HANDBOOK OF PHARMACEUTICAL GRANULATION TECHNOLOGY 4th Edition Dililp M. Parikh


As we prepare this fourth edition of our book, all of us are going through a pandemic caused by Covid-19 worldwide. While we’ve all faced unprecedented challenges this year that we never imagined, this time has underscored the importance of relationships and connectivity, of humanity and kindness, and of strength and resilience. The disaster caused by this virus in terms of human lives lost and the economies of so many countries almost destroyed has affected all of us. Some of the authors were personally affected as well. Despite these difficulties created by the virus, most of the authors have spent valuable time updating or writing new chapters in time. I sincerely appreciate all the hard work of all the authors in making this fourth edition possible. My sincere thanks to all the authors and staff at the publisher Taylor and Francis (Informa Healthcare). 


Handbook Of Pharmaceutical Granulation Technology


The first edition of this book was published in 1997. Before that, most pharmaceutics textbooks devoted a small portion to the granulation unit operation because they were generally focused on retail and hospital pharmacy students and academia. As granulation is a critical unit operation in the manufacture of solid dosage forms, the first edition of this book gave comprehensive treatment to the area of granulation from an industrial perspective. The book appealed not only to members of academia and students of pharmacy and pharmaceutics but also professionals in pharmaceutical and related industries, where agglomerating particles is one of the critical unit operations. Subsequent editions in 2005 and 2009 demonstrated that the book has been able to provide comprehensive coverage of this critical unit operation by updating and adding relevant technologies that provide a knowledge base essential for the pharmaceutics student, academia, researchers, and operational professionals in the industry. During these intervening years, the pharmaceutical industry has endured considerable changes and challenges. The industry is under intense pressure to accelerate the drug development process, shorten the development timelines, and launch new pharmaceutical products. Applications of continuous manufacturing, artificial intelligence (AI), additive printing, or 3D printing are starting to affect product development and manufacturing of pharmaceutical dosage forms. Concurrently, there have been rapid developments in the science of granulation, particle engineering, and process controls, that called for publication of this fourth edition. 

The concept of design space, process optimization, and harmonization of regulations by the global health authorities are being implemented in the industry. The United States and international regulatory bodies are restructuring their oversight of pharmaceutical quality regulation by developing a product quality regulatory system that provides a framework for implementing quality by design, continuous improvement, and risk management. This edition addresses topics generated by these technologies as well as regulatory changes in the unit operation of particle generation and granulation. 

After the introductory chapter, Chapter 2 provides a detailed theory of granulation with an emphasis on the engineering aspect. 

Subsequent chapters are divided into the five following sections: 

Section one “Particle Formation” contains chapter “Drug Substance and Excipient Characterization,” which critically evaluates the techniques, ranging from common to state-of- the-art, employed to analyze individual and bulk properties of particles, (e.g., size, shape, surface area, density, solubility, crystal form, flow, sticking, and microstructure). For greater insight, drug substance-excipient physical (e.g., segregation and compaction) and chemical (e.g., compatibility) interactions are also discussed. The next chapter “Binders in Pharmaceutical Granulation” is important because to agglomerate the primary particles, particles must bond together. The selection and mechanism of binder functionality are detailed in this chapter. Because excipient functionality and their variability can affect the final product attributes as well as a batch-to-batch variability, a new chapter is added “Excipients and Their Attributes in Granulation,” which I am sure the readers will find very helpful in selecting the right excipient for their formulation. The next updated chapter is on the spray drying technology, which is a critical particle formation technology. In keeping to provide the most comprehensive research and development and manufacturing led me to combine two chapters from the third edition on nanotechnology and supercritical technology to present a new chapter “Emerging Particle Engineering Technologies.” This chapter addresses various newer approaches that already have started to have an impact on the pharmaceutical industry in general and the dosage form developments and manufacturing in particular. Electrospinning has emerged as the most viable approach for the fabrication of nanofibers with several beneficial features that are essential to various applications ranging from the environment to biomedicine. Along with the nanotechnology, supercritical fluid technology, the inclusion of 3-D printing, machine learning, and artificial intelligence (AI), and their impact are explored in this chapter. The nanoparticulate technology offers a potential path to the rapid preclinical assessment of poorly soluble drugs. It offers increased bioavailability, improved absorption, reduced toxicity, and the potential for drug targeting. Supercritical fluids have emerged as the basis of a system that optimizes the physicochemical properties of pharmaceutical powders. Three-dimensional printing has set off a true manufacturing transformation, and chemical and pharmaceutical industries are incorporating the technology in their research and development activity as well as commercial manufacturing as can be seen by the US Food and Drug Administration (FDA)-approved products on the market recently. Machine learning and artificial intelligence (AI) are in their infancy as far as how they affect particle generation, but I think it is just the beginning of their impact in pharmaceutical processing since these technologies are revolutionizing every facet of our life and have benefited other areas of the pharmaceutical industry immensely. 

Section two “Granulation Processes” covers the well-established and revised granulation process chapters on roller compaction, fluid bed granulation, single-pot processing, extrusion spheronization as a granulation technique, and continuous granulation. The chapter on wet granulation was completely revised as “Advances in Wet Granulation of Modern Drugs” and includes small molecule granulations as well as therapeutic protein granulation, various formulation strategies, and process technologies involved in producing stabilized granules or powdered therapeutic proteins. The application of AI in the process modeling of high-shear granulation is presented via several case studies in the final section of this chapter. 

Section three “Product-Oriented Granulation” covers technologies specifically addressing the technologies to produce the various dosage forms with specific quality attributes. For example, chapters “Effervescent Granulation,” “Granulation of Plant Products and Nutraceuticals,” Granulation Approaches for Modified Release Products,” “Granulation of Poorly Water-Soluble Drugs,” “Granulation and Production Approaches of Orally Disintegrating Tablets,” and “Melt granulation” are included. All these chapters are updated by well-known researchers and revised to provide cutting-edge information in these areas. 

Section four “Characterization and Scale-Up” provides a critical area of understanding the product. Chapter “Sizing of Granulation” discusses the technique of producing the right particle size for subsequent processing. Next chapter “Granulation Characterization” provides how to evaluate the properties of granulation and characterize it. Chapter “Bioavailability and Granule Properties” discusses the importance of the ideal properties of granules, including its composition and physical attributes, and their impact on the delivery of the active ingredient to the “site of action.” Chapter “Granulation Process Modeling” was substantially rewritten to bring together the new material added into the chapter. There are several benefits from the use of process modeling, such as an increased understanding of the governing mechanisms through endeavoring to represent them in the model description, capturing of insight and knowledge in a mathematically usable form, an increased understanding of the relative importance of mechanistic contributions to the output of the process, and application of the models for improved control performance and process diagnostics. Chapter “Scale-Up Consideration in Granulation” discusses unique challenges in scaling up a process, from a chemical engineering perspective, and understanding through 


considering granulation as a combination of rate processes. Chapter “Advances in Process Controls and End-Point Determination” explores various approaches for monitoring the process. End-point determination of a granulation process is the most prominent concern of any practicing industry professional as well as an academician. Advances on both sensors and surface characterization of powder properties are presented in this chapter. Overall, this chapter provides an overview of the considerable refinement in our quantitative understanding of granulation, based on growing knowledge on materials functionality, advances in measurement science that have advanced process understanding, and granulation techniques used. The revised chapter discusses this very important topic and provides helpful guidance. 

Section five “Optimization Strategies, Tools, and Regulatory Consideration” contains two chapters, namely, “Use of Artificial Intelligence and Expert Systems in Pharmaceutical Applications” and “Regulatory Issues in Granulation: Leading Next-Generation Manufacturing” both focused on optimizing the process. Future success in all areas of pharmaceutical science will depend entirely on how fast pharmaceutical scientists will adapt to the rapidly changing technology. It is common in most formulation development studies that the formulation scientist may have extensive knowledge of the active ingredients and yet still needs to know, which excipients to select, and their proportions. At this stage, a knowledge-based so-called an expert system can be helpful to the scientist in selecting suitable excipients. Another case where such an expert system could be of use in formulation studies is the determination of the design space for manufacturing conditions. Chapter “Use of Artificial Intelligence and Expert Systems in Pharmaceutical Applications” (titled as “Expert Systems and Their Use in Pharmaceutical Application” in the previous edition) discusses developments in this emerging field. As a complement to the US FDA regulations for Good Manufacturing Practices, chapter “Regulatory Issues in Granulation: Leading Next-Generation Manufacturing” (titled as “The Pharmaceutical Quality for the 21st Century – A Risk-Based Approach” in the previous edition), reflects the impact of these regulations. This important topic is critical in building and maintaining the desired quality of a pharmaceutical product. It covers current regulatory guidelines that dictate approaches one needs to take to optimize granulation processing, possibly using an expert system. Optimization of a process has a greater chance of success if the product is developed with Process Analytical Technology (PAT) tools (PAT)and the following Quality by Design (QbD), which the chapter on QbD and PAT addresses with current approaches in the industry 

Over the past 10 years since the last edition of the book was published, there are several changes in regulations worldwide. This manuscript is completely revised to reflect these changes supporting next-generation manufacturing. Specifically:  

ICH Q12 covers pharmaceutical product life cycle management.

FDA guidance on continuous manufacturing issued in Feb 2019 is new and ICH has also just embarked on a similar guideline.

Data integrity is currently a hot topic with regulatory agencies from FDA, EMA, Japan PMDA, and others.

The book includes references to guidance from regulatory agencies such as ANVISA (Brazil) and NMPA (China), indicating the importance of emerging economies in global trade and quality/regulatory expectations.

This book is designed to give readers comprehensive knowledge of the subject. As in the earlier editions, all chapters include an appropriate level of theory on the fundamentals of powder characterization, granulation, and state-of-the-art technologies, modeling, application of expert systems, and manufacturing optimization. 

Pharmaceutical professionals, such as research and development scientists, manufacturing management professionals, process engineers, validation specialists, process specialists, quality assurance, quality control; regulatory professionals; and graduate students in industrial pharmacy  and chemical engineering programs will find the level of theory appropriate and the wealth of practical information from renowned pharmaceutical professionals from respective industry and academia invaluable. The knowledge provided will help select the appropriate granulation technology while keeping in mind regulatory requirements and cost-effectiveness. 

I feel very confident that the assembled experts in their respective field will give the readers fresh and updated information in their respective chapters and readers will be able to use this book as a text or reference or for troubleshooting process problems they may encounter. 

I’d like to thank the authors who contributed to this book despite their busy schedules. All of them are recognized and respected experts in the areas they wrote about. 

I am also thankful to all the equipment manufacturers who graciously granted permission to use their product information and photographs in this book. 

The most appreciation goes to my wife, Leena, who endured many missing evenings and weekends while I worked alone in the office. 

Finally, you, the readers are to be thanked for your support and comments. I trust you will find that the fourth edition of Handbook of Pharmaceutical Granulation Technology continues the high standards as set by its predecessors. As always, I welcome your comments and suggestions for new titles. 

I am very thankful to Jessica Poile and Hillary LaFoe of Informa Healthcare for their guidance and constant inspiration during this endeavor. I am also thankful to Ms. Madhulika Jain Project Manager at MPS and her team for keeping this publication timeline on track with planning and hard work. 

INTRODUCTION 

Solid-dosage forms encompass the largest category of dosage forms that are clinically used. Several types of tablet solid dosage forms are designed to optimize the absorption rate of the drug, increase the ease of administration by the patient, control the rate and site of drug absorption, and mask the taste of a therapeutic agent. This also applies to the capsules of various sizes and various release profiles. The formulation of tablets and capsules involves the use of several components, each of which is present to facilitate the manufacture or to control the biological performance of the dosage form. The practice of delivering medicinal powder by hand rolling into a pill by using honey or sugar has been used for centuries. The delivery of some of the botanical and herbal extracts in homeopathic and ayurvedic branches of medicine by rolling into a pill is still practiced in India along with allopathic medicine. 

Drug Substance  and Excipient Characterization

Characterization of drug substances and excipients is often considered to be in the realm of pre- formulation studies. It is recognized that the quality of finished products is dependent on process intermediates such as granules and certain properties of the raw materials employed. Thus, the characterization of drug substances and excipients is an integral pre-formulation step. Good  knowledge of different test methods is necessary to select the most appropriate methods for the wide range of raw materials. The usefulness of the tests to give relevant information on the properties of the raw materials and their effects on the manufacturing, functionality, and esthetics of the intermediate and finished products should be carefully considered to avoid unnecessary testing and additional cost. This chapter aims to provide an overview of the more important properties of raw materials to granulation and the test methods that are available to evaluate these properties. Readers are strongly encouraged to refer to the appropriate references for an in-depth discussion of the related scientific theories. 

Binders in  Pharmaceutical Granulation

Granulation processes are among the most widely practiced unit processes in oral solid dosage form manufacturing. Granules are an important dosage form in and of themselves; however, most granules are prepared as an intermediate step during tablet and capsule manufacturing. Granulation (also referred to as agglomeration) can be used to improve powder flow properties and reduce fine dust through size enlargement and densification, thus improving tableting operations. Frequently, granulation provides the means to intimately combine a thermoplastic binder with other formulation components, thus improving the compactibility of tablet formulations [1]. In controlled release formulations, granulation is often used to embed the drug in release controlling polymers, thereby retarding dissolution more effectively than a dry blend would. Granulation is also used to prevent powder segregation, thereby ensuring uniform drug distribution. This is especially important in low-dose, high-potency drugs. Lastly, granulation is used to improve the  solubility and dispersibility of powders and tablets in water. This may also be referred to as “instantizing” or “hydrophilizing.” 

Excipients and  Their Attributes in Granulation

Anyone who has ever tried to compress a powder or mixture of powders to form a hard compact probably discovered that not all powders are compactible. What they likely learned is that in many cases, the challenges of making these powders routinely flow into the compaction device, and form a cohesive monolithic structure, required some degree of manipulation of the physical characteristics of the powder. These characteristics ultimately affecting the flowability and com-pactability of the powder mixture include the deformations characteristics of the material, the density, and particle size distribution. Converting powders, which are typically finely divided, and may also be light and fluffy, into denser, larger granules enhances flow and depending on the material characteristics, may enhance compactability as well. The development of modern wet granulation techniques to enable processing of fine powders has opened a window of opportunity to include other benefits that add to the quality of the products produced, such as the inclusion of buffers to modulate the pH of the microenvironment of the tablet itself, or surfactants to enhance the solubility of the drug, as two examples. Many active ingredients used in the production of pharmaceuticals or nutraceuticals are so difficult to process due to their physical characteristics, that they are limited to granulation (wet or dry) as the best or maybe even the only choice for processing into a quality finished product. Just as some of these active ingredients can only be produced using some form of granulation, there are several commonly used inactive ingredients or excipients that have physicochemical characteristics making them perform well and in some cases even enhancing the wet granulation process and resulting product performance. This chapter at-tempts to cover the most widely used and effective excipients for pharmaceutical granulation applications, processed primarily by wet granulation (high-shear, low-shear, and fluid-bed pro-cesses) but also including melt granulation, or by dry granulation (roller-compaction and slugging).

Spray Drying and Pharmaceutical Applications 

Spray drying is one of the oldest forms of drying and one of the fewest technologies available for the transforming of a liquid, slurry, or low-viscosity paste to a dry solid (free-flowing powder) in one-unit operation. The idea of spray drying, consisting of the transformation of feed from a fluid state into a dried particulate form by spraying the feed into a gaseous drying medium, has been expounded for a very long time. The first detailed description of the drying of products in spray form was mentioned in a patent of 1872 entitled “Improvement of Drying and Concentration Liquid Substances by Atomizing” [1]. The spray dryers of that time were primitive devices, and there were problems with the process efficiency, continuous process performance, and process safety, all of which stood in the way of the successful utilization of the spray drying process. However, this process found its first significant applications in the milk and detergent industries in the 1920s [2]. At that time, spray dryer devices underwent a degree of evolution that enabled their use in milk powder production. This was the first industrial application of the spray drying method.



  


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