Pharmaceutical Pelletization Technology 1138477737, 9781138477735

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Pharmaceutical Pelletization Technology

DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Edited by James Swarbrick

School of Pharmacy University of North Carolina Chapel Hill, North Carolina

Volume 1.

PHARMACOK INETICS, Milo Gibaldi and Donald Perrier (out of print)

Volume 2.

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS: A PLAN FOR TOTAL QUALITY CONTROL, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV (out of print)

Volume 3.

MICROENCAPSULATION, edited by J. R. Nixon

Volume 4.

DRUG METABOLISM: CHEMICAL AND BIOCHEMICAL ASPECTS, Bernard Testa and Peter Jenner

Volume 5.

NEW DRUGS: DISCOVERY AND DEVELOPMENT, edited by Alan A. Rubin

Volume 6.

SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS, edited by Joseph R. Robinson

Volume 7.

MODERN PHARMACEUTICS, edited by Gilbert S. Banker and Christopher T. Rhodes

Volume 8.

PRESCRIPTION DRUGS IN SHORT SUPPLY: CASE HISTORIES, Michael A. Schwartz

Volume 9.

ACTIVATED CHARCOAL: ANTIDOTAL AND OTHER MEDICAL USES, David 0. Cooney

Volume 10. CONCEPTS IN DRUG METABOLISM (in two parts), edited by Peter Jenner and Bernard Testa Volume 11. PHARMACEUTICAL ANALYSIS: MODERN METHODS (in two parts), edited by James W. Munson Volume 12. TECHNIQUES OF SOLUBILIZATION OF DRUGS, edited by Samuel H. Yalkowsky

Volume 13. ORPHAN DRUGS.edited by Fred E. Karch Volume 14. NOVEL DRUG DELIVERY SYSTEMS: FUNDAMENTALS, DEVELOPMENTAL CONCEPTS, BIOMEDICAL ASSESSMENTS, edited by Yie W. Chien Volume 15.

PHARMACOKINETICS, Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier

Volume 16.

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS: A PLAN FOR TOTAL QUALITY CONTROL, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

Volume 17.

FORMULATION OF VETERINARY DOSAGE FORMS.edited by Jack Blodinger

Volume 18. DERMATOLOGICAL FORMULATIONS: PERCUTANEOUS ABSORPTION, Brian W, Barry Volume 19. THE CLINICAL RESEARCH PROCESS IN THE PHARMACEUTICAL INDUSTRY, edited by Gary M. Matoren Volume 20.

MICROENCAPSULATION AND RELATED DRUG PROCESSES, Patrick 8. Deasy

Volume 21.

DRUGS AND NUTRIENTS: THE INTERACTIVE EFFECTS, edited by Daphne A. Roe and T. Colin Campbell

Volume 22.

BIOTECHNOLOGY OF INDUSTRIAL ANTIBIOTICS, Erick J. Vandamme

Volume 23.

PHARMACEUTICAL PROCESS VALi DATION, edited by Bernard T. Loftus and Robert A. Nash

Volume 24.

ANTICANCER AND INTERFERON AGENTS: SYNTHESIS AND PROPERTIES, edited by Raphael M. Ottenbrite and George 8. Butler

Volume 25.

PHARMACEUTICAL STATISTICS: PRACTICAL AND CLINICAL APPLICATIONS, Sanford Bolton

Volume 26.

DRUG DYNAMICS FOR ANALYTICAL, CLINICAL, AND BIOLOGICAL CHEMISTS, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz

Volume 27.

MODERN ANALYSIS OF ANTIBIOTICS, edited by Adorjan Aszalos

Volume 28. SOLUBILITY AND RELATED PROPERTIES, Kenneth C. James Volume 29. CONTROLLED DRUG DELIVERY: FUNDAMENTALS AND APPLICATIONS, Second Edition, Revised and Expanded, edited by Joseph R. Robinson and Vincent H. L. Lee Volume 30. NEW DRUG APPROVAL PROCESS: CLINICAL AND REGULATORY MANAGEMENT, edited by Richard A. Guarino Volume 31. TRANSDERMAL CONTROLLED SYSTEMIC MEDICATIONS, edited by Yie W. Chien Volume 32. DRUG DELIVERY DEVICES: FUNDAMENTALS AND APPLICATIONS, edited by Praveen Tyle Volume 33.

PHARMACOKINETICS: REGULATORY· INDUSTRIAL· ACADEMIC PERSPECTIVES, edited by Peter G. Welling and Francis L. S. Tse

Volume 34.

CLINICAL DRUG TRIALS AND TRIBULATIONS, edited by Allen E. Cato

Volume 35. TRANSDERMAL DRUG DELIVERY: DEVELOPMENTAL ISSUES AND RESEARCH INITIATIVES, edited by Jonathan Hadgraft and Richard H. Guy Volume 36. AQUEOUS POLYMERIC COATINGS FOR PHARMACEUTICAL DOSAGE FORMS, edited by James W. McGinity Volume 37. PHARMACEUTICAL PELLETIZATION TECHNOLOGY, edited by Isaac Ghebre-Sellassie Volume 38. GOOD LABORATORY PRACTICE REGULATIONS, edited by Allen F. Hirsch Volume 39. NASAL SYSTEMIC DRUG DELIVERY, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang Additional Volumes in Preparation MODERN PHARMACEUTICS, Second Edition, edited by Gilbert S. Banker and Christopher T. Rhodes

Pharmaceutical Pelletization Technology

edited by

Isaac Ghebre-Sellassie

Parke-Davis Pharmaceutical Research Division Warner-Lambert Company Morris Plains, New Jersey

v~ CRC Press

Taylor & Francis Group Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2010 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works ISBN-13: 9780824780852 (hbk) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Pharmaceutical pelletization technology / edited by Isaac Ghebre-Sellassie p. ; cm. -- (Drugs and the pharmaceutical sceinces ; v. 37) Includes index. ISBN-13: 978-0-8247-8085-2 (alk. paper) ISBN-10: 0-8247-8085-X (alk. paper) 1. Pelletizing. 2. Pharmaceutical technology. I. Ghebre-Sellassie, Issac. II. Series. [DNLM: 1. Dosage Forms. 2. Drug Industry. 3. Technology, Pharmaceutical. W1 DR893B v. 37 / QV 785 P5355] RS199.P36P47 1989 615'.19--dc20

Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

DOI: 10.1201/9781003066231

89-7771

Preface

Spherical oral dosage forms such as pills have been used in the pharmaceutical industry for a long time, but the full impact of systematically agglomerated spherical units or pellets on oral dosage form design and performance was not realized until the early 1950s, when attempts were made to develop extended release products. Since then, the manufacture of pellets has been the subject of intensive research, in terms of both innovative formulations and processing equipment. Consequently, the number of pelletized products available to health professionals and the public at large has been increasing steadily. The trend is expected to continue well into the twenty-first century. In spite of the current popularity of pellets in dosage form design and development, a systematic and organized description of the various formulation routes and pelletization processes pertinent to the pharmaceutical industry is practically nonexistent. Except for a few articles, the available literature on the subject deals with the food, confectionary, veterinary, agricultural, and chemical industries. The objective of this book is, therefore, not only to serve as a formulation and processing guide during the development of pelletized dosage forms, but also to provide the pharmaceutical technologist with basic information about the design aspects of the relevant processing equipment. Chapter 1 gives a general overview of pellet technology and discusses the historical development of pellets and pelletization processes, the factors that impact upon the fabrication of pelletized dosage forms, and the classification of pharmaceutical pelletization processes. General descriptions of the design features

iii

iv I Preface of the most widely used processing equipment-coating pans, fluid-bed machines, extruders /spheronizers, and centrifugal equipment-are covered in Chapters 2 through 5, and each of these four chapters provides a list of the suppliers of the various pieces of equipment. Chapter 6 describes the physical and mechanical forces that govern the mechanism of pellet formation and growth during a given pelletization process. Chapters 7 through 9 are devoted to a thorough discussion of the most popular pelletization processes available to the pharmaceutical industry. Included are descriptions of the critical processing variables during solution/suspension layering, powder layering, and extrusion /spheronization. Formulation variables are discussed in Chapter 10. Although a few excipients are mentioned in relation to some specific processes in order to highlight certain functions, the main thrust of the chapter is description of the functions of excipients in general terms. Practical examples of pellet formulations and processing conditions are given to underscore the role of formulation components during the manufacture of drug-loaded pellets. Chapter 11 describes the techniques that are utilized to evaluate and characterize pellets prior to the start of other unit operations in the dosage form development sequence. The material discussed in the book covers the various areas that are pertinent to the successful development of pelletized pharmaceutical products and is expected to lay the groundwork for further refinement and optimization of modern pelletization processes. It must be emphasized, however, that the book is limited to the processes and equipment relevant to the manufacture of core pellets, and does not address in detail the coating, encapsulation, or compression of pellets. I would like to thank all those who helped in different ways during the preparation of the book, in particular, the authors of the various chapters, who graciously volunteered their leisure time to make the publication of this book a reality. Thanks also to Dr. Mahdi B. Fawzi and Dr. Russell U. Nesbitt, respectively, Vice President and Director, Product Development, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, for their support and encouragement. Moreover, I am very grateful to my colleagues at Parke- Davis for their constructive suggestions and to Mrs. Ruth G. Cohnstein, who did a superb job of typing the manuscript.

Isaac Ghebre-Sellassie

Contents

Preface Contributors

iii vii

1.

Pellets: A General Overview Isaac Ghebre-Sellassie

2.

Conventional and Specialized Coating Pans Walter G. Chambliss

15

3.

Fluid Bed Equipment Kenneth W. Olsen

39

4.

Extrusion and Spheronizing Equipment Douglas C. Hicks and Howard L. Freese

71

5.

Centrifugal Equipment Frank W. Goodhart

101

6.

Mechanism of Pellet Formation and Growth Isaac Ghebre-Sellassie

123

7.

Solution and Suspension Layering David M. Jones

145

8.

Dry Powder Layering Frank W. Goodhart and Steve Jan

165

9.

Extrusion and Spheronization Technology Robert E. O'Connor and Joseph B. Schwartz

187

10.

Formulation Variables Michael R. Harris and Isaac Ghebre-Sellassie

217

V

vi 11.

I Contents Evaluation and Characterization of Pellets Atul M. Mehta

Index

241

267

Contributors

Walter G. Chambliss* Bristol-Meyers, Evansville, Indiana Howard L. Freese

LUWA Corporation, Charlotte, North Carolina

Isaac Ghebre-Sellassie Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Morris Plains, New Jersey Frank W. Goodhart Parke-Davis Pharmaceutical Research Division, Warner- Lambert Comp any, Morris Plains, New Jersey Michael R. Harris Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Morris Plains, New Jersey Douglas C. Hicks

LUWA Corporation, Charlotte, North Carolina

Steve Jan Parke- Davis Pharmaceutical Research Division, Warner- Lambert Company, Morris Plains, New Jersey David M. Jones

Jersey

Glatt Air Techniques, Inc. , Ramsey, New

Atul M. Mehta Nortec Development Associates, Inc., Ramsey, New Jersey Robert E. O'Connor Philadelphia College of Pharmacy and Science, Philadelphia, Pennsylvania

Kenneth W. Olsen Jersey

Glatt Air Techniques, Inc., Ramsey, New

Joseph B. Schwartz Philadelphia College of Pharmacy and Science, Philadelphia, Pennsylvania

*Current affiliation: Consumer Operations, Schering-Plough, Memphis, Tennessee. vii

Pharmaceutical Pelletization Technology

Pellets: A General Ovetview ISAAC GHEBRE-SELLASSIE Plains, New Jersey

I.

Warner-Lambert Company, Morris

DEFINITION

Traditionally, the word "pellet" has been used to describe a variety of systematically produced, geometrically defined agglomerates obtained from diverse starting materials utilizing different processing conditions. These products may be fertilizers, animal feeds, iron ores, or pharmaceutical dosage forms, to mention but a few. It is appropriate, therefore, at the outset to define the words "pellet" and "pelletization" in the context in which they are used in the book in order to avoid confusion. Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units, referred to as pellets. Pellets range in size, typically, between O. 5-1. 5 mm, though other sizes could be prepared, depending on the processing technologies employed. The most widely used pelletization processes in the pharmaceutical industry are extrusion/spheronization, solution/ suspension layering, and powder layering. Each of these processes is discussed in detail later in the book and need not be defined here. Other processes with limited application in the development of pharmaceutical pelletized products include globulation, balling, and compression (Figure 1) and are briefly described below . Globulation or droplet formation describes the two related processes of spray drying and spray congealing [ 1] . During spray drying, drug entities in solution or in suspension form are sprayed, with or without excipients, into a hot-air stream DOI: 10.1201/9781003066231-1

1

""'

'(;')

;:r' (I)

O"

~

I Cl)

(I)

PELLETIZATION

s

I I I I

AGITATION

BALLING

FIGURE

~-

I I

I

I I I I I

Cl) Cl)

COMPACTION

LAYERING

I I I

COMPRESS ION

I I

GLOBULATION

I

I

I I

EXTRUSION/ SPHERONIZATION

Classification of pellitization processes.

I

I I I

POWDER

I I I

SOLUTION/ SUSPENSION

(From Ref. 1.)

I

I I

SPRAY DRYING

I I I

SPRAY CONGEALING

Pellets:

A General Overview I 3

to generate dry and highly spherical particles. Though the technique is suitable for the development of controlled -release pellets, it is generally employed to improve the dissolution rates and, hence, bioavailability of poorly soluble drugs. Spray drying has been used for years for a variety of reasons. Consequently, the literature is replete with descriptions of both process and equipment. Spray congealing is a process in which a drug is allowed to melt, disperse, or dissolve in hot melts of gums, waxes, fatty acids, etc. , and is sprayed into an air chamber where the tern perature is below the melting points of the formulation components, to provide, under appropriate processing conditions, spherical congealed pellets. Depending on the physicochemical properties of the ingredients and other formulation variables, pellets with immediate- or controlled-release behavior can be produced. Compression is a pelletization process in which mixtures or blends of active ingredients and excipients are compacted under pressure to generate pellets of defined shape and size. The pellets are small enough to be filled into capsules. The formulation and processing variables that govern the production of pellets during compression are similar to those that are routinely employed in tablet manufacturing. In fact, pellets produced by compression are nothing but small tablets that are approximately spheroidal in shape. Balling describes a pelletization process in which finely divided particles are converted, upon the addition of appropriate quantities of liquid, to spherical particles by a continuous rolling or tumbling motion. The liquid may be added prior to or during the agitation stage. Pans, discs, drums, or mixers may be used to produce pellets by the balling process. II.

HISTORICAL DEVELOPMENT

Although various industries have routinely utilized pelletization processes since the turn of the century to manufacture particles with defined sizes and shapes, it was only in the early 1950s, in response to a desire to sustain the release of drugs over extended periods of time, that the pharmaceutical industry developed a keen interest in the technology. Pellet-based extendedrelease products initially employed conventional pills [ 2] . Pills of different release profiles were combined in predetermined proportions and encapsulated in hard gelatin capsules to produce

4 I Ghebre-Sellassie

sustained-release oral dosage forms. However, the number of pills that could be filled into a single capsule was limited, and the duration of release could not be extended beyond a few hours [ 2] . In addition, the manufacturing process of the pills was cumbersome and labor-intensive. It also required experienced artisans to do the job, thereby making the process an art rather than a science. As the processing equipment got more sophisticated, tablet machines that were capable of producing thousands of tablets in a matter of minutes became available. However, in spite of the tremendous strides made in reducing processing times and perfecting the technology that led to the production of minitablets suitable for encapsulation, the approach did not alleviate the size limitation that was encountered during the development of pills-based sustained-release products. That is, the volume that could be made and the number of pellets that could be filled into a capsule were prohihitively small. Con sequently, extensive research was conducted to develop alternative techniques to provide pelletized dosage forms that exhibit extended-release properties. A major breakthrough occurred in 1949 when a pharmaceutical scientist at Smith Kline & French (SKF) realized the potential application of candy seeds in sustained-release preparations and embarked on the development of tiny drug pellets that could be loaded into capsules [ 2] . The candy seeds were nothing but small sugar particles that were used for topping decorations on pastries and related foodstuffs, and were prepared by a process, at the time, unknown to the pharmaceutical industry. However, in 1951 a landmark paper, which described in detail the manufacturing process of the seeds, appeared in the Confectioners Journal and revolutionized the production of pelletized products [ 3]. The process utilized standard coating pans and involved successive layering of powder and binder on sugar granules un til spherical seeds of the desired size were obtained. The process was lengthy and required days to be completed. It, nevertheless, spearheaded a new era and provided the basis for the development of future pelletization processes. Not only was the process directly applicable to drug candidates, but also the candy seeds or nonpareils, which are inert and innocuous, functioned as starter seeds upon which drugs were layered, with or without sustaining materials. During the early days, the technology was refined and perfected by SKF and was applied to a number of its prescription drugs, for which the company received a series of patents [4-6]. It was, however, the major success of the long-acting cold remedy, Contac, that partially

Pellets:

A General Overview I 5

fueled a renewed interest in the development of extended-release pelletized products [ 2]. While substantial effort was made to further improve and refine the existing pelletization techniques, major resources were also allocated toward exploring alternative methods that were faster, cheaper, and more efficeint, both in terms of formulations and processing equipment. In 1964, a new pelletization technique that provided sustained-release pellets ranging in size between O. 25- 2. 0 mm was patented by SKF [ 7] . It comprised a spray congealing process in which the drugs were dissolved or dispersed in a lipid material in the molten state to form a slurry, followed by atomiza tion of the slurry into a low-temperature gas chamber until spherical congealed pellets were produced. The sizes of the pellets obtained from a given formulation and a set of processing conditions were determined by the nozzle orifice. The pellets were manufactured in a spray dryer, a piece of equipment that already had a wide application in the industry. At about the same time, the Marumerizer was commercially introduced. This new machine was developed in Japan and could produce large quantities of spherical pellets in a relatively short time. The Marumerizer and variations of it were subsequently patented in the United States [ 8-10] . Basically, the process involves extrusion of a wetted mass of a mixture of active ingredients and excipients to provide cylindrical segments or extrudates followed by spheronization of the extrudates in the Marumerizer or Spheronizer. Extruders and spheronizers, which are the main pieces of equipment employed for this process, are described at length in Chapter 4. Suffice it to say that the emergence of the process as a practical pelletization technique enhanced the status of pellets in pharmaceutical drug dosage form development. The process is capable of producing pellets containing more than 90% active, provided that the physicochemical properties of the drug and other formulation consti tuents are optimum. Direct pharmaceutical applications of the process for the development of pellets were first published in the literature in the early 1970s [ 11-14] and the process has been the subject of intensive research ever since. As drug delivery systems became more sophisticated, the role of pellets in drug dosage form design and development increased substantially, and both manufacturers of processing equipment and private investigators have intensified their search for highly efficient processing equipment in order to accommodate the increased demand. Not only are already existing pieces of equipment being continuously improved upon, but also new de-

6 I Ghebre-Sellassie signs are reaching the market at an increasing rate. is expected to continue in the foreseeable future. Ill.

The trend

RATIONALE FOR PELLETIZATION

Pellets are of great interest to the pharmaceutical industry for a variety of reasons. Pelletized products not only offer flexibility in dosage form design and development, but are also util ized to improve the safety and efficacy of bioactive agents. However, the single most important factor responsible for the proliferation of pelletized products is the popularity of controlledrelease technology in the delivery of drugs. When pellets containing the active ingredient are administered in vivo in the form of suspensions, capsules, or disintegrating tablets, they offer significant therapeutic advantages over singleunit dosage forms [ 15] . Because pellets disperse freely in the gastrointestinal tract, they invariably maximize drug absorption, reduce peak plasma fluctuations, and minimize potential side effects without appreciably lowering drug bioavailability. Pellets also reduce variations in gastric emptying rates and overall transit times. Thus, intra- and inter-subject variability of plasma profiles, which are common with single-unit regimens, are minimized. Another advantage of pellets over single-unit dosage forms is that high local concentrations of bioactive agents, which may inherently be irritative or anesthetic, can be avoided. When formulated as modified-release dosage forms, pellets are less susceptible to dose dumping than the reservoir-type, singleunit formulations. Controlled-release pellets are manufactured either to deliver the bioactive agent at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time. While these results have been traditionally achieved through the application of a functional coating material, at times the core pellets themselves have been modified to provide the desired effect. In vivo experiments involving ileostomy patients showed that the average transit time of pellets in the intestine increased with an increase in the specific weight or density of the pellets [ 16]. Although the findings have yet to be substantiated using healthy subjects, and there has been a report to the contrary [ 17] , the studies were able to stimulate considerable interest and further enhanced the role of pellets in oral dosage form development. As a result, a number of studies aimed at prolonging the gastrointestinal transit time of pellets, and, hence,

Pellets:

A General Overview I 7

the duration of action of a bioactive agent through the modification of the surface property or core of pellets have been conducted [18, 19]. Pellets also provide the pharmaceutical scientist with tremendous flexibility during the development of oral dosage forms. For instance, pellets composed of different drug entities can be blended and formulated in a single dosage form. Such an approach has numerous advantages. It allows the combined delivery of two or more bioactive agents, that may or may not be chemically compatible, at the same site or at different sites within the gastrointestinal tract. It also permits the combination of pellets of different release rates of the same drug in a single dosage form. In addition, pellets have a low surface area-tovolume ratio and provide an ideal shape for the application of film coatings. Because pellets flow and pack freely, it is not difficult to obtain uniform and reproducible fill weights in capsules, provided that the size and densities of the pellets are favorable. Pellets can also be made attractive due to the various shades of color that can easily be imparted to them during the manufacturing process. IV.

MANUFACTURING CONSIDERATIONS

Whenever pellets are considered as vehicles for the delivery of drugs, there are certain manufacturing constraints that must be examined before a decision for production is made. Production of pellets generally involves expensive processes or highly specialized equipment. Equipment, which is readily available in a given setting due to its suitability for other applications such as coating, tends to obviate the need for the purchase of a new and specialized machine. Pellets could be prepared in the same equipment, with or without modification. Unfortunately, except in special cases, the pelletization processes are usually lengthy and expensive. Processing of a single batch may sometimes require hours or even days to be completed. As a result, the processing cost incurred offsets the savings made due to the availability of equipment, and boosts the overall manufacturing cost. Conversely, if a short processing time is desired, it becomes mandatory to utilize highly efficient and, at times, unique pieces of equipment that require the allocation of substantial capital investment. Extruders, spheronizers, and rotor granulators fall under this category. Formulation variables should, therefore, be manipulated to accommodate the availability of the equipment and the cost-effectiveness of the process.

8 I Ghebre-Sellassie

Another processing step that heavily impacts on the successful development of pelletized products is coating of the newly formed drug pellets. Although pellets could conceivably be coated in any tablet coating equipment, they generally require specialized coating machinery for optimum processability, whether the intent of the coating is for aesthetic, identification, or controlled release purposes. Therefore, accessability of the relevant coating equipment should be assessed before a decision is made to develop pelletized products. Since the performance of the coated product is dictated by the surface morphology, shape, and composition of the core pellets, drug pellets that possess surface properties optimum for the application of coherent films must be selected. Finally, pellets must be encapsulated in the appropriate sizes of hard-gelatin capsules or compressed into tablets before they are packaged for distribution. Irrespective of the pelletization process, pellets are not uniform in size and generally represent a narrow mesh fraction. These pellets may be coated with functional membranes to provide the target release profiles. They may also be blended with other pellets to generate a unique release profile or to produce combination products. Placebo pellets may also be added to active pellets to adjust for potency. It is obvious, therefore, that attaining content-uniformity and reproducibility could be a serious problem, especially if segregation occurs. Segregation occurs whenever a homogeneous blend of pellets is subjected to any kind of vibration. It is primarily induced by differences in size or density. Lighter or larger pellets tend to float at or near the top of the pellet mass, thereby severely altering the uniformity of the pellet blend and causing variability in the drug content or potency of the dosage form. Segregation resulting from differences in size and density is overcome if a narrow mesh cut of pellets that have similar den sities is employed. While it is relatively easy to manufacture active pellets of the same densities, it may be difficult to prepare active and placebo pellets that have identical densities. In that instance, differences in densities may be compensated for by blending the active pellets with slightly larger or smaller placebo pellets, as the case may be [ 20]. Other factors that lead to segregation are static electricity and surface morphology. Static electricity may be generated during the blending process as a result of interparticle friction and may cause the particles to segregate. Similarly, if the surface of the pellets is rough and uneven, it is almost impossible

Pellets:

A General Overview I 9

to achieve uniform blending, particularly when the pellets are mixed with smoother pellets. Both of these problems, however, may be overcome by the addition of a small amount of separating agents, such as talc or magnesium stearate [ 20] . An important variable, which is not directly related to the factors that promote segregation and yet may determine the success or failure of an encapsulated pelletized dosage form, is the drug content of individual pellets. If the drug content of the pellets is very high, it may be extremely difficult to maintain content uniformity in the final dosage form, especially when dealing with potent drugs. Loss of a few pellets during the encapsulation process is likely to be accompanied by a significant loss in potency. It is imperative, therefore, that pellets containing potent drugs should contain extremely low quantities of active, with the bulk of the pellet weight being composed of inert excipients, as dictated by the intended capsule size.

V.

MARKETED PELLET PRODUCTS

In spite of the specialized processing equipment required and the high cost of the pelletization processes involved, the use of pellets in the development of oral dosage forms has steadily been increasing in popularity. While pellets are considered as poten tial delivery systems for new chemical entities, they are predominantly utilized for products already in the market. Pellet products not only possess the advantages cited earlier, but they also appear to have an edge in marketability over other solid dosage forms. Other factors that have led to the wide use of pellets during dosage form development include ( 1) the passage of legislation that allows companies to have exclusivity for a period of three years for the marketing of uniquely formulated products and (2) the long approval time required for the introduction of new chemical entities into the market. These realities, coupled with generic competition, have forced management of research- based drug companies to include the development of pellet products in their strategic plans. As a result, capsule and tablet dosage forms, whenever applicable, are being replaced by pellets at an increasing rate. At present, there are a number of products that utilize pellets as delivery systems. A partial list of these products is given in Table 1.

10 I Ghebre-Sellassie

TAB LE 1

Partial List of Pellet Products

Product

Company

Bontril SR

Carnrick Laboratories, Inc.

Brexin L.A.

Savage Laboratories

Catazyme S

Organon Pharmaceuticals

Combid

Smith Kline

Comhist L.A.

Norwich Eaton

Compazine

Smith Kline

Dilatrate S. R.

Reed and Carnrick

Duotrate

Marion Laboratories

Elixophylline

Berlex Laboratories

Eryc

Parke-Davis

Fastin

Beecham Laboratories

Fedahist

Kremers-Urban

Fergon

Winthrop-Breon

Hispril

Smith Kline

Inderal L.A.

Ayerst Laboratories

Indocrin S . R.

Merck Sharp

Isordil Tembids

Ives Laboratories

Levsine

Kremers-Urban

Melfiat

Reid - Rowell

Nicobid T . S.

U . S . Vitamin

Nitrobid S . R.

Marion Laboratories, Inc.

Nitrostat S . R.

Parke-Davis

Novafed L.A.

Merrel-Dow

Ornade

Smith Kline

Papaverine HCl, T .D.

Lederle Laboratories

Russ-Tuss

Boots Pharmaceuticals

Slow-bid

Rorer

French

&

Fench

&

French

&

&

&

Dohme

French

Pellets: TABLE 1

A General Overview I 11

(Continued)

Product

Company

Sudafed S.A.

Burroughs-Wellcome

Temaril

Herbert Laboratories

Theo-24

Searle Pharmaceuticals, Inc.

Theobid S .R.

Glaxo

Theoclear L.A.

Central Pharmaceuticals

Theodur S. R.

Key Pharmaceuticals

Tuss-ornade

Smith Kline

VI.

&

French

SUMMARY

Since the concept of multiple-unit formulations for controlledrelease applications was initially introduced in the late 1940s and early 1950s, the technology for the manufacture of pellets has evolved from an art that was practiced by a few skilled artisans to what is now a well-controlled and even automated process performed in highly specialized and efficient pieces of equipment. Processing times have been reduced from days to hours and production-size batches are routinely manufactured in very short periods of time. As the application of pellets in the development of oral dosage forms increases, so does our understanding of the basic principles governing pellet formation and growth. Critical process and formation variables are being systematically evaluated and characterized. Consequently, general processing conditions are being adapted to fit to specific manufacturing needs. Because of their unique properties and the flexibility of the manufacturing processes involved, pellets are expected to continue to play a major role in the design and fabrication of solid dosage forms . REFERENCES

1.

P. J. Sherrington and R. Oliver, Globulation processes, in Granulation, Heyden and Son Ltd., London, pp. 118-140 (1981).

12 I Ghebre-Sellassie

2.

Special Delivery:

Advances in drug therapy, The Research

News, University of Michigan, p. 1 (1986).

3.

L. E. Cimicata, How to manufacture and polish smallest pan goods-nonpareil seeds, Confectioners J., 41-43 (January 1951).

4.

R. H. Blythe, U.S. Patent 2,783,303 (March 1956).

5.

D. R. Reese, M. Station, and J. V. Swintosky, U.S. Patent 2,921,883 (January 1960).

6.

K. R. Heimlich and D. R. MacDonnel, U.S. Patent 3,119,742 (January 1964).

7.

R. J. Lautz and M. J. Robinson, U.S. Patent 3,146,167 (August 1964).

8.

N. Nakahara, U.S. Patent 3,277,520 (June 1966).

9.

N. Moriya, U.S. Patent 3,579,719 (May 1971).

10.

N. Moriya, U.S. Patent 3,584,334 (June 1971).

11.

J. W. Conine and H . R. Hadley, Preparation of small solid pharmaceutical spheres, Drug and Cosmet. Ind., 90: 38-41 ( 1970).

12.

C. W. Woodruff and N. 0. Nuessle, Effect of processing variables on particles obtained by extrusion-spheronization processing, J. Pharm. Sci., 61:787-790 (1972).

13.

I. M. Jalal, H. J. Malinowski, and W. E. Smith, Tablet granulations composed of spherical-shaped particles, J. Pharm. Sci., 61: 1466-1468 (1972).

14.

H. J. Malinowski and W. E. Smith, Effects of spheronization process variables on selected tablet properties, J. Ph arm. Sci., 63:285-288 (1974).

15.

H. Bechgaard and G. H. Nielson, Controlled release multiple units and single-unit doses, Drug, Dev. Ind. Ph arm., 4: 53-67 (1978).

16.

H. Bechgaard and K. Ladefoged, Distribution of pellets in the gastrointestinal tract. The influence on transit time exerted by the density or diameter of pellets, J. Ph arm. Pharmac. , 30: 690- 692 ( 1978).

17.

S. S. Davis, A. F. Stockwell, M. J. Taylor, J. C. Hardy, D. R. Whalley, 0. G. Wilson, H. Bechgaard, and F. N. Christensen, The effect of density on the gastric emptying

Pellets:

A General Overview

I 13

of single- and multiple-unit dosage forms, Pharm. Res., 3: 208-213 (1986). 18.

H. Bechgaard, Distribution of different types of dosage forms in the gastrointestinal tract, in Topics in Pharmaceutical Sciences (D. A. Bremer and P. Speiser, eds.), Elsevier, New York (1983).

19.

R. Groning and G. Henn, Oral dosage forms with controlled gastrointestinal transit, Drug Dev. Ind. Pharm., 10: 527539 (1984).

20.

Blending, capsule-filling, and storage of Duffucap and Chronodrug pellets, Product Manual, Eurand America.

Conventional and Specialized Coating Pans WALTER G. CHAMBLISS*

I.

Bristol-Myers, Evansville, Indiana

INTRODUCTION

Coating pans have been used in pharmaceutical coating operations since the early 19th century when they were used extensively for sugar coating. Blythe described the first pelletization process in the coating pan in a patent issued in 1956 [ 1). As coating technology progressed from sugar to solvent to aqueous film coating, the coating pan evolved to meet the increased demands. Rear- and side-vented pans, for example, were developed to enhance the airflow, and process control systems were added. These and other adaptations have significantly improved tablet coating operations, but not pelletization. Al though McAinsh and Rowe [ 2) described the use of a side-vented pan for pellet coating in a patent issued in 1979, most pelletization processes today rely on the same basic equipment used in the 19th century. This chapter contains information on both conventional and modified (side- and rear-vented) coating pans. The conventional pan is emphasized because the vast majority of companies involved in pelletization processes use this type of equipment. 11.

EQUIPMENT DESCRIPTION

A.

Conventional Coating Pans

Conventional coating pans are used extensively in pelletization processes for several reasons. Companies may want to take ad*Current affiliation: Consumer operations, Schering-Plough, Memphis, Tennessee. DOI: 10.1201/9781003066231-2

15

16 I Chambliss

vantage of available capacity in pans used for sugar coating, film coating, or capsule polishing operations. Economics may be a consideration if new equipment must be purchased because conventional coating pans are less expensive than most other types of pelletization equipment. Conventional pans are also extremely versatile in that both drug layering and pellet coating are possible. Modified coating pans, on the other hand, are not used as extensively because the perforations exclude the use of dry powders. Although conventional pans are less expensive to purchase than most other types of pelletization equipment, the lower purchase price may be offset by higher labor costs, longer processing times, and lower yields. The most serious disadvantage of the conventional coating pan process is the lack of process control. Although attempts, which will be discussed later, have been made to automate the equipment, the pelletization process remains very difficult to develop , and even more difficult to validate. Despite the advances that have been made for tablet coating processes in coating pans, pelletization-like sugar coating-remains a pharmaceutical art. Unlike sugar coating operations, where batch-to-batch variability may be acceptable, reproducibility in pelletization is critical and must be controlled. A typical conventional pan installation for pelletization is shown in Figure 1. The basic components are the rotating pan, air-supply system, spray system, and powder-addition system. Each of these components is discussed below.

Rotating Pans Coating pans are available in a wide variety of shapes and sizes. Pear, hexagonal, angular, spherical, elliptical, and donut-shaped pans can be purchased in sizes ranging from 6- 90 inches in diameter. The pan may be jacketed if needed. Many suppliers will custom-fabricate coating pans to the buyer's specifications. The shape, size, tilt angle from the horizontal, and rotation speed of the pan, as well as the load size, influence the mixing efficiency and, therefore, must be considered during process development studies [ 3-6] . Pellet movement is best described as cascading, with maximum turbulence in the center of the load. Dead spots can form at the front and back of the pan, and it is not uncommon to see large or agglomerated particles riding along the perimeter of the pan. Elliptical pans have fewer stagnant areas than cylindrical pans, but dead spots will form at both ends of the vortex that occurs at the mouth of the pan. A re-

Coating p ans

FIGURE 1

Schematic of a conventional coatmg .

duction of the .

a

I

17

.

p n mstallation

thes;.mce deadthe spo::\ ;~gle from 450 to 250 reported! • · ticles will tendsurfac~s of most y mlldmi,es

the pan, that . to slide. Mixin pans are smooth the walls with':,; roughening ,/:e action is enha~O:!herical par· e coating solutionsurface of the and th en by. "prepping" sp raying . dust·pa n by mg with the ac-

18 I Chambliss

FIGURE 2 Partially coated microcapsule cores in a roughened coating pan. (From Ref. 3, p. 153.)

tive drug powder or an inert dusting powder [ 3] . The inside of a roughened pan is shown in Figure 2. Baffles of various sizes and shapes may also be used to enhance the mixing action.

Air-Supply Systems Conventional pans are normally equipped with both drying and exhaust-air lines. The airflow is very inefficient since all of the air ducts are located in the front opening of the pan. Hot air is used in many pellet coating processes to facilitate solvent evaporation. Hot supply air is usually used in intermittent pelletization processes to dry the pellets between spray intervals. The supply air duct should be positioned close to the bottom of the cascading bed. The pellets, however, may have to be re-

Coating Pans I 19

moved from the pan for drying in an oven or fluid bed dryer to minimize residual moistures levels, or to cure the product. Drying air may not be needed in continuous pelletization processes if bed equilibrium can be maintained by balancing the solution and powder addition rates. An advantage of not using drying air is that less dust is generated during the drug layering process. Adequate exhaust air, on the other hand, is vital. The exhaust must keep dust and solvents from escaping into the area surrounding the pan. The exhaust duct should be situated in the upper third of the pan. The exhaust airflow rate has a direct effect on the wetness of the bed, and, therefore, on the spray and powder application rates. The dissolution rate of controlled-release pellets is also affected by the exhaust airflow rate, possibly due to an effect on the surface morphology. The exhaust airflow rate should, therefore, be set at a fixed level such as 450- 650 CFM. The flow rate should be at least twice the drying airflow rate. If several pans share a main exhaust line, the airflow in each pan must be standardized. The exhaust system may be as simple as a single flexible duct inserted into the pan, or more elaborate, as shown by the schematic in Figure 3 in which the pan opening is surrounded by an exhaust plenum. Exhaust air, drawn through ducts by a fan, is usually vented outside the building after passing through a dust collector. A solvent recovery system may be added if economically justified or required by environmental regulations. Air exchange in a conventional pan can be improved by the use of a Strunck Immersion Tube or the Glatt Immersion Sword Process [6, 7]. In the Strunck Immersion Tube (Strunck GmbH & Company, Cologne, West Germany), the inlet air duct is immersed into the moving bed, as shown in Figure 4. The spray gun is inserted into the duct such that the coating solution is sprayed into a pocket of air. The air is then exhausted from the top of the pan, as usual. The Immersion Sword Process (Glatt Air Techniques, Ramsey, New Jersey) contains two perforated swords which, when inserted into the bed, allow for introduction of drying air through one chamber and removal of exhaust air through a second chamber. A diagram of the process is shown in Figure 5. Spray Systems

Solutions and suspensions may be sprayed into the pan by either pneumatic (air spray) or hydraulic (airless spray) systems.

20 I Chambliss

FIGURE 3

tem.

Schematic of a conventional coating pan exhaust sys-

Pneumatic systems operate by adding turbulent streams of air into the flowing liquid, either inside the nozzle or just outside the nozzle tip. The air pressure supplied to the nozzle may range from 10-100 p .s .i. Hydraulic systems operate by forcing the liquid under high pressure (250-3000 p.s.i.) through the

Coating Pans I 21 HEATED DRYING AIR

EXHAUST AIR

COMPRESSED AIR

LIOU ID FEED

FIGURE 4 Schematic diagram of Strunck immersed tube coating apparatus. (From Ref. 19, p. 28. Reproduced with permission of the copyright owner, Childwall University Press Ltd.)

nozzle orifice. In both cases, the spray pattern and droplet size are a function of the size and shape of the nozzle orifice and the pressure. Pneumatic systems are often preferred for use in laboratory studies because they are more accurate at low spr1;1y rates. Hydraulic systems, on the other hand, are more popular in production because the spray pattern is more uniform and easier to control, and spray drying is less prevalent since the spray droplets are not exposed to a high airflow rate. A variety of spray patterns is possible, depending on the design of the spray gun nozzle. Flat spray patterns are normally preferred in pan coating to maximize the area of coverage [ 4] . Although multiple guns are commonly used in productionsize perforated pans, one or two guns are usually used in a conventional coating pan process. The gun should be positioned so that the spray is applied perpendicul arly to the moving bed. The spray is usually directed at the leading edge of the cascad -

22 I Chambliss

FIGURE 5 Schematic diagram of the Glatt immersed sword apparatus. (From Ref. 19, p. 29. Reproduced with permission of the copyright owner, Childwall University Press Ltd.)

Coating Pans

I 23

ing bed. A distance of 9-12 inches from the bed is optimum in many processes. The angle of the spray should be adjusted such that bed turbulence is minimized [ 8] . The gun position must be changed during drug layerfng to maintain the same distance throughout the coating operation. A spray pattern that is too close to the bed will result in localized overwetting and pellet agglomeration. If the gun is too far away, spray drying can occur, especially if an airspray system is used. Multiple gear pumps, piston pumps, and pressure tanks are commonly used to transfer the solution to the spray gun(s). The pump may be used to deliver solution to a single pan or to several pans connected in a series. Pumps may be equipped with simple timers and manual switches or sophisticated computercontrolled panels.

Powder Delivery Systems Accurate feeding of active and/or dusting powders is a vital part of many pelletization processes. Powder feeders with feed rates ranging from less than 1 g to over 10 kg per minute are available. A typical feeder is shown in Figure 6. There are two major types of feeders used in conjunction with coating pans: volumetric and weigh feeders. Volumetric feeders are designed to deliver a precise volume of powder per unit of time. Since most volumetric feeders operate by auger feeding the powder, it is critical that the auger remains filled with powder. Material transfer from a hopper to the auger may be accomplished by gravity, vibration, internal mixers, or flexible vinyl hoppers [ 9] . The feed rate is a function of the diameter and rotation speed of the screw assembly in the auger. This type of feeder should be calibrated before each use to ensure that the desired feed rate is maintained. Weight feeders, or "loss-in-weight" feeders, have a counterbalanced scale under the base of the feeder that measures the weight loss during powder delivery. A microprocessor monitors the weight loss or adjusts the rate of feed, as needed, to maintain the target feed rate. Material is fed into the coating pan, in most of the units, by an auger or a vibrating tube. Regardless of the type of delivery device that is used, it may be necessary to add a glidant such as silicon dioxide to the powder to prevent "rat-holding" and "bridging" in the feeder. Powder must be fed into the pan in a way that minimizes dust. This may be accomplished by delivering the powder into the vortex that forms at the mouth of the pan. The powder is

24 I Chambliss

Continuous weigh feeder for delivering powders. ( Courtesy of Acrison, Inc., Moonachie, New Jersey.)

FIGURE 6

Coating Pans I 25

then swept into the vortex and mixed into the bed. The size of the vortex is a function of the load-size and the positioning of internal baffles. An L-shaped extension tube can be attached to the end of the powder feed tube to direct the flowing powder into the vortex.

Operational Capabilities Conventional pans are commonly used for one or more of the following steps in pelletization: 1. 2. 3. 4.

Addition of a drug as a dry powder onto an inert substrate (e.g., nonpareil seeds)-drug layering Formation of pellets starting from dry drug granules or crystals-drug layering Addition of a drug in the form of a solution or suspension onto an inert substrate (e.g., nonpareil seeds)-drug layering Addition of an outer controlled-release layer to drug-layered pellets-pellet coating

These applications are described in various patents [ 1, 1016] . Detailed descriptions of each of these processes in coating pans and other pelletization equipment are given in Chapter 7 and 8. Coating pans have also been used to prepare pellets by wet granulation [ 17] and by melting mixtures of the active powder and wax in the pan [ 18] . B.

Modified Pans

Side- and rear-vented pans have become workhorses for tablet coating operations and have replaced conventional pans for tablet coating in many production plants. The modified pans are much more efficient than conventional coating pans due to improved airflow and superior bed mixing. Although modified pans have not replaced conventional pans for most pelletization processes, the reader should become familiar with the basic engineering designs of the various models. The use of modified pans for pelletization is more limited than for conventional pans. Vents located in the side, rear, or baffles of the pan prevent the use of dry powders in layering processes. Although suspension/solution drug layering is possible, the coating process is as lengthy as in a conventional pan, and coat erosion may be greater.

26 I Chambliss

Modified pans, however, can be used successfully for pellet coating. McAnish and Rowe described the process in a 1979 patent assigned to Imperial Chemical Industries [ 2]. Screens with openings as fine as 0. 25 mm can be retrofitted to most existing pans to allow for granule or pellet coating. General Description

Modified pans are commonly available over the entire range of laboratory- (0.6 kg) to production- (1,400 kg) scale. Table 1 lists the different models available. Capacities as large as 6,000 kg are not unusual in the confectionery industry. Special features such as reversible airflow systems, self-contained cleaning and air- handling systems, and automated product discharge systems are available in many units. Explosion-proof pneumaticcontrol panels, microprocessor-control systems, and complete spray systems are standard features on most pilot- and production-scale units. All of the units designed for the pharmaceutical industry meet GMPs. A typical production installation is shown in Figure 7. Specific Equipment Pellegrini Pan. The Pellegrini pan features an angular pan that is rotated on a horizontal axis. Two types of air-handling systems are available. In the GS system, hot, filtered air is blown from the back of the pan through the bed and is exhausted by means of two immersion swords. A closeup of two disassembled swords is shown in Figure 8. In the PLG system, the drying air is partially blown over the surface of the bed and partially inside the bed through a tube. The air is exhausted out the back of the pan. Pellegrini pans for the pharmaceutical industry are available in four sizes, as shown in Table 1. Seven pans, ranging from 10-1,000 liters in capacity, are available for use in the confectionery industry. These pans are painted on the outside and are not enclosed by stainless steel panels. Accela-Cota. The Accela-Cota is an angular pan that rotates on the horizontal axis. It differs from the Pellegrini pan in that the periphery of the pan is completely perforated. The airflow pattern that results from this design is shown in Figure 9. The drying air enters from above and is exhausted through a station ary plenum that almost covers the entire bed. The pans are equipped with two to six baffles, depending on the size. The

Coating Pans I 27

FIGURE 7 Pellegrini coating system. Englewood, New Jersey.)

(Courtesy of Nicomac,

different models available are given in Table 1. The Multi-Cota is the only model specifically designed for pellet coating, since the 3-mm perforations are covered by a 50-mesh screen.

Hi-Coater. The Hi-Coater is similar to the Accela-Cota, except that four perforated panels are used instead of the perforated periphery. The perforated panels are linked to air ducts. As the pan rotates, the panels pass by an exhaust plenum. Drying air is introduced directly into the front opening of the pan. As shown in Table 1, the Hi-Coater is available in a wide range of sizes. The 2-mm perforations can be covered by screens to allow for pellet coating. The Driacoater has perforated panels like the in that the pan is polygonal in shape. differs but Hi-Coater Drying air can be introduced from the top or bottom of the pan and can be exhausted from the top , bottom, or rear. The perforated panels can be covered by screens as fine as O. 25 mm.

Driacoater.

TABLE 1

Specifications for Modified Coating Pans

Manufacturer Pellegrini

Thomas Engineering/ Manesty

Distributor Nicomac

Thomas Engineering

(Accela -Cota)

Model

Rated capacity

Machine dimensions (meters) w

d

h

Pan speed (rpm)

Motor capacity

SP25

25 liter

1.1

1.1

1.1

4-20

0.5 hp

SP70

70 liter

1. 2

0.8

1.8

4-18

1.5 hp

SP150

150 liter

1.5

1.1

2.1

4-18

2 hp

SP300

300 liter

1.8

1. 4

2.2

2-13

3 hp

24-IV

20 kg

1.0

0.9

1. 5

12-36

48-VI

185 kg

1.6

1.4

2.0

2-14

2 hp

60-IV

400 kg

2.0

1. 7

2.2

2-13

5 hp

66-I

815 kg

2.1

1. 9

2.2

2-12

10 hp

24-II

20 kg

1.0

0.9

1. 5

12-36

0. 75 hp

500

5 kg

1.0

1. 6

1. 6

5-30

0.5 kW

800

60 kg

1.2

1. 7

1.8

5-30

1.1 kW

1200

120 kg

1.6

1.8

1. 9

5-30

1.5 kW

1600

300 kg

2.0

2.4

2.2

5-30

2.2 kW

0. 75 hp

(Multi-Cota) Driam (Driacoater)

Cantab

Glatt

Freund (Hi-Coater)

Glatt

Vector

1600/1

500 kg

2.0

2.6

2.2

5-30

4.0 kW

1600/1.25

600 kg

2.0

2.8

2.2

5-30

4.5 kW

GC-750

45 kg

1. 2

1. 2

1.8

2-20

1.0 kW

GC-1000

90 kg

1.5

1. 4

2.1

2-20

1.5 kW

GC-1250

160 kg

1.6

1. 6

2.2

2-20

2.2 kW

GC-1500

360 kg

2.0

2.0

2.5

2-20

3.6 kW

GC-1750

650 kg

2.2

2.3

2.7

2-20

5.5 kW

GC-2000

1,000 kg

2.6

2.8

2.9

2-20

7.5 kW

HCT-20

0.6 kg

0.6

0.7

1.1

12-68

40 W

HCT-30

2.2 kg

0.7

0.8

1. 2

12-48

0.25 hp

HCT-48

8 kg

1.1

1.0

1.8

4-40

0.25 hp

HCT-60

28 kg

1.1

1. 4

2.0

4-40

0.5 hp

HCT-100

100 kg

1. 3

1. 4

1. 7

4-16

2 hp

HCT-130

216 kg

1.6

1. 6

2.1

4-16

3 hp

HCT-150

334 kg

1.8

1. 9

2.4

4-16

5 hp

HCT-170

527 kg

2.1

2.2

2.5

3-12

7.5 hp

HCT-200

864 kg

2.6

2.6

3.1

2-8

10 hp

HCT-17A

739 kg

2.3

3.4

2.7

3-12

5 hp

TABLE 1

( Continued)

Manufacturer

Distributor

Freund ( Continued) Dumoulin

Raymond

Model #

Rated capacity

Machine dimensions (meters) w

d

h

Pan speed Motor (rpm) capacity

HCT-17B

1,136 kg

2.3

4.1

2.7

3-12

7.5 hp

HCT-l 7C

1,477 kg

2.3

4.7

2.7

3-12

10 hp

IDAX 5

5 kg

0.9

1.2

1.8

2-12

0. 25 kW

IDAX 30

30 kg

1.3

1. 9

2.1

2-12

0. 58 kW

IDAX 80

80 kg

1. 3

1. 9

2.1

2-12

0. 75 kW

IDAX 150

150 kg

1. 7

2.7

2.2

2-12

1.5 kW

IDAX 250

250 kg

1. 7

2.7

2.2

2-12

1.5 kW

IDAX 500

500 kg

2.1

2.2

2.4

2-12

5.5 kW

IDAX 750

750 kg

2.1

2.9

2.4

2-12

7.5 kW

IDAX 1000

1,000 kg

2.1

3.5

2.4

2-12

7.5 kW

IDAX 2000

2,000 kg

2.5

4.6

2.8

2-12

15. 0 kW

(b) PELLEGRINI-TYPE

Key: I. Immersion Sword

2. 3. 4. 5. 6. 7. 8. 9.

Coaxial conduit Coating pan Pan cover Clear control cover Silicone seal Stand Coaxial conduit adjustment Coating bed

FIGURE 8 Immersion swords for Pellegrini Pan. Nicomac, Englewood, New Jersey.)

(Courtesy of

31

32

I

Chambliss EXHAUST AIR HEATED AIR SUPPLY

l

COMPRESSED AIR

/

LIQUID FEED

SINK

FIGURE 9

Schematic diagram of a 40" Accela Cota. (From Ref. 19, p. 29. Reproduced with permission of the copyright owner, Childwall University Press Ltd.)

Glatt Coater. The Glatt Coater is similar to the AccelaCota. The angular pan has perforations completely around the periphery. The 4-mm perforations can be covered by a screen to allow for pellet coating operations. Dumoulin Coater. The Dumoulin pans are the latest modified pans to be introduced in the United States, although they have been available in France for over 50 years. The Dumoulin I .D .A. X pans have perforated drums like the Accela-Cota and Glatt coater but differ in that the production-size pans are cylindrical. Drying air can be introduced from the top and/or the bottom, and is exhausted out the top. Standard I.D.A. X pans have

Coating Pans I 33

4-mm perforations, although pans with 2-mm perforations are available. The pan can be equipped with systems for distributing coating solutions and dry powders into the bed. A belt dryer under the pan can be used to dry one batch while a second batch is being coated. Ill.

EQUIPMENT OPERATION

Both conventional and modified pans are easy to operate and require very little training time. The art of pelletization in coating pans, however, is much more difficult to master. Terms such as "too wet" and "too dry" are commonly used to describe the condition of the bed. Fast, correct decisions by operators may be needed to save a batch that starts to agglomerate. The primary goal of process development studies is to remove as much of the "art" as possible. Detailed manufacturing instructions with defined ranges for spray and powder rates at each specified time interval can be developed and used to main tain reproducibility. Critical processing steps for powder layering and solution/suspension layering are described in Chapters 7 and 8, respectively. IV.

AUTOMATION

Pan coating has always been considered to be a pharmaceutical art. Wagner and colleagues conducted a series of studies in the late 1950s designed to determine the causes of large batch-tobatch variations in commercially available enteric-coated tablets. They discovered that the amount of coating material and dusting powder added to the pan varied from coater to coater and from day to day for the same coater [ 21] . This practice, unacceptable today in light of CGMP and validation requirements, was slowly replaced by more reproducible coating techniques. Lachman and Cooper made the first significant strides toward automating a conventional coating pan for film coating operations by using baffles to eliminate the need for hand mixing and by replacing the ladeling technique of applying coating solu tions and dusting powders with spray coating. They also used a tape transmitter to control pan rotation, spray intervals, and drying air [ 22] . Lantz and colleagues were the first to report that the temperature of the pellet bed during solvent coating operations could

34 I Chambliss

be used for automation purposes. They showed that product temperature profiles were a function of the spray rate and drying time and could be used to establish process conditions [ 23] . Most automated systems today monitor bed temperature as well as inlet and outlet temperatures, flow rates, and humidites [ 2426].

Automated control systems are included as a part of most modified-pan installations. Comparable systems for conventional pans are available, but not from most suppliers. One example is the production -size pans offered by Carle and Montanari, Inc. The pans are equipped with automatic spray systems in the base of the pan and fully automatic, minicomputer-operated consoles external to the pan [ 27] . Systematic approaches to in-house design and installation of automated spray systems and complete process control systems for conventional pans have been described by Huberfield [ 28] and Thomas [ 29] , respectively. Although the system described by Thomas is for a sugar coating process, the concepts can be applied to pelletization. The system automatically controlled the temperature and volume of the supply air, the exhaust air vol ume, the pan speed, and the pump and damper cycles. An important feature of the system was that the controls could be operated in either a "hand" or "automated" mode. This allows the operator to alter the process if needed.

V.

SAFETY CONCERNS

Most pelletization processes in coating pans generate large amounts of dust and organic vapors. An explosive environment, therefore, surrounds the pan. The problem is especially critical in conventional pans, which are not enclosed systems. Taking precautions such as flooding the bed with nitrogen, maintaining an adequate exhaust system, using nonsparking tools, grounding all equipment, and using explosion-proof motors will reduce the chances of having an explosion. Dust or gas masks, special nonconducting shoes, and leg ground wires should be worn by operators. Explosion meters and static charge meters may be used to determine where potential problem areas exist. The operators should be advised of the inherent dangers of the process and must know what to do in the case of an emergency.

Coating Pans I 35

VI.

A.

LIST OF SUPPLIERS

Coating Pans

Advance Engineering, St. Louis, MO 63133 B & G Machine Company, Inc. , Bohemia, NY 11716 Cantab Industries Ltd., Toronto, Ontario, Canada M4T 2L7 Carle & Montanari, Inc., Hackensak, NJ 07601 Coating Place, Inc. , Verona, WI 53 719 Erweka Instrument Corporation, Milford, CT 06460 Glatt Air Techniques, Ramsey, NJ 07446 Groen Process Equipment Group, Elk Grove Village, IL 60007 Jaygo, Inc., Mahwah, NJ 07430 K Manufacturing Company, Philadelphia, PA 19124 Keith Manufacturing Company, Philadelphia, PA 19124 Key Industries, Englishtown, NJ 07726 Littleford Brothers, Florence, KY 41042 Madison Equipment, Chicago, IL 60612 Meltech, Inc., East Hanover, NJ 07936 Nicomac, Inc., Englewood, NJ 07631 Pietro Pellegrini, Milan, Italy Sharples-Stokes Division, Penwalt Corporation, Warminster, PA 18974 C. Skerman & Sons, London, England Thomas Engineering, Hoffman Estates, IL 60195 Vector Corporation, Marion, IA 52302 Raymond Automation, Norwalk, CT 06856 B.

Powder Feeders

AccuRate Division, Moksnes Manufacturing Corporation, Whitewater, WI 53190 Acrison, Inc., Moonachie, NJ 07074 Arjo Volumetric Feeders, Toronto, Ontario, Canada Control & Metering Ltd. , Toronto, Ontario, Canada Merrick Corporation, Roseland, NJ 07068 Vibranetics Division, Carrier Vibrating Equipment, Inc., Louisville, KY 40201 Wallace & Ternan Division, Pennwalt Corporation, Belleville, NJ 07109 C.

Spray Systems

Binks Manufacturing Company, Franklin Park, IL 60131 Carle & Montanari, Inc. , Hackensack, NJ 07601

36 I Chambliss

CAT Pumps Corporation, Minneapolis, MN 55440 Glatt Air Techniques, Ramsey, NJ 07446 Graco, Inc. , Minneapolis, MN 55440 Spraying Systems Company, Wheaton, IL 60189 Strunck GmbH & Company, Cologne, West Germany Thomas Engineering, Hoffman Estates, IL 60195 Vector Corporation, Marion, IA 52302 VI I.

SUMMARY

This chapter describes the types of conventional and modified coating pans used for pelletization. Conventional pans have been widely used for many years because they are extremely versatile and less expensive than most types of pelletization equipment. Conventional pan processes, however, may have higher labor costs, longer processing times and lower yields. A typical conventional pan installation includes a rotating pan, air-supply system, spray system and powder-delivery system. Each of these units fr described in the chapter. Although modified pans have replaced conventional pans in many tablet coating operations, they are not widely used for pelletization, due to lack of versatility. Over 40 different models from six manufacturers are available. A basic description of the different models is provided. Pelletization processes must be optimized to eliminate as much of the "art" as possible. Several approaches to automation are described. Pelletization processes are inherently dangerous, especially when organic solvents are used. Safety precautions, which would be followed, are described. REFERENCES 1.

R. H. Blythe, U.S. Patent 2,738,303 (March 13, 1956).

2.

J. McAinsh and R. C. Rowe, U.S. Patent 4,138,475 (February 6, 1979).

3.

P. B. Deasy, Pan Coating, in Microencapsulation and Related Drug Processes, (J. Swarbrick, ed.), Marcel Dekker, Inc., New York, pp. 147-148 (1984).

4.

J. R. Ellis, E. B. Prillig and A. H. Amann, Tablet Coating, in The Theory and Practice of Industrial Pharmacy, 2nd

Coating Pans

I 37

Edition, (L. Lachman, H. A. Lieberman and J. L. Kanig, eds.), Lea & Febiger, Philadelphia, 1976, pp. 377-381. 5.

M. J. Robinson, Coating of Pharmaceutical Dosage Forms, in Remington's Pharmaceutical Sciences, 15th Edition, (A. Osol, ed.) , Mack Publishing Company, Easton, Pennsylvania, pp. 1608-1611 (1975).

6.

S. C. Porter, C. H. Bruno, and G. J. Jackson, Pan Coating of Tablets and Granules, in Pharmaceutical Dosage Forms: Tablets, Volume 3, (H. A. Lieberman and L. Lachman, eds.), Marcel Dekker, Inc., New York, pp. 73--116 ( 1982).

7.

S. C. Porter, Tablet Coating, Drug and Cosmetic Industry, pp. 42- 44 (August l 981~.

8.

R. E. Pondell, Scale Up of Film Coating Operations, Aqueous and Non-Aqueous, Coating Place, Verona, Wisconsin.

9.

J. M. Kocher, Dry Material Feeding Handbook, AccuRate, Inc., Whitewater, Wisconsin (1986).

10.

W. Wizerkaniuk, U.S. Patent 4,129,666 (December 12, 1978).

11.

W. Fulberth and E. Neitzer, U.S. Patent 3,835,221 (September 10, 1974).

12.

M. E. Corn, U.S. Patent 3,499,959 (March 10, 1970).

13.

D. Peters, F. W. Goodhart, and H. A. Lieberman, U.S. Patent 3,492,397 (January 27, 1970).

14.

M. Greif, U.S. Patent 3,078,216 (February 19, 1963).

15.

M. Shepard, U.S. Patent 3,080,294 (March 5, 1963).

16.

K. R. Heimlich and D. R. MacDonnell, U.S. Patent 3,119,742 (January 28, 1964).

17.

"Avice! Spheres", Technical Bulletin, FMC Corp., Philadelphia.

18.

M. S. Blichare and G. J. Jackson, U.S. Patent 4,132,753 (January 2, 1979).

19.

S. C. Porter, Film Coating Equipment, Int. J. Pharm. Tech. and Prod. Mfr., 3(1):27-32 (1982).

20.

"Multi-Cota Model 24-II", Specifications Sheet #77A, Thomas Engineering, Hoffman Estates, Illinois ( 1986).

38

21.

I

Chambliss

J. G. Wagner, Biopharmaceutics and Relevant Pharmacokinetics, Drug Intelligence Publications, Hamilton, Illinois, pp. 158-165 (1971) .

22.

L. Lachman and J. Cooper, A Programmed Automated FilmCoating Process, J. Pharm. Sci., 52: 490-496 ( 1963).

23.

R. J. Lantz, A. Bailey and M. J. Robinson, Monitoring Volatile Coating Solution Applications in a Coating Pan, J. Pharm. Sci., 59:1174-1177 (1981).

24.

A. Heyd, Variables Involved in an Automated Tablet-Coating System, J. Pharm. Sci., 62:818-820 (1973).

25.

D. S. Mody, M. W. Scott and H. A. Lieberman, Development of a Simple Automated Film-Coating Procedure, J. Pharm. Sci., 53:949-952 (1964).

26.

A. Heyd and J. L. Kanig, Improved Self-Programming Automated Tablet-Coating System, J. Pharm. Sci., 59:11711174 (1970).

27.

"BE. 5, BE .10; Automatic Coating Pans for the Candy and Pharmaceutical Industries", Technical Bulletin, Carle and Montanari, Inc. , Hackensack, New Jersey.

28. 29.

D. H. Huberfield, Tablet Coating:

Ladels to Computers,

Pharm. Technol., pp. 52-71 (October, 1977).

R. Thomas, Pan Coating Control Systems, Pharm. Eng., pp. 16-18 (August-October, 1981).

Fluid Bed Equipment KENNETH W. OLSEN

Jersey

I.

Glatt Air Techniques, Inc., Ramsey, New

INTRODUCTION

Batch -type fluid bed processes for pharmaceutical manufacturing have been in use for some 30 years. Originating in Europe, this technology gradually found its way into U.S. manufacturing facilities, beginning with the use of fluid bed dryers. The earliest fluid bed dryers were a cabinet-type construction with a simple cylindrical product container over which was located an exhaust air filter. These simple dryers showed immediate superiority over conventional tray drying ovens and soon attracted considerable interest from manufacturing personnel. The introduction of an expansion space between the product container and the filter chamber, and the inclusion of a liquid-spray nozzle in that space, gave rise to fluid bed agglomeration (more commonly referred to as fluid bed granulation)-an effective alternative to conventional low-shear mixing and tray or fluid bed drying. In more recent years, unique processes for the coating of granu lates, pellets, and powders have expanded the use of fluid bed manufacturing technology, particularly in the pharmaceutical field of solid dosage forms. The fluid bed industry has made significant advances in key manufacturing areas such as conformance to Current Good Manufacturing Practices (CGMP's) and in the safety issue of explosion protection. This discussion of fluid bed processing equipment will include batch-type food and pharmaceutically oriented fluid bed dryers, granulators, top spray coaters, and bottom spray coaters.

DOI: 10.1201/9781003066231-3

39

40 I Olsen Although they perform different functions, the various types of equipment have numerous common design characteristics. Figure 1 depicits a typical production-scale fluid bed granulator installation. Process air enters the equipment through the air handler (Figure 1, section A). From there it is drawn into the product processing components of the machine (Figure 1, section B) . In most cases an exhaust-air filter (Figure 1, section C) or a product-retention screen is provided in this part of the machine to separate the product from the process air before it is transferred by duct to an exhaust-air turbine (Figure 1, section D) and discharged to the atmosphere. Of course, all fluid bed equipment requires controls (Figure 1, Section E) and most production-size units consider product handling (Figure 1, Section F) in their design. This oversimplified description identifies the basic components of most batch-type fluid bed processors. The major areas to be discussed are inlet air-handling systems, product-processing components-including design modifica tions for the four different processing functions identified earlier, exhaust-air systems, spray nozzles, product-handling (discharge) systems, solvent-recovery systems, CGMP considerations, and the issue of safety. II.

AIR HANDLING

A discussion of air-handling units is basic to the understanding of fluid bed operations. Figure 2, an enlarged view of the air handler seen in Figure 1, shows the elements that can be included in a complex system. All fluid bed processes require conditioning of the process air to greater and lesser degress, depending on the sophistication of the process. Air-handling units can be designed to provide control over the temperature and humidity of the process airstream, resulting in improved batch-to-batch reproducibility. A.

Airflow

The most generally accepted means for producing airflow in fluid bed machines is by suction. Thus, slight imperfections that may exist in the seals in ductwork flanges will not result in dust leakage into the building. Similarly, if organic solvents are used, solvent vapor contamination within the building will not occur. This approach is also most compatible with the explosion protection methods employed in fluid bed equipment.

Fluid Bed Equipment

I

41

A A - Air Handling Unit

B - Processing Zone

C - Exhaust Air Filter

E

B

D - Exhaust Air Turbine

E - Controls

F - Product Discharge Components

FIGURE 1

Typical production-size fluid bed granulator.

F

42 I Olsen A

A. B. C. D. E. F. G. H. I.

B

C

o

E

BIRD SCREEN PRE FILTER DEHUMIDIFIER PRE HEATER HUMIDIFIER FACE AND BYPASS FINAL HEATER HE.P.A. FILTERS INLET QUICK ACTING EXPLOSION PROTECTION VALVE

FIGURE 2 Air-handling system. Since most fluid bed processors are susceptible to the danger of explosion, a means for safely venting it to the atmosphere must be provided. The explosion-relie f flaps, located in the exhaust-air filter housing, are sensitive to minor positive pressure within the machine. If the airflow came from a pressure supply, rather than a suction supply, this method of explosion venting could not be employed. Finally, a suction system allows better regulation of process air and better control over fluidization characteristics of the product.

B.

Conditioning of Process Air

Simplest Air Handler

The simplest air handler would most likely include a prefilter and a simple heat exchanger with a modulating steam valve to control the heating medium. The majority of fluid bed installations employ medium pressure (40-70 psig) steam-heat exchangers. Temperature control for this type of system can be expected to fall within ±2-3°C. H.E.P.A. (High Efficiency Particle Attenuation)

Fluid Bed Equipment I 43

FIGURE 3 Face and bypass dampers, with bypass dampers open and face dampers closed. ( Courtesy Glatt Air Techniques, Inc. , Ramsey, New Jersey.)

filtration, required by pharmaceutical applications, is provided in the air-handling unit. Face and Bypass System

A newer alternative to the modulating steam valve for temperature control is the face and bypass system (see Figures 2 and 3) , which employs a set of dampers that permit mixing of the airstream passing over the heat exchanger with a bypass airstream. The heat exchanger is always on; temperature is controlled by mixing the heated air with a portion of ambient bypass air. Advantages of this approach are the ability to change temperatures very rapidly and maintain tight control over a given preset temperature (with ±1°C).

44 I Olsen

Dehumidification

The next addition to an increasingly complex air handler would be a dehumidification section (see Figure 2). Here the humidity of the air is adjusted to a maximum desirable level. Moisture is condensed out of the process air by passing over cooling coils. Condensate is collected and removed from the system so that it is not entrained by the moving process air. Humidification

During cold or dry seasons, air humidity may actually be lower than that obtainable with the dehumidification coil. Thus, a humidification section may be necessary (see Figure 2). When combined with a dehumidifier, absolute control is attained over the dewpoint of the process airstream. Steam injection is the method of choice for humidification, since pharmaceutical and food applications require a source of clean steam. If humidification is required, this portion of the air handler may also require a heater to bring the process air to a temperature warm enough to allow it to hold the desired moisture. Bypass Loop

A design factor to consider when preconditioned air is used is the inclusion of a bypass loop, which allows the process air to bypass the product until it reaches preset temperature and humidity parameters. The bypass capability is particularly important for temperature and /or humidity-sensitive products. The inclusion of all of these devices, while adding to the costs of equipment and operation, can provide identical process air year round regardless of the outside weather conditions. C.

Location of Air Handler

The location of the air handler provides another opportunity for variation. Air handlers can be attached directly to the processing portion of the equipment and be located in the process area. The main advantage of this configuration is the very close proximity of the air handler to the product, allowing for minimial heat loss between air handler and processing portions of the machine. Disadvantages include more surface area to clean in the process area, added heat load on the room's air-conditioning system and, perhaps, aesthetic considerations. An alternative to locating the air handler in this manner is to design the

Fluid Bed Equipment

I 45

facility to include a separate equipment room behind an adjoining wall. Some installations require remote mounting of the air-handling unit. Locations may include interstitial equipment areas or equipment rooms within the building or, in some cases, outside the building on the roof or on a ground- level concrete pad. Outdoor installations require attention to insulation, weather proofing, and freeze protection for coils. Since air- handling units are normally not constructed to withstand the positive pressures of an explosion, they should be isolated from the product portion of the machine by some type of explosion protection safety valve. 111.

A.

PRODUCT PROCESSING COMPONENTS

Fluid Bed Dryers

In Figure 4, photographs show a fluid bed granulator and dryer while Figure 5 is a diagram that illustrates the basic components of a fluid bed dryer. The product handling portion of a fluid bed dryer consists of a product container to hold more than the full volume of the unfluidized product (at its lowest bulk density), an expansion zone into which the product may be fluidized, and a filter section to separate entrained particles of product from the exiting process air stream. Since the object in fluid bed drying is to remove moisture from the product with the highest efficiency, and since heat transfer is optimized at a level just above incipient fluidization, expansion space for a fluid bed dryer need not be extensive. A balance must be made between providing enough process air to fully fluidize the material and providing sufficient air volume to carry off the moisture efficiently. As the product dries, more and more fine particles will be trapped in the exhaust-air filter and so the expansion space should be high enough to minimize the number of filter-shaking (cleaning) cycles during a batch. The product containers for fluid bed dryers are designed with relatively steep walls, and the ability to change the open area of the bottom screen. Uniform fluidization is dependent on the open area of the bottom screen, a design point that may vary from product to product. The product container can also be equipped with a sample collection port and perhaps an observation window to monitor movement of the product during the process.

(A)

(B)

FIGURE 4 (A) Fluid bed dryer /granulator. ( Courtesy Glatt Air Techniques Inc.) (B) Fluid bed dryer. ( Courtesy Fitzpatrick Co.)

46

Fluid Bed Equipment I 47

FILTER HOUSING

EXPANSION CHAMBER PARTICLE FLOW PATTERN PRODUCT CONTAINER

AIR INLET

FIGURE 5

LOWER PLENUM

Fluid bed dryer.

The inclusion of an agitator system and /or other types of fluidization assisting devices and /or delumping devices may be included for specific product requirements. These devices add to the cost of the equipment and require additional maintenance and cleaning. Their inclusion does not always guarantee successful fluidization of product. The consistency of certain products requires very high torque agitators, while others do not. B.

Fluid Bed Granulators

Fluid bed granulators require adjustments to some of the design considerations discussed for fluid bed dryers. Note in Figure 6 that the expansion space is increased at least 50% over the height of the dryer's expansion chamber. The most significant difference from the dryer configuration is the addition of a liquid spray nozzle in the expansion area. A "binding" liquid is sprayed in at a controlled rate to convert fluidized powders into granulates or pellets. The product container should be deeper and narrower for a given batch size than the typical product container used for fluid bed drying. This facilitates more organized movement of

48 I Olsen

FILTER HOUSING

EXPANSION CHAMBER

- - - - LIQUID SPRAY NOZZLE

PARTICLE FLOW PATTERN PRODUCT CONTAINER

AIR INLET

FIGURE 6

LOWER PLENUM

Fluid bed granulator.

the material with a very obvious downbed along the perimeter of the container and a fairly constant upward motion of particulates in the central portion. Multiple windows in the product container are an asset for observing the motion of the material along the entire circumference of the container. Long, rectangular windows in the expansion chamber are preferable to the "port hole" style to allow for full view of the expansion area. A product temperature-sensing device is important in granulating processes; the ports for the product temperature probes can be provided with a cap and plug to allow use of the container without the probe inserted. C.

Fluid Bed Top Spray Coaters

Although it is not the system of choice for pellets, top Spray Coating is a method for applying liquid material in a countercurrent manner to the fluidized particles or pellets. The ma chine configuration, which is shown in Figure 7, is similar to a fluid bed granulator; however, there are significant design modifications .

Fluid Bed Equipment I 49

Filter Housing

Expansion Chamber

0

f:t O

1

o

0----D

l

: 0:

!

i

""""_---+l..,1;.:.f[~EEJ----C 0

Product Container Lower Plenum FIGURE 7

---A Expanded View A - Product Container

C - Spray Nozzle

B - Air Distribution Plate

D - Expansion Chamber

Top spray coater.

The spray nozzle is located lower in the expansion chamber so that liquid is applied when the particles are moving at a higher velocity. Applying liquid spray at this point serves to minimize surface wetting and to inhibit agglomeration (particles sticking together). The fact that particles or pellets are fluidized at a higher velocity requires that top spray coaters generally be designed with a longer expansion chamber. Expansion heights may exceed two and one-half times that supplied for fluid bed drying (see Figures 5 and 7). The expansion space shape is changed from a right circular cylinder to a conical formation because that configuration serves to decrease particle velocity as it moves toward the filter. Finally, a major design difference between fluid bed coaters and dryers or granulators is in the filter and its clearing mechanism. In dryers and granulators a one-piece filter is commonly used. To clear the filter of entrapped product, airflow through the machine (and fluidization) stops while the filter is shaken. In coating operations it is preferable not to interrupt

50 I Olsen

Filter Housing

flHi D

®

Product Container

Product Container Expanded View

Lower Plenum

A - Coating Chamber

D - Spray Nozzle

B - Partition

E - Expansion Chamber

C - Air Distribution Plate

FIGURE 8

Wurster (bottom spray) coater.

fluidization. So, coaters are commonly equipped with multiple filters. Airflow is stopped through one filter at a time while that filter is cleared, but product fluidizes continually. D.

Fluid Bed Bottom Spray (Wurster) Coaters

The Wurster process for bottom spray coating has been in use for well over 18 years. Figure 8 illustrates Wurster coating equipment. The Wurster coating chamber is cylindrical in shape and contains an inner cylindrical partition normally one -half the diameter of the outer chamber. At the base of the chamber is a perforated plate (Figure 9) with larger holes located underneath the partition. The liquid-spray nozzle is located in the center of the orifice plate and the partition is positioned above

Fluid Bed Equipment

I 51

FIGURE 9 Orifice plate of a Wurster that shows the smaller holes around the perimeter (area outside the coating partition) and larger holes in the middle (inside the coating partition) area. (Courtesy Glatt Air Techniques, Inc., Ramsey, New Jersey.)

the plate to allow movement of material from outside the partition to the higher velocity airstream located inside the partition. This design creates a very organized flow of product with upward motion through the partition into the expansion area and a downbed of particles in near-weightless suspension outside the partition. As the batch size for the Wurster is increased to a production scale, the number of inner partitions increases (rather than their size) as well as the diameter of the cylindrical outer wall. Figure 10 shows the interior of a 46" diameter Wurster product container with seven partitions. As shown in Figure 11, there are three basic design differences for processing particles of different size ranges.

52 I Olsen

Production size (46") Wurster powder coater. (Courtesy Glatt Air Techniques, Inc., Ramsey, New Jersey.)

FIGURE 10

Type I

Wurster coaters for tablets generally have minimal expansion space with the up-bed usually not extending above the partition more than 300-400 mm. A filter system is neither necessary nor desirable as reintroduction of dust onto the tablet surfaces would decrease the quality of the coating. Wursters for tablet coating should be cylihdrical with cylindrical partitions. The percent of open area in the orifice plate should be adjustable as the ratio of airflow through the center partition versus the airflow outside the partition will need to be adjusted according to tablet size, shape, and density. The partition height above the orifice plate needs to be adjusted for the same reason. Type II

The next type of Wurster applies to a smaller range of pellets. For pellets, the expansion space above the partition should be

Fluid Bed Equipment I 53

Filter Housing

Product Retention Screen ········•·, ...•···········

Product Container

Type I

Type II

Type III

FIGURE 11 Three configurations of Wurster product containers and expansion chambers.

increased to allow greater expansion of the fluidized bed. The shape of the expansion chamber should be changed from cylindrical to conical to permit a deceleration zone for the particles. The orifice plate of the Wurster will require a finer screen to retain product in the Wurster chamber. Elongated windows in the expansion area and coating chamber can be provided for observation of the motion of the material. A product temperaturesensing device may also be added and a sample port is desirable for this smaller particle-size range. Since the bottom spray coating method is frequently used for applications in which a large amount of coating or drug layer is applied to a substrate, it may be necessary to adjust the partition height during the operation. Thus, an external means for this adjustment may be required.

Type I II As the substrate particle size gets even smaller, a longer expansion chamber is necessary to allow for particle deceleration. Attention should be paid to the angle of the side of the expan-

54 I Olsen

pansion chamber. A steep angle is desirable to permit rapid movement of the fluidized powder back into the Wurster chamber. A filter system that allows continuous fluidization is necessary, and the capability for partition height adjustment is more critical since the partition must be moved very close to the bottom screen without inhibiting the flow of material. In some cases, when attempting to coat very fine, cohesive powders, a specially designed partition may be helpful. It would be cylindrical (as the others are) but flaring at its lowest part into a conical shape to provide a greater area at the base of the partition for powders to be transported into the partition and coating zone. A summary of Wurster size ranges and their corresponding batch -sizes appears in Appendix A. IV. A.

EXHAUST-AIR SYSTEMS Outlet Air Filter

Exhaust-air systems include the filter (also an integral part of the product-processing section) and the turbine or fan. Selection of filter material should take into account both the need for maximum retention of the product and sufficient permeability to permit adequate airflow. The ability of a fabric to shed entrapped material is important; as much product as possible should fall back into the product container. Ideal fabric would have a very smooth surface. Often electrically conductive material is used to minimize buildup of static electricity on the filter. As with the product-processing and air-handler sections, exhaust filter systems may be simple or complex. The most basic configuration includes one filter that contains numerous "socks", which increase the functional surface area of the filter. The simplest design, used in many drying and granulating operations, clears the filter by stopping fluidization, shaking the filter, and restarting the fluidization again. The more complex designs feature a multichambered approach. Airflow is stopped through one chamber at a time, and that filter is mechanically shaken to allow the fines to fall back into the expansion zone and be reincorporated in the material being processed. Each chamber goes through a similar operation at a frequency selected by the process operator. Figure 12, which is a dual-chambered filter housing, shows one filter lowered toward the position where it can be removed for cleaning or replacement. The numerous socks, which increase the filter's surface area, are visible in Figure 12.

FIGURE 12 Exhaust-air filters configured for alternate shaking system for processes that need uninterrupted fluidization. ( Courtesy Glatt Air Techniques, Inc. , Ramsey, New Jersey.)

55

56 I Olsen

Another filter-clearing mechanism is the pulse /blowback system. In this design, the inverted sock is pulsed with air, forcing most of the dislodged particles to fly away from the sock in a lateral direction. Because of the close proximity of the adjoining socks, some of the dislodged product particles may be recaptured before travelling back into the batch. Pulse /blowback systems are often mechanically complex and require more maintenance and cleaning time.

B.

Exhaust Fan or Turbine

Most modern fluid bed installations are designed with the turbine mounted remotely from the fluid bed processor-usually external to the building, either on the roof or a ground level cement pad. The advantages of exterior location are: reduced inside noise, access for maintenance, and ease in controlling discharge of the turbine. When the turbine is located externally, attention must be given to the potential for outside noise pollution. Therefore, many installations require insulated fan housings, insulated motor housings and noise attenuators on the discharge of the turbine. Provision can be arranged for a vibration detection device on the fan housing which will warn of an imbalance of the fan wheel due to material becoming attached to it, a situation which, if not detected quickly, could result in catastrophic destruction of the unit. Other environmental considerations with regard to the fan installation are centered around the potential discharge of particulates and/or solvents into the atmosphere. In the case of particulates, a final dust collector may be required. Explosion hazards must be considered when deciding whether to locate the dust collector between the fluid bed processor and the fan or on the discharge side of the fan. The added pressure drop created by the dust collector must also be considered when specifying the turbine. Another factor affecting requirements for the turbine is the length of the duct between the turbine and the fluid bed processor. Attention must not only be given to the overall length and diameter, but also to the number of elbows. These factors all add to the total pressure drop of the system and could seriously affect performance of the equipment. Ductwork must also be strong enough to withstand the total pressure drop the fan is capable of producing. If not isolated from the fluid bed processor by an explosion protection valve, the ductwork and

Fluid Bed Equipment

I 57

fan must also be able to withstand the anticipated pressure rise of an explosion. V.

LIQUID-SPRAY NOZZLES

Although several types of spray nozzle systems are availableincluding air atomizing, hydraulic, and ultra sonic-air atomizing nozzles predominate for several reasons. A brief explanation of each type of nozzle will help further understanding of fluid bed equipment operation. A.

Hydraulic Nozzles

Hydraulic nozzles have been commonly used in film coating processes especially when volatile organic solvents are involved. The droplet size is a function of the nozzle orifice size, sprayrate, and liquid line pressure. The advantage of this system is that little if any evaporation occurs as a result of the droplet formation process. However, since droplet size is dependent on spray-rate (also hydraulic pressure) , it is difficult to change the flowrate independently of droplet size. A further limitation is that hydraulic nozzles have difficulty in atomizing effectively at flowrates lower than approximately 250 ml per minute, which may be common in a particle coating process. Finally, some of the more modern coating processes are latex-, or pseudolatexbased and are very sensitive to pressure, making it difficult or impossible to use a hydraulic nozzle for their application. B.

Ultrasonic Nozzles

The recent introduction of ultrasonic nozzles offers yet another means for the spraying of liquids. Liquid is supplied at low pressure and droplets are formed by an ultrasonic frequency at the discharge tip of the nozzle. This frequency is a function of the nozzle design and power source. Here again very little evaporation occurs as a result of the droplet formation process, which is an advantage, especially when using volatile organic solvents. Although there is a significant ad vantage in certain applications, a disadvantage for use in fluidized beds is in the fact that droplet velocity away from the nozzle is very low, therefore the coating zone is small, and the spray-rate would be lower than that attainable when using other types of nozzles.

58

C.

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Olsen

Air-Atomizing Nozzles

The air-atomizing nozzle uses air pressure and volume to produce droplets from liquid that is supplied at low pressure. The ad vantages of this type of system include the ability to control droplet size independently of flow rate. For instance, at a given liquid-spray rate, an increase in atomizing air pressure and volume will result in a smaller droplet size. A further benefit is that this type of nozzle is capable of functioning with very slow flow rates ( 10 ml per minute or less). Lastly, the high air pressure at the nozzle results in a high air velocity that helps keep the fluidizing particles from fouling the nozzle. A shortcoming of this type of nozzle is that the air used to produce droplets causes some evaporation of the coating or granulating media. Although this is not a severe problem when spraying water, it may be more pronounced with the use of organic solvents. With few exceptions the air-atomizing nozzle is used in fluidized beds. It offers the flexibility to produce droplets in various size ranges, from liquids of numerous viscosities, and at very low liquid-spray rates. The impact of evaporation of the media during droplet formation, an ad vantage of the other nozzles, is not enough to offset the benefits of the air-atomizing nozzle. The single-tube coaxial nozzle system offers other advantages in the area of application of hot melts and suspensions. Atomization air can be heated and will surround the liquid as it moves to the nozzle tip, thus eliminating the need for heat taping or steam tracing the nozzle delivery tube. The nozzle head should be quickly detachable from the delivery tube to permit the rapid exchange of a clean nozzle head either during the batch or between batches. There are many variations for nozzle assemblies. In general, the nozzle assembly should permit an even distribution of the spray material, with good control over droplet size, and with the capacity to handle the volume of liquid required for a given product formulation. For large fluid bed granulators, the multiple headed, single coaxial nozzle system offers advantaged in the areas of control and cleanability. In production-scale granulating operations, a single nozzle with six spraying ports is common. Multiple nozzle-wand entrance ports should be provided in granu lators and top spray coaters to facilitate vertical height adjustment of the nozzle while maintaining a nozzle position in the vertical center of the processing area. The nozzle assembly should be designed to be easily removable during the process in

Fluid Bed Equipment I 59

the event of a nozzle clog or other trouble-shooting requirement. As few tubes as possible should extend into the expansion chamber, thus limiting areas where materials can collect and reside during the process. VI.

CONTROL SYSTEMS

In evaluating the appropriate control system for a fluid bed processor, many factors need to be considered. The first would concern itself with explosion protection. If the process requires a Class I or Class II environment ( "Class I" and "Class II" are defined by the Naitonal Fire Protection Association in their publication National Electrical Code), and controls need to be in that room, pneumatic controls are the first choice. Electronic con trols with appropriate, approved intrinsic safety barriers would be the alternate route; the "main controls" would be remotely mounted in a "safe" control room area and controls in the process area would meet the Class I or Class II requirements. Except for very high-level automated applications that require the use of electronic microprocessor controls, pneumatic systems provide an excellent level of control with the highest standard of safety. An advantage of microprocessor-based control systems over corresponding pneumatic systems is the relative ease with which interlocks, sequences, recipes, etc. can be modified. Another point to consider is that the pneumatic system is not capable of supplying the requirements of data aquisition and analysis that the electronic system can. An optimum solution at times would be the utilization of pneumatic control components in the process area, interfaced through safety barriers, with a microprocessor control system located in a "safe" control room. The control system should complement the level of sophistica tion of the equipment and the process. A particular problem, routinely associated with fluid bed processes, is their susceptibility to influence by variations in the moisture content of the process air as ambient conditions change. Automation of the process is difficult unless a preconditioned air- handling package is employed, providing process air with the same dewpoint for each and every batch. Automation of the air-handling system can reduce the batch-to-batch variations that cause problems with product specifications and can certainly streamline the validation process. Further considerations for automating processes employing a binding or coating solution are to be able to control the spray

60 I Olsen

rate accurately and to know by either volume or weight when the required amount of material has been applied. A further complication may be the necessity to purge and rinse the liquid lines before going on to the drying phase of the process. If those factors are accounted for, a relatively straightforward automation system can be designed, employing intrinsically safe logic and controls. An important component of such controls should be the monitoring and protection by interlocks of critical process parameters such as liquid-flow rate, process airflow rate, atomization air pressure and volume, exhaust air or product temperature, and others that might be specific to a given process. The design and incorporation of these interlocks, whether pneumatic or electronic, should safeguard the product, equipment, and personnel against mishaps or losses. Should integrated feedback or batch recipe control of the process be desired, a more complex microprocessor or computerbased control system would be necessary. Similarly, a sophisticated real-time printed batch record would require microprocessorbased controls. The application program and the system information should be easily read by the user but with the installation of sufficient security safeguards to prevent unauthorized usage. Another important factor to evaluate when considering sophisticated process controls is the impact of equipment and control system validation requirements. If validation is a requirement, proper documentation and criteria must be recognized in the early stages of the design plan. VII.

PRODUCT-HANDLING (DISCHARGE) SYSTEM

How to get product efficeintly in and out of the fluid bed processing equipment represents a major consideration in any production setting. The techniques for handling product vary greatly with the type of fluid bed processing equipment used. A.

Dryers, Granulators, and Top Spray Coaters

Movable Product Container The most traditional method of charging and discharging product in dryers, granulators, or top spray coaters employs the use of a movable product container. The product container rests on a

Fluid Bed Equipment I 61

detachable trolley and, except for very large equipment, is able to be moved by one individual. Ergonomic design of the trolley is critical with regard to positioning of handles, and size and type of casters. A standard procedure would be to have the product container stationed on a floor-scale with dust collection provided near the top of the container. The raw materials would be poured into the container and the container would then be moved from the raw material staging area to the machine. Once processing is completed, the container would be moved from the machine to a lifting device for discharging. A typical design employs a dis charge cone with a modulating valve. The cone is clamped over the top of the product container, then container and cone are lifted by the hoist, inverted, and placed over a tote, mill, sieve, blender, etc. for emptying. Because the system is essentially closed, it provides a relatively dust-free method of handling the product. It is important when this methodology is employed, to provide multiple product containers so that processing can continue while one container is being loaded or discharged. Vacuum Discharge

Another method of evacuating material from the product container would be to use a vacuum evacuation device. By creating a vacuum in the target container, such as a blender, and connecting it by hose to the fluid bed product container, product is "vacuumed" from one container to the other. Bottom Dumping

A third approach is bottom dumping. With this configura tion, the container stays in the machine and the bottom plate opens to allow material to fall out of the container, through a transition plenum, through a modulating valve, into either a portable tote or a fixed-surge hopper. Evacuation of the machine is rapid and turnaround time between batches can be kept to a m1mmum. The major drawback of bottom dumping equipment is the height requirement for the process room. Machines with 300-500 kg batch-size ranges generally require rooms in excess of 25 ft high. Charging of the machine is efficiently handled by gravity, with a charge port connected to either a portable hopper or a fixed -charge hopper attached to the side of the machine. Vacuum charging is another option, but requires more time than charging by gravity.

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B.

Bottom Spray (Wurster) Coaters

Wurster, or bottom spray coating, equipment may require other approaches to product handling.

Movable Container Although Wurster chambers can be designed to be removed on a trolley and placed in a hoist for discharging, since the chamber is much more expensive to duplicate, having multiple containers makes this approach more costly.

Bottom Dumping Another way is to hinge the Wurster chamber to the support leg of the machine. Then, for discharging, the Wurster chamber is swung away to the side and the bottom plate is lowered at an angle via a pneumatic piston to discharge the material into drums or totes. A further method is to design internal bottom dumping. In this case, the bottom plate is shrouded within the machine housing and lowered internally to allow discharge of the product through the bottom of the machine much like a fluid bed dryer or granulator equipped with bottom discharging. In each of these two cases, turnaround time is very rapid and requires only one coating chamber. VIII.

SOLVENT-RECOVERY SYSTEMS

The use of organic solvents in fluid bed processors may require solvent scrubbing and/or recovery systems. Available methods fall into two basic categories: (1) Solvent-scrubbing systems, which, by various means, eliminate used solvent from the sys tern and (2) solvent-recovery systems, which collect the solvent for either disposal or reuse. A.

Solvent Scrubbing

Absorption In the absorption system, exhaust air passes through a rinsing apparatus that absorbs gases in a "scouring" solution. The absorption system is especially adaptable to water-soluble solvents, since water is a commonly used scouring solution. The solution is kept in a closed loop ; when it becomes saturated, it can either be discharged into the environment or regenerated by

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a process that distills the water out. The remaining mixture is disposed by other methods. An obvious shortcoming of this system is the environmental impact of the waste solution.

Adsorption In the adsorption method, exhaust air is directed through an adsorption tower that is commonly filled with active charcoal. Organic compounds are adsorbed by the large inner-surface area of the charcoal. When the carbon bed reaches its intended load of solvent, it must be regenerated. Generally, this is done by steam cleaning; the resulting solvent /water mixture then passes through a condenser to separate them and, again, further disposal methods must be considered, along with their environmental concerns. For this adsorption method, the fluid bed processor must have a very effective exhaust air filter since dust particles will quickly block the carbon element and prevent its efficeint operation.

Combustion Other solvent disposal methods include combustion systems, either thermal or catalytic. Thermal combustion systems require very high temperatures in the combustion chamber ( 600- 1000°C) , are energy intensive, and may have some byproducts that require further treatment. Catalytic combustion requires the use of precious-metal catalysts or metallic oxides, but combustion temperatures are lower (300- 500°C). B.

Solvent Recovery

Once-Through Systems In most recovery systems, the basic mechanism for removing the solvent from the process gas stream is condensation. In oncethrough systems, the process gas stream passes through singleor multistage condensors and is discharged to the atmosphere. Therefore, there is always a residual amount of solvent in the discharge gas.

Closed-Loop Systems In closed-loop solvent recovery systems, as depicted in Figure 13, the process gas is usually inert and passes over the condenser in either a partial or full stream. Once spraying is complete, each successive pass reduces the concentration of solvent

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FIGURE 13 Fluid bed equipment installation with solvent recovery system. (Courtesy Glatt Air Techniques, Inc., Ramsey, New Jersey.)

until the desired mm1mum concentration is obtained. The col lected solvent is either recycled or disposed. No matter what method is used, attention must be given to the impact on the safety of the whole fluid bed system and on the added resistance to airflow created by such a device. IX.

CURRENT GOOD MANUFACTURING PRACTICES (CGMPs)

Adherence to CGMPs for equipment cleaning is an area that is frequently neglected in the process of selecting fluid bed equipment. Attention to this issue can save numerous hours of cleaning that would be better spent in production. The complete ex-

Fluid Bed Equipment I 65

terior of the machine can be made easily accessible. The ma chine should be pedestal mounted so that the underside of the machine can be cleaned. Doors and other access points can be provided so that the interior of the machine and all product contact surfaces may be cleaned. The surface of the machine should be as free from ledges, tubes, sills, etc., as possible. Welds on any product-contact part of the machine should always be continuous and ground smooth. This includes welds in gasket channels. All gasketting should be solid, easily accessible and removable. Windows should be glass, as other materials tend to be easily scratched and grazed. Filters should be easily accessible and removable . Large machines should be easily cleaned with minimum requirements for moving heavy parts; if CIP (Clean In Place) systems are selected, their limitations should be discussed and understood. Provisions should be made for a sealing flap to separate the product-handling portion of the machine from the clean side of the H .E .P .A filters when the fan is not operating. This minimizes contamination of the clean side of the filter and facilitates cleaning of the machine between batches. Nozzle systems should be easily removable for cleaning. Location of the control panel should be selected to keep it dry while hosing the machine exterior. Drains in the machine and in the production area should be close enough to each other to facilitate removal of waste water from the cleaning process. X.

SAFETY

Safety of fluid bed processing equipment is an area in which one will find rather diverse opinions. At present there is no standard for safety, even though it is well known that fluid bed processes are susceptible to dust, gas, or dust /gas (hybrid) explosions. The safety area has been explored in great detail by regulatory agencies in Europe and they have set into law what is known as the 2-bar construction standard for fluid bed processing equipment. This standard requires the fluid bed equipment be able to withstand a 2-bar pressure differential across the vessel for a short duration. Therefore, it is recom mended that all fluid bed equipment should be constructed of sufficient strength to provide for this pressure shock resistance.

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Venting is absolutely necessary, as unvented dust or hybrid explosions could easily approach a 10-bar pressure. Explosionrelief flaps are best located on the clean side of the filter for CGMP reasons and must release at very low differential pressures, (.06bar). Machines can be constructed to relieve the pressure of an explosion either horizontally or vertically, but the length of the explosion relief duct is critical. Presently, acceptable standards indicate that the duct should not exceed a length of 6 meters nor have any one deflection angle greater than 20°. Rectangular explosion relief ducts need to be reinforced at regular intervals along the length of the duct. Explosion relief duct caps must be designed to relieve at very nominal pressures and these caps, as well as the relief vents, must be restrained to prevent them from becoming projectiles in the event of an explosion. The non-product handling portion of the machine must also be taken into consideration. Ductwork , the fan, and any parts between the process chamber and the fan must be able to withstand the same 2-bar pressure shock differential unless a quickacting explosion protection valve is placed between the machine and the exhaust ductwork. Since nearly all air-handling systems for fluid bed processing equipment are not capable of withstanding a 2-bar pressure, it is imperative that attention be given to isolating those devices from an explosion. Consideration must also be given to door-latching designs, thickness of sight glasses, and any other ports or openings in the processing vessel. All of these must be designed with the explosion hazard in mind. XI.

EQUIPMENT SUPPLIERS

Fluid Bed Equipment

Aeromatic Corporation, Towaco, New Jersey 07082 Fitzpatrick Company, Elmhurst, Illinois 60126 Fluid Air Corporation, Naperville, Illinois 60566 Glatt Air Techniques, Inc., Ramsey, New Jersey 07446 Vector Corporation, Marion, Iowa 46952 Spray Nozzles

Binks Manufacturing Company, Franklin Park, Illinois 60131 Gustav Schlick, GmbH and Company, Coburg, West Germany Sono-Tek Corporation, Poughkeepsie, New York 12602

Fluid Bed Equipment I 67

XI I.

SUMMARY

Fluid bed equipment has become an integral part of the pharma ceutical, food, and chemical processing industries. Its applications are in the areas of drying, granulating, and the applica tion of many types of coatings to a variety of substances. As the technology of fluid bed batch-processing equipment has evolved and become commonplace in production settings, atten tion has turned to the more sophisticated pelletizing processes, issues of safety, adherence to CGMPs, product-handling systems, and process automation. As the foregoing has shown, there are many factors to consider in specifying both the fluid bed process and equipment best suited to a certain application. APPENDIX:

A.

EQUIPMENT SIZE AND RANGES

Dryers, Granulators, and Top Spray Coaters

Processing equipment is available in size ranges relative to four different job objectives: feasibility testing, research and development, product development (pilot plant) , and production.

Feasibility-Testing Scale Most vendors supply fluid bed equipment in very small sizes that allow for exploring the feasibility of a process. These units generally range in batch size from 1/2-3 kg and are usually designed to be located on a lab bench top or a portable stand for easy relocation. For the most part, this equipment is sup plied with electrically operated heat and control systems and is generally not rated for use with flammable solvents. In-process data acquired from the lab-scale machine usually requires some, or perhaps considerable, scale-up work, and success is not always guaranteed in production -sized equipment.

Research and Development Scale This equipment generally ranges from 3-30 kg batch sizes. The machines usually are more geometrically faithful to production scale equipment and, by consequence, are more scaleable. They are available in multifunction designs offering a variety of fluid bed technologies in one machine. They should be well instru mented and have the possibility of sophisticated data collection, display and analysis.

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TABLE 1 Typical Wurster Sizes and Their Respective Average Batch Sizes

Wurster diameter (inches)

Batch sizesa (kg)

7

3-5

9

7-10

12

12-20

18

35-55

24

95-125

32

200-275

46

400-575

aThese ranges are approximate and are based on a product bulk density of 0. 89 g /cc. Charges will vary with different bulk densities. Product-Development (Pilot} Scale

Equipment for this task ranges in batch sizes from 30-100 kg and is usually a scaled down geometric and functional duplicate of production equipment. It allows the user to refine process parameters without excessive consumption of raw materials. Again, a good array of instrumentation and data collection devices are recommended. Production Equipment

Production -manufacturing-scale equipment ranges from 100-1, 500 kg per batch. Designs for this large equipment should pay significant attention to easy cleanability and rapid product handling to meet the requirements of a production setting. B.

Bottom Spray (Wurster) Coaters

Wurster equipment sizes are usually designated by the outer cylinder's diameter in inches. For example, a typical Wurster for research and development work would be designated as a 611 Wurster and would usually include a 3" inner partition; its batch

Fluid Bed Equipment

I 69

size would vary from 1/2-2 kg. Table 1 shows typical Wurster sizes and their respective average batch sizes.

ACKNOWLEDGMENT For substantial editing, writing assistance, and graphic contributions, a special aknowledgment goes to Catherine Sperber, Glatt Air Techniques, Inc.

Extrusion and Spheronizing Equipment DOUGLAS C. HICKS and HOWARD L. FREESE tion, Charlotte, North Carolina

I.

LUWA Corpora-

INTRODUCTION

Various methods for forming larger particles from small particles have been performed on a commercial scale for many years. This chapter will look at the equipment used to execute two of the shaping or forming methods-extrusion and spheronization. Equipment manufacturers are mentioned in the text as references for the reader, as a resource in identifying and selecting equipment for specific needs. An effort has been made to limit this discussion to equipment that is used in the pharmaceutical industry and, as a result, some manufacturers whose equipment is employed predominantly in other industries may be omitted. Melt, polymer, and cooking extruders will not be discussed, as they have technologies of their own. The design aspects of some nonpharmaceutical extruders are mentioned to give an overall understanding of the equipment and how they work. A comprehensive process and equipment development program can be undertaken by the reader if a specific application requires special equipment considerations. II.

EXTRUSION-GENERAL

Extrusion, a method of applying pressure to a mass until it flows through an orifice or defined opening, is a technique that determines two dimensions of an agglomeration of particles. Because the cross sectional geometry is defined by the orifice, exDOI: 10.1201/9781003066231-4

71

72 I Hicks and Freese

trudate length is usually the only dimensional variable. The extrudate length may vary, depending on the physical characteristics of the material to be extruded, the method of extrusion, and how the particles are manipulated after extrusion. Various types of extrusion devices have been grouped into the following general classifications: screw, sieve and basket, roll, and ram extruders. Screw extruders are the only strictly continuous extrusion devices, since product can exit in a smooth continuous flow. The remainder of the extrusion devices produce surges of material. A.

Screw Extruder

A screw extruder, as the name implies, utilizes a screw to develop the necessary pressure to force material to flow through uniform openings, producing uniform strands or extrudates. The screw extruder has three major zones that are defined by the principal mechanical operation being performed (Figure 1) : feed zone, transport and compression zone, and extrusion zone. The feed zone is the area where material is first introduced into the extrusion device. It consists of a hopper to channel the flow of material into the chamber where the screws are located. In some units, a conditioning mechanism is located in this zone so that liquid can be introduced into the powder and the material can be kneaded into a moist, homogeneous mass. Some coarse mixing of different powders can also be accomplished. Material in the transport zone is moved by the auger-like screws from the feed zone into the compression zone. Most extruder manufacturers have both single-screw and twin-screw

Feed Hopper

Screw Cooling/Heating Jacket

Gear Box and Drive Mechanism

t. ~ ~ Feed Zone

FIGURE 1

I ~ ~ I.

Compression Zone

~ I

~

I'.

I

~Extrusion Zone

~,

Schematic of screw extruder (axial type).

Extrusion and Spheronizing Equipment I 73 Feed

Vacuum Restriction

FIGURE 2

Die Plate

I

Outline drawing of vented extruder.

machine designs. The twin-screw extruder has the advantages of less "bridging" at the feed zone and better transport into the extrusion zone. Also, a greater capacity per screw is achieved in a twin-screw extruder. The single-screw extruder generally delivers an extrudate that is slightly more compact (higher density). In the compression zone, air is forced out from between the loose agglomerates and from the interstitial voids as particles are compacted together. Some extruders have vents in the com pression zone to release the expelled gases from the processing environment (Figure 2). A vacuum can be applied to vented extruders to facilitate the gas release and improve product quality or extruder performance. Note, however, that there must be a sufficiently long restriction in the barrel, which will "seal" the vacuum source to prevent product being entrained with the flow of outside air. The seal is usually created by enlarging the base of the screw until it is very close to the barrel wall. It is also possible to have an internal die plate so that the product is extruded into the vented chamber. Screw design varies in accordance with how much compression is needed. A low -pressure extruder may have regularly spaced screw flights which will give some compression, but the main function of these flights is to transport the material down the barrel of the extruder. Another design utilizes progressively closer screw flights, a decreasing helix angle, to develop very high compressive forces. A space is sometimes left at the front of the extruder, between the end of the screws and the die plate ; rheological properties of the material are such that some compression in this "surge" space can take place, and a more dense extrudate is possible. Less compression and a less dense extrudate are obtained when this gap is minimized. When the gap is small, material is compressed in the nip angle between the blade and the die face, forcing the product to flow through the

74 I Hicks and Freese

die openings utilizing "drag flow" pressure. When the gap is large, the total mass is compressed and higher "hydrostatic" pressures are developed which induce hydraulic flow. Extruders that rely solely on the pressure forces developed by the rotating screws employ "hydrostatic" pressure as a transport mechanism; these devices are generally high-pressure extruders. Those extruders that utilize a dragging or rolling motion have a localized "drag flow" transport mechanism and, consequently, the rate of work performed and internal pressures that are developed are much reduced. Abrasion rate, power consumption, extruder geometry, and capital and operating costs are positively correlated with the internal working pressure, so there are some compelling reasons to consider lower-pressure extruders. Several types of screw extruders utilize an extrusion blade to create a wiping effect at the die plate. Two fundamentally different mechanisms for screw extrusion are possible: axial (Figure 1) and radial (Figure 3). The extrusion bade for axial discharge extruders can be a continuous screw (Figure 4D) or look at perform in a fashion somewhat similar to an airplane propeller (Figure 4C). The material egresses at the end of the barrel in the same direction as it is transported. However, for a radial discharge extruder, the extrusion blades are either tapered cylinders or intermeshing-type blades (Figures 4A and 4B) . Material is extruded circumferentially through openings in the screen; the pathway for extrudate flow is perpendicular to the axis of the screws. Radial discharge extruders have the advantage of higher capacity, but because of the thinner dies, the extrudate is usually less dense. Material flow and compression behavior in a radial-type extruder, as well as an extrusion blade and nip angle, are shown in Figure 5. For both axial and radial extruders using extru sion blades, angled elements on the blades push material toward the die area, creating a region of localized higher pressure and, thus, product is forced through the die. If the material has unusual flow characteristics, some product may collect in front of the extrusion blade and tend to rotate across the screen or die plate with the motion of the screw. In this case, the screws must impart more driving force (work) so the material can be forced through the die openings, and the internal pressure in creases. The die openings in the screen or die plate may be of several basic designs. The shape- of the opening varies with the application. If a more dense product is needed, a thicker die

Extrusio n and Spheron izing Equipme nt

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75

(A)

Gear (Transfers power to driven shaft in a twin screw extruder) Extrusion Blade

Bearings

Feed Hopper

\

Cooling Water Oil Bath

Screw

Screen

Sprocket (B)

(A) Picture of twin screw radial discharg e extrude r. (B) Schemati c of twin screw radial discharg e extruder .

FIGURE 3

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FIGURE 4 Various extrusion blades: (A) conical radial, (B) intermeshing radial, (C) blade-type axial, and (D) continuous screw axial.

Extrusion Blade

Screw Force ~Friction

Blade

~ Perforated Screen

F o rc e ^

Nip Angle

t t

Die Forces

FIGURE 5

Radial screw extrusion forces.

Extrusion and Spheronizing Equipment

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TAB LE 1 Equipment Specifications for the Xtruder-Type Twin Screw Extruder

Model number EXD-60 Barrel diam meter (mm)

60

EXD-100 100

EXD-130 130

Capacity (kg/hr)

30-50

Drive motor (kw)

1. 5

5.5

7.5

Weight (kg)

500

800

1100

100-300

200-900

EXD-180 180

EXD-230 230

800-3000

2000-4500

15-18.5

22-30

1800

2500

plate or screen is required to withstand the greater extrusion pressure used. Care must be taken that force to overcome the pressure drop through the die does not exceed the horsepower rating of the drive train and motor. Bending of the die plate, a large temperature rise in the product, excessive wear, or overloading of the drivemotor can result. Equipment specifica tions for the Xtruder-type twin-screw extruder are given in Table 1. Figure 6 shows some of the common die configurations. For thin screens or die plates, the hole is typically straight with a slight neck or taper at the entrance due to the punching method; hole sizes from 0. 5-1. 5 mm are typical. Holes in die plates greater than about 1. 5 mm thick are usually drilled. The upper limit on hole size is determined by flow properties of the particular formulation, extrusion rate, and the ability of the extruder screws to compress and transport the material so that a consistent extrudate is obtained.

Cylindrical Tapered Inlet and/or Outlet Conical FIGURE 6

Alternative die designs.

2 3

78

I Hicks and Freese

'"

Drive """" "'' ""'

Side View FIGURE 7

Screen End View

Schematic of sieve extruder.

The extrudate is usually slightly curved, since it bends under its own weight after leaving the orifice. Gravity acting on the overhanging mass of extrudate causes tearing across a weak cross-section when the gravitational force exceeds the cohesive forces that bind the extruded mass together. Accordingly, the segments of extrudate have a somewhat irregular length, usually four to five times the length. For axial-type extruders, it is sometimes difficult to cut the extrudate into uniform lengths because the material extrudates at a faster rate on the periphery and at a lower rate near the axis. This phenomenon is a result of the complex flow and pressure patterns that are developed in the extrusion zone. A rotary knife or an oscillating wire can be used. B.

Sieve- and Basket-Type Extruders

Sieve extruders are constructed rather like the flour sifter used in baking. That is, they have a chamber that contains the material to be extruded and a plate or screen (Figure 7). A rotating or oscillating arm presses the damp material through a sieve or perforated screen to form short or long extrudates, depending on the moisture content. These devices generally give the least compaction of the various extrusion devices and, therefore, the number of attractive applications for this extrusion technique is rather limited. Some sieve extruders are used with moist materials to form granules suitable for feeding to tablet presses.

Extrusion and Spheronizing Equipment I 79

Basket-type extruders are similar to sieve extruders except that the sieve or screen is part of a vertical, cylindrical wall (Figure 8). The extrudate falls vertically from the sieve plate of a sieve-type extruder, while, in a "basket" extruder, the extrudate is formed in the horizontal plane as it is forced through the vertical holes. Actually, a basket extruder is similar to the radial -discharge extruder, except that material is fed into the extrusion zone by gravity rather than by screws. The perforated cylinder sits upright so that feed material falls into the chamber and in front of the extrusion blades. The ma terial is compressed in the nip, forced through the screen, and the resulting extrudate is diverted into a discharge chute by means of a slowly rotating, horizontal table. The pressure forces that develop are similar to those described for the screw extruders with extrusion blades, except that the extra compressive forces of the screws are not present. C.

Roll Extrude rs

Roll extruders, which are also known as "pellet mills," operate by feeding material between a roller and a perforated plate or ring die, a method that forces a moist formulation through the die. The basic designs can vary considerably and are summarized as follows: Type 1-- A ring die rotates around one or more rollers installed inside the cylindrical die chamber, each of which rotates on its stationary axis (Figure 9). Multiple rollers can be used to distribute or balance the forces and to increase capacity. All rotating components turn in the same direction. Feed material is introduced onto the inside surface of the ring die and pressed outward by the rollers. The orientation of the perforated cylinder is horizontal, sometimes with a slight inclination to facilitate feeding. Type 2-The roller or rollers are mounted on the outside of the ring die and material is fed from a hopper, occasionally with a screw, into the region between the roller and the die (Figure 10). Material is extruded into the center of the ring die and flows out one end. The roller and the die move in opposite directions. The orientation of the ring die is horizontal or slightly inclined. Type 3-Rollers are positioned above and roll along the surface of a flat, stationary die plate (Figure 11). The device resembles a muller with a perforated base, rather than a solid

80 I Hicks and Freese

(A)

Wiping Blades

Feed~ Hopper §

i

R otating D isch a rg e Plate

Screen

Stationary Side Wall E xtrusion Blade

Bevel Gears

Geared Drive Motor (B)

FIGURE 8

(A) BR Granulator-type basket granulator. (B) Schematic of basket ( gravity feed) extruder.

Extrusion and Spheronizing Equipment

I 81

Ring Die

Cutter

Direction of Rotation

Cutter Fl GU RE 9

Pellet mill with internal roller.

one. Feed material is charged into the top of the chamber and is pressed out the bottom through the die plate. The forces generated by the roll extruder are similar to those described for the screw extruder (Figure 12) with the following exceptions: 1.

Because there are no screws, the feed compression force is eliminated.

Flow of Material

Roller ._Ring Die

Direction of Rotation FIGURE 10

Direction of Rotation

Pellet mill with roller external to die.

82 I Hicks and Freese

-----------/eed

c:::=="""

Cutter

Side View FIGURE 11

2.

Top View

Pellet mill with rollers on flat die plate.

The rollers, as they rotate, transmit a nearly normal pressure force to the material rather than a diagonal drag-flow force. The shear rates developed in a pellet mill are usu ally less than in a similarly sized screw extruder.

Die configuration and layout are important design points for a pellet mill because these devices are often chosen for high capacity production and typically lower-value end products, and relatively high extrusion pressures can develop in the die area. The ring die is usually quite thick for mechanical design considerations, and a straight-through hole is most often used. Typical die configurations are shown in Figure 6. Along the exit side of the die, one or more fixed knives cut the pellets into fairly uniform lengths. Because the rollers induce a periodic, pulsing-type flow, some variation in length occurs. A variation in length of plus or minus a few extrudate diameters is possible. D.

Ram Extrude rs

The ram extruder is believed to be the oldest type of extruder. A piston riding inside a cylinder or channel is used to compress material and force it through an orifice on the forward stroke (Figure 13). Each return stroke allowance material to fall

Extrusion and Spheronizing Equipment

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83

__

_ 1_1

_

I

I

Frictional Force

1

t t t t t Die Force

FIGURE 12

Pellet mill extrusion forces.

into the chamber. The back pressure, due to friction in the die and from the compression of material against the walls, com presses the material, and a dense extrudate is formed. The important process variables are the length of the piston stroke, the frequency or period between strokes, the degree to which the cavity is filled on the backstroke, flow characteristics of the material, and configuration of the channel.

1-1 I

;...-Die Plate I I

► Piston Movement

FIGURE 13

Ram extruder.

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I Hicks and Freese

Reasonably exact extrudate length can be achieved, since the stroke of the press can be varied and controlled; but, because only one cut can be made per stroke, the specific capacity is limited when compared with other extrusion techniques. Any variation in length is due to incomplete filling of the cavity. E.

Automation and Instrumentation

Extrusion can be a batch, semibatch, or continuous operation. Pharmaceuticals, low-volume products, and materials requiring extremely complex manufacturing methods are processed batch wise. A semibatch production mode, or "campaign, 11 has a continuous character, e.g. , production lasting for one shift or one week. For batch operation, all the precursor steps and operations are controlled separately. The extruder should have the following process parameters monitored: feed rate, feed temperature, drive-motor or torque- developed power, extrudate temperature, coolant inlet and outlet temperatures, screen or die temperature, and compression chamber pressure. It is very important to note and record the equipment setup parameters, which include die size, die thickness, die configuration, type extrusion (axial or radial) , screw speed, coolant rate, and other equipment design variables. Figure 14 shows a typical laboratory extruder in operation. Animal feeds, industrial chemicals, and other high-volume materials are generally manufactured in a continuous, highly instrumented process. A typical continuous extrusion line includes other unit operations to make an integrated process. An extruder is simply a link in a chain of equipment, each of which has a unique design and a specific purpose. From this perspective, the extruder is usually required to perform these three functions: mixing /homogenizing, densification, and shaping or forming. The many operations in an extrusion system can be considered separately: powder metering, powder moistening and kneading, feeding to the extruder, extrusion, drying, and sieving. Since the sequence of these operations is generally fixed, there are some design and operating considerations common to many extrusion systems, even though the products are substantially different. A system can be automated so that powder is loaded into the front end and the finished product leaves the back end. This is, of course, the ultimate goal of a process engineer; in fact, well -trained operators and mechanics are needed for any state-of-the-art extrusion process. They must monitor the extrusion system and its related equipment to ensure

Extrusion and Spheronizin g Equipment I 85

FIGURE 14

Laboratory extruder in operation.

that production quality and rate standards are achieved, and to be prepared to quickly make setup changes or repairs to ma chinery. Automation usually begins in the bulk storage area. However, in the process area, it is the constant-ra te powder feeder that must control the powder input rate within a certain narrow range. This range may vary with material processed and with the type of equipment installed. It is easy to engineer and in stall a control system with a maximum 2% deviation from the feed rate setpoint, and less than a 1% deviation is possible with more sophisticate d controls. A microproces sor is a good choice when the process demands high precision. A loss-in -weight measuremen t scheme, where the computer compares a reading with an earlier measuremen t,

86 I Hicks and Freese

is a proven method that is used often. These control systems work independently from the extruder or can be integrated with it by programmable logic that prevents a piece of equipment from operating until all alarm conditions are satisfied. In the next step, the powder is moistened in a continuous kneader, pug mixer, muller, ribbon blender, or other device until a homogeneous "damp" mass is obtained. Note that the wetting /mixing is incorporated into some extruders. The rate of liquid addition can be controlled independently or by ratio, based on the powder-feeding rate via signals from the powder feeder. Since most mixers have some resident volume control, mixing time can be varied by raising or lowering a weir. Other important variables to monitor are liquid temperature, exit-mix temperature, powder requirements, and efficiency of mixing. The damp, well-homogenized material is then introduced into one of the various extrusion devices that are reviewed above. On leaving the extruder, the moist pellets can be introduced into a dryer to achieve final moisture specifications. Belt, fluid bed, or tray dryers are the most common types. Inlet- and outlet-air temperatures, final product moisture and temperature, inlet-air volume, bed height, and drying time are variables. It is important to know and understand the thermal properties of the product, including the "drying curve," which is an intensive property of a formulated material, determined by its chemical and physical properties. Next, the material is sieved to remove the over- and undersized particles and is then sent to a hopper for the packaging operation. A flow sheet for a simple, continuous production facility using screw extrusion is shown in Figure 15. Ill.

SPHERONIZING-GENERAL

Spheronization is not a relatively new technique. References to it start with the patent by N. Nakahara in 1966 [ 1]. It has been continually modified and improved ever since. The early trade name was Marumerizer, which means "round maker." Marumerization is still used to describe the process. A sphere has several geometric advantages over other forms. It has the lowest surface-to-volume ratio and, because of its shape, it is the easiest to coat. Spheronization typically begins with damp extruded particles, granules from one of the extruders presented earlier in this chapter. The extruded, cylindrically shaped particles are broken into uniform lengths almost instantaneously and

Extrusion and Spheronizing Equipment

0

l

I 87

3

Exhaust Air

t

5

Constant Feeder Continuous Mixer Liquid Addition Radial Extruder Fluid Bed Dryer Sieve

0 2

3 4

Inlet Air

5 6

To Packaging

FIGURE 15

Flowsheet of continuous extrusion plant.

are gradually transformed into spherical shapes; this shaping process is akin to "plastic deformation. 11 Because the feed was extruded strands, and these were first broken into nearly uniform lengths, all three dimensions of the agglomerate shape are determined, and spheres with a nearly uniform diameter are produced. In addition, powdered raw materials, which require the addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer. Both types of units will be discussed in this chapter.

88 I Hicks and Freese

(A)

(A) Marumerizer spheronizing machine. schematic of Marumerizer-type spheronizer.

FIGURE 16

(B) Parts

Extrusion and Spheronizing Equipment

Charge Chute

Moving Moving Baffle Baffle Assembly Assembly

Side Wall Jacket

I 89

Discharge Valve Discharge Chute

-

Friction Plate

^

S cra p e r

■

Spacer

Rotating Shaft

Fines Discharge

Product Discharge

V-Belt Sheve

(B)

A.

Spheronizing Equipment

A spheronizer is a device consisting of a vertical hollow cylinder (bowl) with a horizontal rotating disk (friction plate) located inside (Figure 16). Extrudate is charged onto the rotating plate and broken into short segments by contact with the friction plate, by collisions between particles, and by collisions with the wall. Mechanical energy introduced by the spinning friction plate is transmitted into kinetic energy in the form of a "mechanically fluidized bed," a more-or-less random mixture of airborne particles moving at high velocities. Further processing will cause the extrudate to deform gradually into a spherical shape. A typical processing cycle consists of charging a predetermined amount of material, allowing the material to be processed until desired shape or degree of spheronization is accomplished, discharging and resetting for the next batch. Changing the processing cycle time is tantamount to changing the mean num ber of collisions (plate, interparticulate, and wall) expected and, thus, changing the expected shape. This cycle time is quite reproducible and can be determined and predicted from

90

I

Hicks and Freese

TAB LE 2

Specifications for the Marumerizer-Type Spheronizer Model number QJ-230

QJ-400

QJ-700

QJ-1000

Plate diameter (mm)

230

400

700

1000

Working capacity(a) (liters)

0.25-1.5

1-5

5-25

25-60

Motor size (kw)

0.75

2.2

3.7

5.5

Weight (kg)

350

1100

1400

580

(a)Bulk densities are typically around O. 5 kg /liter for most pharmaceuticals. laboratory work. Table 2 shows the specifications for the four Marumerizer units. Figure 16 shows the fundamental components of a spheron izer. The most important component is the friction plate (Figure 17), which can have a variety of surface textures designed for specific purposes. The cross-hatch pattern is most common where the grooves intersect each other at 90° angles. A possibly more efficient pattern is the radial design plate, where grooves emanate from the center like spokes of a bicycle whell. More cutting edge is perpendicular to the direction of rotation so the resulting transfer of energy is greater. Unfortunately, as the grooves move outward from the center, the distance between the cutting edges becomes greater, reducing its effectiveness. The grid pattern is usually matched with the desired particle size. For example, a 1. 0-mm granule would be processed on a friction plate with an opening (groove) that is 50-100% larger. In this example, a plate with a 2. 0-mm groove would be selected. The wider groove allows the extrudate to fall into the opening so that the leading edge of the peak will fracture the extrudate into uniform lengths. (Usually, the length -to-diameter ratio of fractured pellets is 1.0-1. 2.) Various grid patterns are described in Figure 17. Other plate designs use a ring of Teflon or similar material at the outer circumference of the plate to prevent material buildup along the outside edge and to increase the upward motion of the particles after they collide with the wall. The proper motion of the moving aggregate of particles should resemble a twisting

Extrusion and Spheronizing Equipment

I 91

- ---~

I I

(A)

(B)

p

w

H

2

1

1

3

1.8

1.2

5

3

2

H

(C)

FIGURE 17 Typical grid pattern of friction plate. (A) Detail of grid pattern (cross-hatch design) . (B) Typical dimensions of plate design (mm). ( C) Cut away view of plate.

rope that seems to turn at an angular velocity significantly less than that of the spinning friction plate. Several auxiliaries are used, in certain cases, to speed and facilitate the rounding process. Figure 16A shows a unit with a powder feeder, an automatic plate cleaning device, a jacket for heating or cooling the wall, and a rotating baffle. The powder feeder is used either when the moisture content of the extrudate is slightly too high or when the material exhibits thixotropic behavior. Powder coats the outside of the particles and absorbs any moisture that would otherwise migrate to the surface of the particle during spheronization. This slight "dusting" also reduces the likelihood that particles will stick together after a collision and form an agglomerate. The powder should be a component of the formulation or a subsequent coating, or, at least, be compatible, since it is retained by the particle. In some cases, product will begin to collect on the wall due to the accumulation of moisture or an organic solvent, if one is used. The jacket can be used to elevate the temperature of the inside wall and drive off the moisture. Very little product drying can be accomplished by the jacket because of the low rate of heat transfer from the wall to the particle. For temperaturesensitive products, cooling the wall could help remove the heat

92 I Hicks and Freese

generated by the processing of the product. A temperature rise in the product is typical of any extrusion process, and work performed on the pellets to break them and change their shape is also transformed into a temperature increase; the most significant pickup of energy and temperature rise occurs in the extrusion step. Because viscosity, plasticity, and sticking tendency are all temperature-dependent properties, the ability to trim the wall temperature by using a heating or cooling medium in the jacket can be helpful in process control. Note, however, that the vessel design precludes the use of high fluid pressures, vacuum, and extreme temperatures. The plate cleaning device is simply a brush at the end of a hydraulic cylinder that extends downward and contacts the plate periodically, according to a preset pattern that can be determined from tests or experience. The baffle consists of several arms with pitched blades that rotate on the same axis as the friction plate, but in the opposite direction. Baffles are placed in close proximity to the wall and to the friction plate. A moving baffle is used to increase agitation by wiping the inside wall and directing the product into better contact with the friction plate. Wiping the wall helps to force material that may be "floating" around on top of a ragged rope back down to the friction plate; a spatula in a mixing bowl is an everyday example of how the baffles perform. A baffle riding across the top of the plate can direct material toward the plate, thus causing more uniform extrudate fracture and faster spheronizing. Variable-speed drives are standard options with extruders and spheronizers, since processing conditions can vary dramatically between applications and a need to change formulations or production rates can arise. For some products, a greater rate of energy is needed at the beginning of a processing cycle to break the pellets into proper lengths. Lower speeds are used to reduce attrition and abrasion of the particles.

Air-Assisted Spheronizers Dry air can be introduced under the plate to remove some of the surface moisture from the particles; this allows the granules to slide across each other more easily and facilitates the mechanical ly induced fluidization. Utilizing a small amount of sweeping air, it is possible, also, to directly spheronize dry powder. In this mode, the spheronizer performs like a mixer/ granulator wherein the binding liquid is injected directly into a mechanically fluidized

Extrusion and Spheronizing Equipment I 93 mass of fine-solid particles. The plate design is different because more agitation of fine powder is needed in order to achieve intimate dispersion of the binder. This type of spheronizer is very similar to a fluid bed granulator. The friction plate for an air-assisted unit looks rather similar to a plate for a standard Marumerizer unit , except for what appears to be a propeller-like device that is mounted on top (Figure 18) . The base is perforated (holes, slots, channels) so that air can be distributed throughout the product. Air also flows through the gap between the plate and the wall, and from the trailing edge of the propeller blades. Air-assisted spheronizers usually require an air filtration system for the discharging air, and some air pretreatment is also needed (heating, cooling, filtration, and/or possibly humidity control). B.

Automation and Instrumentation

Like extrusion, spheronization can be designed to proceed either batchwise or continuously. For batch operation, automa tion is relatively simple since only a few parameters need to be monitored. Processing time, jacket and product temperatures, and plate speed can be monitored by the use of timers, temperature recorders, and a tachometer. Some parameters are fixed before the unit is started: the size of friction plate, batch size , and whether the baffle , powder feeder, or other devices are used. Two methods for continuous production are possible: multiple batch and "cascade" flow. Both require a continuous flow of extrudate at a constant rate. Batch operation is necessary when a highly spherical product is needed, for it is with this method that it is possible to ensure that every particle "sees" the same spheronizing time. For multiple-batch operations (Figure 19), two or more spheronizers are used with the cycle time set so that one unit is discharging while the other is in the middle of the spheronizing cycle. A reversing belt can be used to, alternately, feed each spheronizer unit. Microprocessor control is recommended if the process requires speed changes, cleaning cycles , or powder addition. Cascade operation (Figure 20) is similar to the reaction kinetics concept of a number of continuous stirred tank reactors in series. Two or more units are linked in series to extend the total "residence" time. The friction plates are lowered below the discharge ports; because there is a step up, a fixed-volume

94

I

Hicks and Freese

(A)

FIGURE 18 (A) Air assisted Marumerize r. air assisted Marumerize r.

(B) Schematic of

chamber is created through which particles must flow before overflowing through the exit. Product is continually charged into one unit and continuousl y overflows into the next unit. Spheronizin g times in excess of three minutes use the "staggered batch" to achieve continuous production; products with spheronizing times shorter than three minutes can use the cascade approach. Compared with a batch installation, a cascade system produces granules that are less spherical, and the size distribu tion of the product is wider. However, much higher production rates are possible with the cascade approach. The wider distribution of particle sizes is attributable to the fact that some particles take a "short cut" and manage to flow immediately through

Extrusion and Spheronizing Equipment

►~

Air

I 95

Air Exhaust

Filter

----
>-

.i:s.

---c;) 0 0

TABLE 5

Q.

Specificat ions for the GRG Rotor Granulato rs

Descriptio n/ model

Disc diameter (m)

Disc speed (rpm)

Air volume (m 3 /hour)

;:r

Q

~

Motor capacity, disc (kW)

Turbine capacity (kW)

Rotor inserts GRG 3/5

.306

200-1000

580

0.55

GRG 5/9

1. 85

.480

200-1000

750

1. 5

GRG 15/30

4.0

.620

150-735

1500

4.0

GRG 30/60

7.5

. 780

120-615

3000

5.5

15.0

GRG 60/100

1.000

100-500

4500

7.5

GRG 120/200

18.5

1.400

70- 340

6000

11.0

22.0

Rotor units

Centrifugal Equipment I 115

nonperforated rotating disc at the base. The similarity, however, ends there. The cylindrical wall is truncated inward toward the disc, presumably to enhance smooth material motion. The disc height is also easily adjustable either automatically or by means of a hand lever, depending upon the size and model. This allows effective control of the air velocity, independent of the air volume. In addition, provision is made for the installation of a waffle plate on the disc surface to enhance pellet movement. The product chamber may also be fitted with a sample port, product temperature probe, vertically stacked and/or horizontally spaced nozzle ports, powder delivery port, and windows for viewing product movement. The installation of vertically stacked nozzle ports permits in-process adjustment of liquid spray nozzle position with an expansion of the product bed. Horizontally spaced nozzle ports are needed when production size units are employed. This permits more efficient layering and short processing times comparable to or better than small units. Powder Delivery

The design of the powder feed device is very critical. Criteria include ability to move the powder from a hopper into the bed at a uniform rate without bridging or pulsating. These criteria become particularly formidable when the air supply system or fluidization is mediated by suction instead of positive pressure. The negative pressure that develops within the machine during operation tends to disrupt the controlled delivery of powders from ordinary feeders. Provision should, therefore, be made in the design of the feeders to circumvent this constraint. Several types of screw feeders that differ in design and performance are available commercially. Selection of a feeder should, therefore, be based on the compatibility of the feeder with the type of air flow directed through the rotary machine. Numerous tests with specific powders of different physical properties should be made, preferably before final selection of the powder feed device. Air-Handling and Exhaust Systems

The air supply and exhaust systems for Glatt rotor granulators are very similar to those employed with fluid bed dryers, granu lators, and coaters, and the reader is referred to Chapter 3 for detailed description of the systems.

116

I Goodhart

Expansion Chamber

Because the Granu-Glatt and the GPCG-5 are designed to handle traditional fluid bed granulation and coating, their expansion chambers are relatively high. They are intended to facilitate fluidization of particles vertically at high velocities. By contrast, the expansion space of the GRG-series, where the flexibility of having fluid bed granulating and coating options is not required, is much more shallow. The machine is suitable for pelletization by powder and solution/suspension layering. Product Discharge

Depending on the sizes of the machines, the product is discharged in a variety of ways. In small units, the product container is easily removed with the help of a detachable trolley and the product is manually transferred to drums or other containers. Obviously, this approach is not practical with larger machines. Processed material is discharged from production-size units either by gravity or centrifugal forces. The centrifugal action created by the rotating disc allows the product to be discharged through an outlet chute located at the base of the product cham ber. Spray Systems

The spray systems of the Glatt rotor granulators are similar to those described in Chapter 3, except that liquid is sprayed tangentially into the bed. The position of the gun is such that it is totally immersed in the rotating product throughout the layering process. Control Panel

The control systems that are currently employed with fluid bed processors, as well as with Glatt rotary equipment, are discussed in detail in Chapter 3. The controls for rotor granulators include inlet-air volume, inlet- and exhaust-air temperatures, spray rates, atomization pressures, disc height, and disc speed. Dewpoint measurement and control of inlet air is also useful in monitoring the process. The measurement of the moisture saturation of the outlet air is also helpful in establishing an optimal process.

C.

Roto-Processor

Aeromatic, Inc. has developed basic equipment, known as the Multi-Processor (MP-1), which can be utilized for several pro-

Centrifugal Equipment I 117 Powder Feeder

~

Nozzle

Fluidizing Air

(A)

Adjustable Disk

(B)

FIGURE 6 Schematic diagram of the processing portion of a Roto-Processor. (Adapted from technical brochures, Aeromatic, Inc. , Towaco, New Jersey.)

cesses using appropriate inserts or modules. One of these in serts is the Roto-Processor [ 3] , which is dedicated to the production and coating of pellets and spheroids. It differs from other centrifugal machines by utilizing an inner wall that allows for two modes of operation (Figure 6) . Technical data for the unit is given in Table 6.

Product Container The product processing chamber has a rotating disc that is partially perforated toward the periphery, and an outside cylindrical chamber, and an inner bowl. Pellets may be processed with the

118 I Goodhart TABLE 6

Rota-Processor Technical Data (Multiprocessor MP-1)

Description Nominal capacity, kg Air volume in m 3 / s

2-4

0.1-0.15

Drive motor, kW

3.3

Product container, usable volume, liters

3.5

Weight, including table and cart, kg

305

inner walls in the open (Figure 6A) or closed (Figure 6B) position. During the initial stages of the pelletization process, the wall remains stationary until simultaneous binder spraying and powder application produces spheres. Once spheres are formed, the Roto-Processor walls lift up and allow the particles to enter the fluidization air zone. The fluidization air pushes the spheres up and over the Rota-Processor wall before they return to the inner bowl of the product container. The cycle is then repeated until dry pellets are obtained. The disc height and speed are adjustable.

Powder Delivery Device The Rota-Processor utilizes an overhead powder feed system (Figure 6) . The powder is transported from a hopper to the inner bowl through a nozzle filled with a horizontal screw and mounted on the side of the expansion chamber above the product container. Once the powder leaves the screw, it is fed under gravity through a feed tube.

Product Discharge Finished product is discharged by centrifugal force through an exit port into a sealed container or through a pneumatic discharge system where the pellets may be pneumatically conveyed to a holding hopper.

Control System The operator's control panel, which houses the various gauges and control levers, may be floor mounted or recessed into a wall.

Centrifugal Equipment I 119 TABLE 7

Specifications for the Spir-a-Flow

Model SFC-Mini

Working capacity (kg) 0. 5-1

SFC-15

15-30

SFC-50

50-100

SFC-150

150-300

SFC-300

300- 600

Air Supply and Exhaust Systems A blower /motor assembly supplies the processing air. Depending upon the needs of the customer, additional features may be in corporated into the system. These features, which include fil tration and humidification/dehumidification units, are discussed in detail in Chapter 3.

D.

Spir-a-Flow

Spir-a-Flow [ 1] is an enclosed, centrifugal fluid bed unit manu factured by Freund and supplied by Vector. Machines are available in a variety of sizes beginning with the SFC-Mini Spir-aFlow and proceeding to the SFC- 300. The working capacity ranges of these units are given in Table 7. A schematic diagram of the various components of the assembled machine is shown in Figure 7.

Product Chamber The product chamber consists of a partially perforated disc and a cylindrical wall or stator. Fluidization, therefore, is based on positive air flow supplied into bed both through the 0. 3-0. 5 mm openings in the disc and the clearance between the rotor and stator. Dampers control the proportion of air supplied to these two areas independently. Disc height is adjustable. Provisions are also made for the inclusion of high speed mixer blades to prevent lumping during granulation and an agitator to process materials with high moisture content. Pellets, however, are processed upon the removal of the agitator and lump breaker.

120 I Goodhart

~. ~

PROCESSED AIR OUT

FILTER

RAW MATERIAL

SOLUTION SPRAY ' NOZZLES

PROCE~ AIR IN

CIRCULAR AIR/SOLUTION PARTICLE FLOW AREA

PROCESSED MATERIAL OUT

ROTATING DISK

FIGURE 7 Schematic diagram of the processing chamber of Spir-a- Flow. (Adapted from technical brochures, Vector Corporation, Marion, low a. )

Product Charging and Discharging

Product is charged by gravity through a port in the expansion chamber and discharged by centrifugal motion through an outlet port on the stator.

Centrifugal Equipment I 121

Spray System The Spir-a-Flow utilizes a gear pump to deliver the binder to the product bed, although other types may also be used, if desired. The spray guns are positioned high up in the stator wall and, as such, are not totally immersed in the bed during layering. They, however, apply binder solution tangentially and concurrently to the centrifugal movement of the bed.

Powder Delivery Device Spir-a-Flow rotor granulators do not have provrn10ns for powder delivery devices and may not be used for powder layering without further modification.

Expansion Chamber The expansion chamber of the Spir-a- Flow unit is conical in shape to allow gas flow to expand and promote particle deceleration. It may be fitted with viewing windows to permit visual monitoring of bed movement. IV.

SUMMARY

Rotary granulators are the newest, most advanced pieces of processing equipment for formulation and manufacture of pellets. These machines are made by several companies who offer a variety of sizes, starting with laboratory units of 1-5 kg capacity. Larger sizes use the same principle and design features but include additional components such as an increased number of spray ports and added instrumentation and control features. Description of unit size is usually given in the range of working capacity, disc diameter, or disc area. Rotor granulators are ideally suited for automation because all processing variables are identifiable and can be measured and controlled. Automatic operation adds to the initial capital cost and requires validation as well. However, once validated, better uniformity and reliability can be achieved if the processing cycles are complex and require multiple changes in machine settings.

122

I

Goodhart

REFERENCES 1.

Manufactured by Freund and supplied by Vector Corporation, 675 44th Street, Marion, Iowa 52302.

2.

Manufactured and supplied by Glatt Air Techniques, Inc. , 20 Spear Road, Ramsey, New Jersey 07446.

3.

Manufactured and supplied by Aeromatic, Inc. , 1 Indian Lane East, Towaco, New Jersey 07082.

Mechanism of Pellet Formation and Growth ISAAC GHEBRE-SELLASSIE Plains, New Jersey

I.

Warner-Lambert Company, Morris

INTRODUCTION

One of the most significant properties of pellets is their ability to withstand the mechanical forces that act on them during the manufacturing process and the subsequent conditioning and/or coating and handling. If the pellets lack sufficient mechanical strength, they may disintegrate completely or wear down in size due to frictional forces. This phenomenon becomes pronounced during a coating operation, particularly in fluid bed equipment where pellets are in constant motion and rub against each other and against the walls of the machine. The intensity of these interparticle and particle-to-wall frictional forces depends mainly on the atomizing and fluidization air pressures. It is absolutely essential, therefore, that pellets possess sufficient strength to overcome any appreciable abrasion during agitation. The role that pellet strength plays during the development of high-quality products has been well recognized. As a result, a number of procedures that attempt to evaluate the strength of pellets experimentally have been developed, and are discussed in Chapter 11. In addition, various theoretical and mathematical expressions designed to explain the strength of pellets have been proposed [ 1- 5] . An attempt, therefore, is made in this chapter to explain, not only the mechanisms of pellet formation and growth, but also the fundamental bonding forces that determine the strength of pellets during any pelletization process.

DOI: 10.1201/9781003066231-6

123

124

I Ghebre-Sellassie

II.

BONDING FORCES

The strength of pellets depends, to a great extent, on the physical forces that bond the primary particles together. Although, initially, mechanical forces, such as tumbling, kneading, agitating, extruding, rolling, and compressing are needed to bring individual particles in contact with one another [ 6, 7] , these physical forces are also responsible for the inherent strength of other types of agglomerated particles. As a result, the various bonding forces that determine the strength of all forms of agglomerates, including pellets and granulations, have been studied extensively and can be classified into five categories [ 8] •

A.

Attraction Between Solid Particles

Attractive forces are short-range forces that cause solid particles to adhere to each other only if they are brought close enough together. Their effectiveness diminishes dramatically as the size of the particles or interparticle-distance increases. Therefore, the significance of attractive forces in the overall mechanism of agglomerate bonding is not so much that they play a crucial role in the binding of the final product; it is that they initially hold and orientate the particles in a contact region long enough for stronger forces to take over. At times, however, they can be very important in their own right. Attractive forces may be molecular (valence and Van der Waals), electrostatic or magnetic in nature. Valence forces are effective only up to distances of 10 A, and can be disregarded as pellet-forming bonds since, in particulate systems, the effect of surface roughness alone can lead to a separation greater than ten angstroms [ 3] . By contrast, Van der Waals dispersion forces are believed to make the most significant contribution to all intermolecular attractive effects and are partly responsible for the adhesion that exists between particles less than O. 1 micron apart [ 3] . They are thus considered as legitimate bonding forces although their practical significance may be minimal [ 8] . Electrostatic forces are commonly encountered with fine powders, and are primarily produced during size reduction or due to interparticle friction. Sometimes, mere contact between particles may produce the effect [ 3] . This phenomenon is particularly true with particles in the dry state, and depends upon the nature of the material and the type of agitation. Electro-

Pellet Formation and Growth

I 125

static forces exert their influence through excess charge or an electrical double layer. The adhesional forces generated due to excess charge are very small and even then the charges tend to equalize or neutralize as a function of time. Their contribu tion to particle bonding is, therefore, negligible, with one exception. The forces developed between negatively and positively charged particles can be significant enough to provide meaningful contribution to the overall bonding mechanism [ 8]. The electrical double layer that develops whenever particles touch each other is much more significant and generates adhesional forces that are permanent. Magnetic forces, though they may not be encountered during the systematic development of drug pellets, could also be considered as bonding forces. Should they exist, however, they are expected to produce very strong bondings between particles. B.

lnterfacial Forces and Capillary Pressure in Movable Liquid Surfaces

In any wet agglomeration process, it is the liquid phase in the system that initially generates the cohesive forces between particles. Therefore, the amount and type of liquid present at any given time is very critical in determining the strength of the final product (Figure 1). The liquid could be introduced prior to or during the agglomeration step. When liquid is added in itially, part of the void space in a randomly packed material is filled with the liquid to form discrete lens-like rings at the contact and coordination points between particles forming the agglomerate [ 2, 6] . The number of contact points on any one particle is a function of the distribution and surface geometry of the adjacent particles. This stage of the agglomeration process, where the ratio of the liquid to the void volume is low and air is the continuous phase, is known as the pendular state [Figure lA]. Mutual attraction of particles is brought about by the surface tension of the liquid and the negative suction pressure generated at the liquid bridges [ 6] . The forces that bond the particles are, therefore, derived from the interfacial tension at the liquid-gas interface. The capillary state is reached when all the void space within the agglomerate is completely filled with the liquid (Figure lC). The quantity of liquid, however, is not sufficient enough to surround the agglomerate. Since the liquid extends up to the edges of the pores at the surface, a concave meniscus, which creates a negative capillary pressure, develops at the surface of the agglomer-

126

I

Ghebre-Sellass ie

(A)

(B)

(C)

(D)

□

AIR

■

LIQUID

e

SOLID

Liquid saturation in a spherical assembly of particles. (A) Pendular state, (B) funicular state, (C) capillary state, and (D) droplet state. (Adapted from Refs. 6 and 8.)

FIGURE 1

Pellet Formation and Growth

I

127

ate and gives rise to bonding forces. Capillary pressure and interfacial forces create strong bonds between particles, which disappear once the liquid evaporates. Between the pendular and capillary states exists an intermediate state known as the funicular state (Figure 1B). In the funicular state, as in the pendular state, liquid bridges containing gas and pores filled with liquid are present. Here, however, the liquid forms the continuous phase and pockets of air, dispersed throughout the agglomerate, are present [ 6] . The cohesive strength of the agglomerate is attributed to the bonding forces exerted by the pendular bridges and capillary suction pressure [ 2, 8] . In the droplet state, the liquid completely envelopes the agglomerate (Figure lD). The primary particles are held together only by the surface tension of the droplet [ 8] . There is no interparticle capillary bonding. The concave surfaces observed with the capillary state are replaced by the convex surfaces of the liquid droplet. Thus, the strength of the droplet is dependent only on the surface tension of the liquid used.

C.

Adhesional and Cohesional Forces in Bonding Bridges That are Not Freely Movable

Viscous binders and thin adsorption layers provide bonds that are based on immobile liquid bridges [ 8] . Highly viscous binders adhere to the surfaces of solid particles to generate strong bonds that are similar in characteristics to those that exist with solid bridges. Because the effect of the interfacial forces on the mobility of the surface liquid is significantly reduced, a constant liquid pressure, similar to what is commonly observed with freely mobile bridges, cannot be formed. Consequently, the binder retains the shapes of the surfaces on which it is deposited. In addition, many viscous binders harden during the agglomeration process and form solid bridges. Thin -adsorption layers are also immobile and can form strong bonds between adjacent particles by either smoothing out surface roughness and increasing the interparticle contact area or by decreasing the effective interparticle distance and allowing the intermolecular attractive forces to participate in the bonding mechanism (Figure 2A) . The areas of contact of adsorption layers increase appreciably when the solid particles are subjected to a high pressure like compression and produce high bonding forces.

128 I G he br ese na ss

ie

(A)

(B)

(C)

FIGURE 2 Fo rm al re pr es en ta ti on of (A ) (B ) so lid br id th in ad so rp ti ge s, an d ( C ) on la ye rs , m ec ha ni ca l in te rl oc ki ng . fr om R ef s. 4 (A da pt ed an d 8. )

Pellet Formation and Growth I 129 D.

Solid Bridges

Although the bonding mechanisms discussed above contribute significantly to the forces that initially bond the primary particles together, it is the solid bridges that largely determine the strength of the final cured or dried product. Solid bridges are formed by different mechanisms (Figure 2B) and are discussed below [8]. 1. Crystallization of dissolved substances. As the dissolving medium evaporates, the dissolved solids crystallize out and form bonds at the points of contact. The dissolved substance may be identical to the bonded particles in nature or it may be the solid component of the binding liquid. 2. Hardening binders. Binders are commonly applied from solutions to agglomerate primary particles. Upon curing, these binders harden and form solid bridges that owe their strength to the properties of the binder substance itself, the forces of adhesion between the binder and particles, and/or the physicochemical characteristics of the particles forming the agglomerate. 3. Me !ting. Substances that melt on the input of energy tend to solidify when cooled, and invariably form strong, solid bridges between particles. The strength and extent of the bridges formed can be either small or large depending on the chemical composition of the melted material and the other con stituents of the agglomerate. 4. Sintering and chemical reaction. Formation of solid bridges by these mechanisms are not common in the pharmaceu tical industry and are not discussed further. The preceding discussion indicates that solid bridges are formed at high pressures and temperatures. These bridges may consist of solutes left behind after the evaporation of the liquid phase, solids formed on what was originally liquid, or solids derived from the molten material. The most common solidbonding mechanisms that are usually encountered during· the manufacture of drug pellets are hardening of binders, crystallization of solutes during the curing or drying stage of the pelletiza tion process, and melting and subsequent cooling of pellet components tha-c may occur during compression, extrusion, or spray congealing. E.

Mechanical Interlocking

Mechanical interlocking of particles may occur during the agitation and compression of fibrous, flat-shaped and bulky particles

130 I Ghebre-Sellassie [ 8] (Figure 2C). It is probably a minor contributor to pellet strength, although it can provide sufficient mechanical strength to resist the disruptive forces caused by elastic recovery following compression [ 9] . Ill.

ELEMENTARY GROWTH MECHANISMS

It is essential that the fundamental mechanisms of pellet forma -

tion and growth are clearly understood in order to judiciously select and optimize any pelletization process. Various theories that attempt to explain these mechanisms have been postulated. Some of these theories are supported by experimental results, while others are inferences relying on visual observations [ 6, 7, 10, 11] . The most convincing and generally accepted results were obtained from experiments that utilize some form of tracer techniques [ 6, 12, 13] . Based on these experiments, a formal representation of the elementary growth mechanisms of pellet formation was proposed (Figure 3). These mechanisms, known as nucleation, coalescence, abrasion transfer and layering, are believed to constitute a complete set of elementary events which, directly or indirectly influence the growth and formation of pellets during manufacture [ 6]. Although it is the bonding forces discussed earlier that eventually hold the primary particles together, mechanical forces are needed to bring the particles in close proximity to effect the formation of bonds, with or without material bridges. The mechanical forces will be covered later in the chapter. An attempt, therefore, is made in this section to describe the elementary events that lead to the formation of pellets. A.

Nucleation

Nucleation is a growth mechanism in which primary particles are drawn together to form three-phase air-water-solid nuclei (Figure 3A) [ 6]. The particles are held together by liquid bridges, which are pendular in nature. The liquid is either added to the primary particles at once in a carefully controlled manner or sprayed slowly onto a mass of dry powder to produce moist nuclei. An important feature of nucleation is that both the mass and number of the nuclei in the system change as a function of time [ 6] .

IA)

1B)

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