extensive references for further discovery and learning that are appropriate for advanced undergraduates, graduate students and those interested in drug dosage design