Pharmaceutical Science Pharmaceutical Dosage Forms: Tablets, Volume Two examines: s formulation examples for stability, facilitating, and manufacturability s systematic approaches to design formulation and optimization of dosage forms s immediate release and modified release tablets about the editors LARRY L AUGSBURGER is Professor Emeritus, University of Maryland School of Pharmacy, Baltimore, and a member of the Scientific Advisory Committee, International Pharmaceutical Excipients Council of the Americas (IPEC) Dr Augsburger received his Ph.D in Pharmaceutical Science from the University of Maryland, Baltimore The focus of his research covers the design and optimization of immediate release and extended release oral solid dosage forms, the instrumentation of automatic capsule filling machines, tablet presses and other pharmaceutical processing equipment, and the product quality and performance of nutraceuticals (dietary supplements) Dr Augsburger has also published over 115 papers and three books, including Pharmaceutical Excipients Towards the 21st Century published by Informa Healthcare STEPHEN W HOAG is Associate Professor, School of Pharmacy, University of Maryland, Baltimore Dr Hoag received his Ph.D in Pharmaceutical Science from the University of Minnesota, Minneapolis The focus of his research covers Tablet Formulation and Material, Characterization, Process Analytical Technology (PAT), Near Infrared (NIR) Analysis of Solid Oral Dosage Forms, Controlled Release Polymer Characterization, Powder Flow, Thermal Analysis of Polymers, Mass Transfer and Controlled Release Gels Dr Hoag has also published over 40 papers, has licensed four patents, and has written more than five books, including Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third Edition and Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, both published by Informa Healthcare Printed in the United States of America $+ PHARMACEUTICAL DOSAGE FORMS: TABLETS New to the Third Edition: s developments in formulation science and technology s changes in product regulation s streamlined manufacturing processes for greater efficiency and productivity Third Edition The ultimate goal of drug product development is to design a system that maximizes the therapeutic potential of the drug substance and facilitates its access to patients Pharmaceutical Dosage Forms: Tablets, Third Edition is a comprehensive treatment of the design, formulation, manufacture, and evaluation of the tablet dosage form With over 700 illustrations, it guides pharmaceutical scientists and engineers through difficult and technical procedures in a simple easy-to-follow format Volume 2: Rational Design and Formulation about the book… PHARMACEUTICAL DOSAGE FORMS: TABLETS Third Edition Volume 2: Rational Design and Formulation Augsburger r ■ Hoag Edited by Larry L Augsburger Stephen W Hoag Pharmaceutical Dosage Forms: TABLETS Pharmaceutical Dosage Forms: TABLETS Third Edition Volume 2: Rational Design and Formulation Edited by Larry L Augsburger University of Maryland Baltimore, Maryland, USA Stephen W Hoag University of Maryland Baltimore, Maryland, USA Informa Healthcare USA, Inc 52 Vanderbilt Avenue New York, NY 10017 © 2008 by Informa Healthcare USA, Inc Informa Healthcare is an Informa business No claim to original U.S Government works Printed in the United States of America on acid-free paper 10 ISBN-13: ISBN-10: ISBN-13: ISBN-10: ISBN-13: ISBN-10: 978-0-8493-9014-2 (v : hardcover : alk paper) 0-8493-9014-1 (v : hardcover : alk paper) 978-0-8493-9015-9 (v : hardcover : alk paper) 0-8493-9015-X (v : hardcover : alk paper) 978-0-8493-9016-6 (v : hardcover : alk paper) 0-8493-9016-8 (v : hardcover : alk paper) International Standard Book Number-10: 1-4200-6345-6 (Hardcover) International Standard Book Number-13: 978-1-4200-6345-5 (Hardcover) 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 consequence 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 dosage forms Tablets – 3rd ed / edited by Larry L Augsburger, Stephen W Hoag p ; cm Includes bibliographical references and index ISBN-13: 978-0-8493-9014-2 (v : hardcover : alk paper) ISBN-10: 0-8493-9014-1 (v : hardcover : alk paper) ISBN-13: 978-0-8493-9015-9 (v : hardcover : alk paper) ISBN-10: 0-8493-9015-X (v : hardcover : alk paper) ISBN-13: 978-0-8493-9016-6 (v : hardcover : alk paper) ISBN-10: 0-8493-9016-8 (v : hardcover : alk paper) Tablets (Medicine) Drugs–Dosage forms I Augsburger, Larry L II Hoag, Stephen W III Title: Tablets [DNLM: Tablets–pharmacology Drug Compounding Drug Design Drug Industry–legislation & jurisprudence Quality Control QV 787 P536 2008] RS201.T2P46 2008 2007048891 6150 1901–dc22 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Ave., 16th floor, New York, NY 10017 Visit the Informa web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com To my loving wife Jeannie, the light and laughter in my life —Larry L Augsburger To my dear wife Cathy and my children Elena and Nina and those who helped me so much with my education: My parents Jo Hoag and my late father Jim Hoag, Don Hoag, and Edward G Rippie —Stephen W Hoag Foreword We are delighted to have the privilege of continuing the tradition begun by Herb Lieberman and Leon Lachman, and later joined by Joseph Schwartz, of providing the only comprehensive treatment of the design, formulation, manufacture and evaluation of the tablet dosage form in Pharmaceutical Dosage Forms: Tablets Today the tablet continues to be the dosage form of choice Solid dosage forms constitute about twothirds of all dosage forms, and about half of these are tablets Philosophically, we regard the tablet as a drug delivery system Like any delivery system, the tablet is more than just a practical way to administer drugs to patients Rather, we view the tablet as a system that is designed to meet specific criteria The most important design criterion of the tablet is how effectively it gets the drug “delivered” to the site of action in an active form in sufficient quantity and at the correct rate to meet the therapeutic objectives (i.e., immediate release or some form of extended or otherwise modified release) However, the tablet must also meet a number of other design criteria essential to getting the drug to society and the patient These include physical and chemical stability (to assure potency, safety, and consistent drug delivery performance over the use-life of the product), the ability to be economically mass produced in a manner that assures the proper amount of drug in each dosage unit and batch produced (to reduce costs and provide reliable dosing), and, to the extent possible, patient acceptability (i.e., reasonable size and shape, taste, color, etc to encourage patient compliance with the prescribed dosing regimen) Thus, the ultimate goal of drug product development is to design a system that maximizes the therapeutic potential of the drug substance and facilitates its access to patients The fact that the tablet can be uniquely designed to meet these criteria accounts for its prevalence as the most popular oral solid dosage form Although the majority of tablets are made by compression, intended to be swallowed whole and designed for immediate release, there are many other tablet forms These include, for example, chewable, orally disintegrating, sublingual, effervescent, and buccal tablets, as well as lozenges or troches Effervescent tablets are intended to be taken after first dropping them in water Some modified release tablets may be designed to delay release until the tablet has passed the pyloric sphincter (i.e., enteric) Others may be designed to provide consistent extended or sustained release over an extended period of time, or for pulsed release, colonic delivery, or to provide a unique release profile for a specific drug and its therapeutic objective Since the last edition of Pharmaceutical Dosage Forms: Tablets in 1990, there have been numerous developments and enhancements in tablet formulation science and technology, as well as product regulation Science and technology developments include new or updated equipment for manufacture, new excipients, greater understanding of excipient functionality, nanotechnology, innovations in the design of modified release v vi Foreword tablets, the use of artificial intelligence in formulation and process development, new initiatives in real time and on-line process control, and increased use of modeling to understand and optimize formulation and process parameters New regulatory initiatives include the Food and Drug Administration’s SUPAC (scale up and post approval changes) guidances, its risk-based Pharmaceutical cGMPs for the 21st Century plan, and its PAT (process analytical technology) guidance Also significant is the development, through the International Conference on Harmonization of proposals, for an international plan for a harmonized quality control system Significantly, the development of new regulatory policy and new science and technology are not mutually exclusive Rather, they are inextricably linked The new regulatory initiatives serve as a stimulus to academia and industry to put formulation design, development, and manufacture on a more scientific basis which, in turn, makes possible science-based policies that can provide substantial regulatory relief and greater flexibility for manufacturers to update and streamline processes for higher efficiency and productivity The first SUPAC guidance was issued in 1995 for immediate release oral solid dosage forms (SUPAC-IR) That guidance was followed in 1997 with SUPAC-MR which covered scale-up and post approval changes for solid oral modified release dosage forms These guidances brought much needed consistency to how the Food and Drug Administration deals with post approval changes and provided substantial regulatory relief from unnecessary testing and filing requirements Major underpinnings of these two regulatory policies were research programs conducted at the University of Maryland under a collaborative agreement with the Food and Drug Administration which identified and linked critical formulation and process variables to bioavailability outcomes in human subjects The Food and Drug Administration’s Pharmaceutical cGMPs for the 21st Century plan seeks to merge science-based management with an integrated quality systems approach and to “create a robust link between process parameters, specifications and clinical performance”1 The new PAT guidance proposes the use of modern process analyzers or process analytical chemistry tools to achieve real-time control and quality assurance during manufacturing.2 The Food and Drug Administration’s draft guidance on Q8 Pharmaceutical Development3 addresses the suggested contents of the pharmaceutical development section of a regulatory submission in the ICH M4 Common Technical Document format A common thread running through these newer regulatory initiatives is the building in of product quality and the development of meaningful product specifications based on a high level of understanding of how formulation and process factors impact product performance Still other developments since 1990 are the advent of the internet as a research and resource tool and a decline in academic study and teaching in solid dosage forms Together, these developments have led to a situation where there is a vast amount of formulation information widely scattered throughout the literature which is unknown and difficult for researchers new to the tableting field to organize and use Therefore, another objective to this book to integrate a critical, comprehensive summary of this formulation information with the latest developments in this field Thus, the overarching goal of the third edition of Pharmaceutical Dosage Forms: Tablets is to provide an in-depth treatment of the science and technology of tableting that J Woodcock, “Quality by Design: A Way Forward,” September 17, 2003 http://www.fda.gov/cder/guidance/6419fnl.doc http://www.fda.gov/cder/guidance/6672dft.doc Foreword vii acknowledges its traditional, historical database but focuses on modern scientific, technological, and regulatory developments The common theme of this new edition is DESIGN That is, tablets are delivery systems that are engineered to meet specific design criteria and that product quality must be built in and is also by design No effort of this magnitude and scope could have been accomplished without the commitment of a large number of distinguished experts We are extremely grateful for their hard work, dedication and patience in helping us complete this new edition Larry L Augsburger Stephen W Hoag 538 [Formulation challenges, in vitamin/mineral preparations solubility characterictics] vitamin A, 315 vitamin D, 316 vitamin E, 316 vitamin K, 316 Forward chaining procedure, 141 Freeze-drying technology, 297 Frictional force, on drugs, 26–27, 252f Friedman test, 121 FS 30 D, 528 F-test, 120 Furosemide, 209–210 Fuzzy logic, 160–161 Gambir Troches, 362 Garcinia kola, 344 Gaussian functions, 148 Gelcarin GP-379 NF, 449, 474f Gelcarin GP-911 NF, 474f Gel layer, 438 Geomatrix Technology, 461 Geometric mean value, 109 Gibbs energy, of a system, 13, 20–21 Gigartina stellata, 469 Ginkgo biloba, 345 Glass boluses, 411 Glidants or powder flow improvers, assessment of activity, 263–264 tablets, 264–264t Glinus lotoides, 343 Glutaric acid, 67 Glyceryl behenate (Compritol), 179 Glyceryl tri-behenate, Goal driven process, 142 Goădels incompleteness theorem, 140 Gordon-Taylor, 74 GRAS material (Generally Regarded As Safe), 67 Gummy see Lozenges/troches Handbook of Pharmaceutical Excipients, 183, 231, 255 Hardness/friability, of veterinary tablets, 423 Harmonic mean, 109 Heptane, Herbal lozenge, 368 Heuristics, 142 Hexylresorcinol, 372 High-pressure homogenization, 58–59 Hot melt extrusion (HME) process, 75–76 Hot-melt granulation processing, 223, 230 H-test, 121 Human interferon alpha oral lozenges, 368 Index Hybrid matrices, 456–463 coating with permeable and semipermeable films, 460 dome, 462–463f drug release kinetics, example, 457f–458f manufacturing technology, 461 multi-layer, 461 overview, 456 synchronization of swelling, 459 time-dependent coating effect, 461 Hydrogenated vegetable oils, 227, 228 Hydrophile lipophile balance (HLB), of surfactant, 274 Hydrophilic colloid disintegrants, 219–222 Hydrophilic derivatives, 68 Hydrophilic hot-melt binders, 227 Hydrophilic network, 221 Hydrophobic derivatives, 68 Hydroxylated b-CD, 68 Hydroxypropyl cellulose (HPC), 240, 448 Hydroxypropylmethylcellulose (HPMC), 4–6, 441–446, 450–451 Hydroxypropyl methylcellulose phthalate, Hyperbolic tangent function, 147 Hypericum perforatum (St John’s wort), case study, 350–356 Ibuprofen, 198 sustained release coated pellets, 526–527 swellable matrices, 449t Immediate release (IR) solid oral-dosage forms, 52 Impurities, in veterinary tablets, 391–398 aldehydes, 392–393 antioxidants, 397–398, 398t metal, 395–396 peroxides, 391–392 reducing sugars, 393–395 small molecules, 396–397 water, 391 Inert matrices, 434 Inorganic carbonates, 218, 222, 243 Inorganic materials, 241–242 In situ micronization technique, 59–60 In situ particle size control by precipitation technology, 59 Insoluble coatings, 36 Interface energy, 12–13 Interfaces between phases, 12 Internal barriers, Interquartile range, 108 Intestinal characteristics, across veterinary species, 385t Intrinsic dissolution rate, 34–36 Ionizable derivatives, 68 IPDAS (Intestinal Protective Drug Absorption System), 525 Index Irish Moss (Chondrus crispus), 469 IR-spectroscopy, 471 Isotropic solutions, 83–84, 90–97 Itraconazole, 79 Japanese Pharmacopoeia, 255 Java Expert System Shell (Jess), 144 JavaNNS software, 156 Kappapycus alvarezii, 469 Kelvin equation, 56 Ketoconazole, 53 Ketoprofen, 448t Kilogram force unit, 420 Kilopond unit, 420 Knowledge-based (KB) systems, 140–169 applications of, 162–163 for formulations for hard shell capsules, 163–164 immediate release oral solid dosage forms, 162–163 related, 163 Bayesian networks (BN), 157–159 evolutionary computing, 161–162 first order logic (FOL) system, 139–140 future of, 168–169 fuzzy logic and possibility theory, 160–161 languages and tools, 144–146 CLIPS and JESS, 144 decision trees, 145–146 Product Formulation Expert System (PFES), 145 Prolog, 145 neural networks and neural computing, 146 applications, 164–168 backpropagation networks, 149–154 competitive learning and self-organizing map, 155 overview, 146–149 radial basis function (RBF) network, 154–155 support vector machine, 155–156 tools, 156 overview, 138–139 rule-based (RB) system, 140–144 Knowledge representation (KR), 138 Kofler technique, 67 KollicoatÒ, 522 Kollicoat SR 30 D, 529 Kollidon CL, 528–529 Kolmogorov–Smirnov test (K-S test), 116 Korsch rotary tablet press, 163 Kruskal–Wallis test, 122 Kurtosis, 111 539 Lactose, 175, 192–194 Lactose monohydrate, Languages and tools, of KB systems, 144–146 CLIPS and JESS, 144 decision trees, 145–146 Product Formulation Expert System (PFES), 145 Prolog, 145 Larazepam tablets, 275 Leaching, of porous sphere, 43–45 Least significant difference (LSD test), 117 Levenberg-Marquard equation, 478 Levene test, 117 Levodopa methylester (LDME), 461 Linear variable displacement transformer (LVDT), 303 Lipid-based formulations, 83–97 digestibility, 84–86, 85f drug release, 87–90 factors affecting bioavailability, 84–90 isotropic solutions, 83–84, 90–97 lipid solubility, 86 points to consider, 90–97 hygroscopicity, 93–95 manufacturing, 96–97 solubility, 90–93 stability, 95–96 type of lipids, 86–87 Lipophilicity, of drugs, 86 Liquid interface, in a body, 7–8 Logistic function, 147 Low-substituted hydroxypropylcellulose (L-HPC), 301 Lozenges/troches, 364–378 anti-malodor properties, 367 applications, 364–365 as anesthetic, 365 as anti-inflammatory, 365 as antimicrobial, 366 capsaicin, 369 caries prevention, 366 for common cold, 366 composition, 361–370 chewable, 370 hard, 361, 369 soft, 361–362, 369–370 contemporary studies, 365 as cough suppressant, 366 definitions/types, 361 diuretics, 366–367 formulation studies, 371–372 herbal, 368 historical use, 362–364 hormonal changes, 367 human interferon alpha oral, 368 magnesium chloride, 369 pain management, 367 540 [Lozenges/troches] patient counseling, 373 PEG-based, 362 physicochemical considerations, 371 preparation, 370–371 quality control, 372 sample cormulations, 373–378 smoking, 367–368 stability, 372–373 storage/labeling, 372 virucidal, 368–369 for xerostomia, 368 Lubricants, 4, 228, 271–272 evaluation of activity of, 253–255 friction and, 252–253 functions, 251 tablet, 255–261, 256t in tableting process, 253 water soluble and water miscible, 261 LubritabÒ, 179 Lyophilization, 322 M ilicifolia, 346 Magnesium aluminum silicate, 242 Magnesium carbonate, 222 Magnesium chloride lozenge, 369 Magnesium lauryl sulfate, 261, 272 Magnesium stearate, 4, 228, 255–261, 271–273, 527–529 pharmacopoeial specifications for, 257t physicochemical properties, 258t Maltodextrin, 196 Mannitol, 4, 6, 196, 529 Mass balance, of the drug, 22 Material properties and drug release, 7–21 equivalent dimensions, calculation, 18–21 interface energy, 12–13 interfaces between phases, 12 liquids, 7–8 polymers, 9–10 porous medium, 11–12 solids, 8–9 solutes, 13–18 wetting, impact of, 13 Mathematical model, of drug release, 21 Mathematical optimization, 131–134, 132t MATLAB NN Toolbox, 156 Matrix effects, on drugs, 39–47 example, 41–47 polymers, 40–41 porous medium, 39–40 Maxalt-MLTÔ (rizatriptan benzoate), 293, 297 Maxwell–Stefan (MS) equation, 27 Maytenus ilicifolia, 344 Mean emulsion droplet diameter (MEDD), 86 Index Measure of central tendency, 108–110 Media milling process, 57–58, 58f, 74, 224–225 MegaceÒ ES (PAR), 57 Meggle D10, 526 Melt-quenched method, 73 Menthol Troches, 362 Methylated b-CD, 68 Methylcellulose (MC), 4–6, 448–450 Microaggregated egg albumin particles, 516 Microcapsules, 486–487 Microcrystalline cellulose (MCC), 4, 173, 184–192, 240, 277–278, 472, 479–480, 480f, 514 Microparticulate Drug Delivery Technology, 525 Milling method, 224–225 botanical extracts, 341 micronization, 105, 216 Mirtazapine SolTabÒ, 296 MODASÒ, 499 Moisture-activated dry granulation, 173 Molar units, 14 Monobasic compound, 62 Monolithic matrix drug delivery systems, 529 Monoprotic acid, 62 Mucositis, 366 Multi-angle laser-light scattering (MALLS) detector, 471 Multiflash dosage, 525 Multiparticulate systems, 510–529 best conditions to avoid the drug release alteration by compression of, 521t definitions and characterictics, 510–512 examples, 525–529 bisacodyl pellets, enteric coated, 527–528 enteric microencapsulated acetylsalicylic acid, 525–526 ibuprofen sustained release coated pellets, 526–527 piroxicam pellets, enteric coated, 528–529 verapamil hydrochloride pellets, 529 flow characterictics, 513 monolithic matrix drug delivery systems, 529 tableting and drug release characteristics, 513–525 Multiple linear regression analysis, 120–121 Multivariate analysis of variance (MANOVA), 118–120, 124 MYCIN program, 138, 145 NanoCrystalÒ, 57 Nanotechnology, 61 NeoralÒ, 84, 86 Nernst–Planck equations, 35 NeuralMaker program, 156 Neural networks and neural computing, 146–168 applications, 164–168 backpropagation networks, 149–154 Index 541 [Neural networks and neural computing] competitive learning and self-organizing map, 155 defined, 138 learning, 149 overview, 146–149 radial basis function (RBF) network, 154–155 support vector machine, 155–156 tools, 156 NeuralShell program, 156 Newton (N) unit, 420 NexiumÒ 20, core of, 7, 7f ingredients, 2t instructions for consumption, purpose of ingredients, 8t Niacin, 316 Niacinamide, 316 Nicotinamide, 67 Nicotine, 367–368 Nifidepine lipid solution, 89t 5-nitroisophthalic acid, 67 Non-parametric ANOVA, 121–122 Non-swelling matrix tablets, Normal distributions, 110–111 Noscapine, 366 Noyes–Whitney equation, 55 Null hypothesis, 112 OROSÒ Methylphenidate (Concerta Ò), 505–506 OROS Nifedipine (Procardia XLÒ), 503–505 Orosolv dosage, 525 OROSÒ Oxybutynin (Ditropan XLỊ), 505 OsmodexƠ, 496–497 Osmotic pump, 36 Osmotic systems, 493–505 classification and application, 498t commercial products, 496–500 COERÔ, 499 DUROSỊ, 500 EOP-Porous Membrane (PM), 498 MODASỊ, 499 OsmodexƠ, 496–497 Push-PullÔ LCT, 499 SCOTÔ, 497–498 Zer-OsÔ, 499 design, 493–496 examples of oral delivery systems, 503–505 OROSÒ Methylphenidate (Concerta Ò), 505–506 OROS Nifedipine (Procardia XLÒ), 503–505 OROSÒ Oxybutynin (Ditropan XLÒ), 505 formulation attributes, 500–501 therapeutic objectives, 493 unit operations for manufacturing, 501–503 Ostwald–Freundlich equation, 56 Ondansetron hydrochloride, 295 OPS5 program, 144 Orally disintegrating tablets (ODTs), 293–308 benefits, 293 choice of excipients, 300 compendial descriptions of orally disintegrating tablets and related tablet formulations, 307t designed, 293 disintegrating agents, 301 disintegration time, 303–307 formulation considerations, 295–296 inactive ingredients listed, 300t limitations, 294 measurement of taste, 302–303 other forms chewable tablets, 307–308 effervescent tablets, 308 sweeteners, 301–302 technologies for manufacturing, 296–300 cotton candy/candy-floss process, 297 examples of platforms, 296t freeze-drying, 297 tablet compression method, 297–300 versus conventional hydrochlorothiazide tablets, 295t Oral transmucosal fentanyl citrate (OTFC), 367 OraSolvÒ technology, 296 Panthenol, 316 Pantothenic acid, 316 Paracera P/drum dried corn starch/Kollidon CL (50:33.3:16.7; w/w/w), 528 Parametric test procedures, 113–114 ParteckÒ, 196 Particle engineering, 59–60 Particle size reduction, 55–61 effects, 55–56 diffusion layer, 56 lumiar hydrodynamics, 56 saturation solubility, 56 surface area, 55 future trends, 61 main mechanisms, 61f stabilizers and techniques of stabilizing fine particles, 60–61 technologies, 57–60 theoretical aspects, 55–56 Passion flower, 346 PearlitolÒ SD, 196 PEG-6-stearate, 299 Pellet, 296, 308 coated, 296, 509, 511 cylindrical, 409 implantable, 390 inert, 513 542 [Pellet] intraruminal, 411 matrix, 515 porosity of, 515 rigid, 515 soft, 515 sulfate, 295, uncoated, 409 Pellet drying procedure, 515 Peltab System, 525 Peppermint Troches, 362 Permeability classification, of drugs, 52 The Pharmaceutical Recipe Book, 362 Pharmazone, 525 Phenolpthalein Troches, 362 Phenylbutazone tablet formulations, 275 Phoqus LeQtradoseÒ electrostatic dry powder coating, 199 PH-solubility profile, of salt of acid, 63f Phyllanthus niruri, 344 “Pilling,” a pet, 398 Pine Bark extract, 337 Piroxicam pellets, 528–529 Piston-gap homogenizers, 58 Plain tablets, 4–5 Plantago lanceolata, 344 Plasticizers, PlexiglassÒ discs, 439–440 POE glycol monostearate, 274 Polacrillin potassium, 235 Polarity, of solvents, 8f Polar molecules, Polyamidoamine (PAMAM) dendrimers, 98 Polyanion–polycation complexes, 477 Poly(ethyl acrylate), Polyethylene, Polyethylene glycol monostearate, 273 Poly-ethylene glycol (PEG), 389 Polymer (s), 5–6, 9–10, 74, 77 coating, 520–522 matrices, 40–41 Poly(methacrylic acid, ethyl acrylate) 1:1, Poly(methacrylic acid, methyl methacrylate) 1:2, Poly(methyl methacrylate), Polymorphs, 71 Polyoxyethylene (POE), 274 Polyoxyl 40 stearate, 273 Polysorbate 80, 273, 278 Polystyrene, 10 Polyunsaturated fatty acids, 404 Polyvinylalcohol, (PVA, Mowiol 40–88), 441 Polyvinylpirrolidone (PVP), 450–451 Poly vinyl pyrrolidone, 4–6 Poorly water-soluble drugs, 51–98 absorption and bioavailability of, 51 co-crystal formation, 66–67 complexation using cyclodextrin, 68–70 Index [Poorly water-soluble drugs complexation using cyclodextrin] background, 68 complex formation, 68–70 lipid-based formulations, 83–90 factors affecting bioavailability, 84–90 isotropic solutions, 83–84, 90–97 modification of crystal, 70–83 amorphous formulation development, 71–83 conventional approaches, 70–71 opportunities and challenges, 53–55 physical modifications, 55–61 future trends, 61 particle size reduction technologies, 57–60 stabilizers and techniques of stabilizing fine particles, 60–61 theoretical aspects, 55–56 prodrug formation, 97–98 salt formation, 62–66 commonly used salt formers (counter acids) for monobasic drugs, 64t commonly used salt formers for weak acidic drugs, 64t solubility and dissolution rates, 64–66 theoretical aspects, 62–64 Populations, statistical, 110 Porous matrices, 39 Porous tablets, wetting of, 41–43 Possibility theory, 160–161 Potassium Chlorate Troches, 362 Potassium metabisulfite, Poultry digestive tract, 387 Pound force (lbf) unit, 420 Povidone K-30, 529 PPDS (Pelletized Pulsatile Delivery System), 525 Prandtl equation, 56 Precipitation with a Compressed Antisolvent (PCA) technology, 59 Pregelatinized starch, PrejelÒ, 451 Pressure, in a granule, 20 Pressure plasticity, 479 Primogel, 178 Primojel, 304, 304f, 451 Processed euchuma seaweed (PES), 471 Prodrugs, 97–98 Product Formulation Expert System (PFES), 145 Prolog, 141, 145 Propoxyphene napsylate, 211–212 Propylene glycol, 529 Pseudoephedrine HCI, 199–200 Push-PullÔ LCT, 499 Pyridine–carboxylic acid heterosynthons, 67 Pyridoxine hydrochloride (vitamin B6), 317 Pyrilamine maleate, 203–204 Index Quality-by-design (QbD) initiatives, 175–176 Quinine tannate troches, 362 Radial basis function (RBF) network, 154–155 RapamuneÒ (Wyeth), 57 Rapid expansion of the SCF solutions (RESS) technology, 59 RediTabsÔ (loratadine rapidly-disintegrating tablets), 296 REMERON SolTabÒ, 296 Repulsion phenomenon, 221 Response surface methodology (RSM), 129–131 Revalor-XSÒ, 408, 410f Riboflavin (vitamin B2), 316 Roller compaction (RC), 175 Root mean square (RMS) deviation, 120 Rule-based (RB) system, 140–144 Ruminant, 386 Saccharin, 67, 302 Salt formation, of compounds, 62–66 monobasic drugs, commonly used salt formers (counter acids) for, 64t selection of appropriate, 65–66 decision tree, 65f solubility and dissolution rates, 64–66 theoretical aspects, 62–64 weak acidic drugs, commonly used salt formers for, 64t SandimmuneÒ, 84, 86 Santonin troches, 362 Sarnoff Delsys AccuDepÒ electrostatic deposition, 199 Scanning electron micrograph (SEM), 183 Scheffe test, 118 SCOTÔ, 497–498 Self-emulsifying drug delivery systems (SEDDS), 55, 84–88, 96 Self-microemulsifying drug delivery system (SMEDDS), 55, 84–88, 96 Self-organizing map (SOM), 155 Semantics, 138 Semisolid extracts, 338 Senna extract, 337 Shapiro–Wilk test, 116 SICStus Prolog program, 145 Sigmoid functions, 147–148 Silver acetate, 368 Simulated Gastric Fluid (SGF), 53 Skewness, 111 Slow oral dissolution tablets See Lozenges/troches Smecta, 242 Smoking cessation programs, 368 SNNS software, 156 543 SODAS (Spheroidal Oral Drug Absorption System), 525 Sodium alginate, Sodium calcium alginate, 278 Sodium carboxymethylcellulose (NaCMC), 441, 449–450 Sodium glycolate, 274 Sodium lauryl sulfate (SLS), 89, 261, 272–273, 277 Sodium starch glycolate, 4, 178, 236–237 Sodium stearyl fumarate (PRUV), 4, 179 Sodium taurocholate, 275 Sodium tauroglycolate, 275 Softchew tablets, 306 Solid interface, in a body, 8–9 Solid oral drugs, release of See also Dosage forms absorbtion and adsorption, act of transfer, example, 1–2 in burst form, 24 concentration at a certain site, dissolution, of spheres, 46–47 dosage forms, 4–7 coated tablets, 5–6 effervescent tablets, 6–7 non-swelling matrix tablets, plain tablets, 4–5 swelling matrix tablets, effect of a matrix, 39–47 example, 41–47 polymers, 40–41 porous medium, 39–40 forces and velocities of mixture, 26–38 bootstrap relations, 27 Diffusion–Fick’s law, 27–28 diffusivities, 29–29t driving forces, 26 electrical force, 28 example, 29–38 friction, 26–27 inside the body, 2–3 material properties, role, 7–21 equivalent dimensions, calculation, 18–21 interface energy, 12–13 interfaces between phases, 12 liquids, 7–8 polymers, 9–10 porous medium, 11–12 solids, 8–9 solutes, 13–18 wetting, impact of, 13 mathematical model, steps, 21–25 example, 22–25 mass balances, 22 system boundaries, 21–22 no removal of the drug situation, 22–24 passage of drug, 2–3 role of blood, 544 [Solid oral drugs, release of] role of internal barriers, slowly, 24–25 Soluble polymers, 243 Solutes, 13–18 of drugs in water at 25˚C, 16t effect of composition, 14–15 potential, 14 solubilities, rules for, 15 solubility and partitioning, 15–16 weak electrocytes, 16–18 Solvent-controlled precipitation (SCP), 76 Solvent evaporation method, 76 Solvias (Switzerland), 66 Sorbents, 269 Sorbitol, 196 Soy based products, 405 Soy polysaccharide, 240–241 SpasfonÒ, 304 Spray-dried lactose (SDL), 178 Spray-drying process, 77–78, 78f Spray-freezing into liquid (SFL) process, 60 SPSS software, 115–116, 118 SSCI, Inc (USA), 66 St John’s wort See Hypericum perforatum (St John’s wort), case study Stabilizers, 60–61 Standard deviations, 110 Starch, 194–195, 276–277 alginic acid, 234–235 chemically modified, 234 native, 232–233 polacrillin potassium, 235 pregelatinized (pregelled), 233–234 types used as disintegrants, 232t Starch 1500, 178, 241 Statistical considerations, in formulation and process development, 107–122 data, 107–108 data samples and populations, 110–111 measures of central tendency and variability of data, 108–110 non-parametric analysis of variance, 121–122 presentation of data, 108 test statistics, 111–114 univariate analysis of variance (ANOVA), 114–121 Stearic acid, Step function, 147 Steric stabilizers, 60–61 SterotexÒ, 179 Strong–Cobb unit, 420 Student–Newman–Keuls test, 117–118 Sucralose, 302 Sucrose, 195 Sucrose monoesters, 274 Sugar pellets, 519 Index Suggested blending procedure for direct compression or encapsulation, 324–325 Sulfadiazine, 387 Sulfamerazine, 387 Sulfathiazole, 387 Sulfur and Potassium Bitartrate Troches, 362 SUPAC-IR guidance, 53 Supercritical fluid technologies (SCF), 59 Superdisintegrants, 235–239 Support vector machine (SVM), 155–156 SureleaseÒ, 522 Surface tensions, 13 Surfactants, 85 effects on physical properties of tablets, 279 effects on tablet formulations, 276–279 functions of, 271–275 Swellable matrices, 435–463 chain entanglement in, 440f hybrid matrices, 456–461 manufacturing techniques, 436, 442–446 materials and formulation, 446–452 mathematical modeling of drug release, 452–456 cellulose ether-based matrix tablet, scheme of, 453f release parameters, 435–442 structure and physicochemical characteristics of cellulose ethers, 437t trends, 462–463 Swelling front, 438 Swelling matrix tablets, Swelling phenomenon, 220, 244 of a polymer, 5f SyloidÒ, 182 Symyx Technologies Inc (U.S.A.), 66 Syntax, 138 Tablet compression method, 297–300 Tablet formulation expert system, 162–163 Tablets See also Lozenges/troches; Orally disintegrating tablets (ODTs) carrageens in, 478–487 controlled release properties, 483–486 formation properties of, 478–481 physical tablet properties, 481–483 solid dosage forms, 486–487 chewable, 307–308 coated, 5–6 effervescent, 6–7, 308 non-swelling matrix, plain tablets, 4–5 swelling matrix, Tableting See also Multiparticulate systems coloring, 280–286 additives subject to certification, permitted for use in the European Union, 284t Index [Tableting coloring] additives subject to certification, permitted for use in the United States, 282t–283t incorporation of, 281–285 regulatory aspects and issues, 280–281 selection for tablet forms, 285–287, 286t types of agents, 280 uses, 280 disintegrants in, 218–244 definition, 218 general structure and form, 218–219 influence of other formulation components, 226–228 influence of processing, 223–226 methods of disintegration, 244–245 methods of evaluation, 243–244 possible mechanisms, 219–222 review of, 235–243 use and incorporation of, 228–230 disintegration and dissolution, 270 effect of surfactants, 276–279 excipients, 269–270 formulation variables to consider for coated pellets, 520t lubricants in, 253 particle size reduction, 55–61 effects, 55–56 future trends, 61 main mechanisms, 61f stabilizers and techniques of stabilizing fine particles, 60–61 technologies, 57–60 theoretical aspects, 55–56 role of cushioning excipients, 522–525 Taguchi, Genichi, 129 Talc, 4, 261–262, 528–529 Tanacetum parthenium (Feverfew), case study, 347–350 parthenolide stability in, 348–349 pharmaceutical quality and dissolution performance of, 349–350 physical properties, 347–348 Tannic acid troches, 362 Taste and texture, of tablets, 302–303 Terephthalaldehyde, 67 Theophylline, 200–201 Thiamin (vitamin B1), 316 Time plasticity, 479 Toluene, Triaminic Softchews, 306 TriCorÒ (Abbott), 57 Trigeminal, 303 Triglas technology, 525 Trimesic acid, 67 Trimethoprim, 387 Troches See Lozenges/troches 545 Troglitazone, 53 a-tocopherol, Tukey’s “honest” significant difference, 118 Two wet milling (media and homogenizing) processes, 57 Tylenol R, 451–452 Ultraamylopectin, 273 United States Pharmacopoeia National Formulary 24, 255 Univariate analysis of variance (ANOVA), 114–121 USP Veterinary Drugs Expert Committee, 388 Verapamil hydrochloride pellets, 529 Veterinary tablets, 383–424 chewable, 403t, 404f development of, 390–398 choice of excipients, 390–391 impurities, 391–398 manufacturing considerations, 398 dosage form-specific considerations, 398–406 economic considerations, 384 forms, 390 formulations approved for use in companion animal species, 387t intestinal characteristics, across veterinary species, 385t marketing considerations, 389 odor causing molecules, use, 406t oral bolus, 409–422 challenges in product design, 415–416 designing a robustness study, 416–417 FDA-approved formulations, 412t role in therapy, 409–415 validation process, 418–422 physicochemical characteristics, 384–388 species for which there are approved tablet formulations, 386 specifications for forms, 422–424 subcutaneous implant form, 408–409 sustained release, 406–408 time and cost expenditures, 384t Veterinary Biopharmaceutics Classification System (vBCS), 388–389 Virucidal lozenge, 368–369 Viscarin GP-209, 449 Viscarin GP-209 NF, 449, 474f Vitamin A, 315 Vitamin D, 316 Vitamin E, 316 Vitamin K, 316 Vitamin/mineral preparations, formulation challenges in, 318–332 effects of moisture and humidity, 318–320 546 [Vitamin/mineral preparations, formulation challenges in] examples, 325–331 factors enhancing stability adsorbate preparations, 322 antioxidants, 322 chelating agents, 322 coating and encapsulation, 322 lyophilization, 322 reduction of water content, 321–322 homogeneity in blending, 324 liquid formulations, 322–323 mutual interactions of vitamins in combination with each other, 320–321 ascorbic acid and cyanocobalamin, 321 ascorbic acid–vitamin D (ergocalciferol), 321 riboflavin-ascorbic acid, 321 riboflavin-folic acid, 321 riboflavin-niacinamide, 321 thiamin-cyanocobalamin, 321 thiamin-folic acid, 321 thiamin-riboflavin, 320 protection to enhance stability, 323–324 shell life, 331–332 solubility characterictics, 315–318 ascorbic acid (vitamin C), 317 biotin, 317 cyanocobalamin (vitamin B12), 317 folic acid (pteroylglutamic acid), 316–317 niacin and niacinamide, 316 panthenol, 316 pantothenic acid, 316 profile at 25˚C, 315t pyridoxine hydrochloride (vitamin B6), 317 riboflavin (vitamin B2), 316 stability relative to pH, 317–318 thiamin (vitamin B1), 316 Index [Vitamin/mineral preparations, formulation challenges in solubility characterictics] vitamin A, 315 vitamin D, 316 vitamin E, 316 vitamin K, 316 Vitamin stability, 314 Void fraction, 11 Volume fractions, 14 Welch approximation, 116 Wet granulation binders, 227 Wet granulation processing, 222–223, 229–230 Wetting, 13 impact on drug release, 13 of porous tablets, 41–43 Wicking phenomenon, 220 Wilcoxon test, 121 Working memory (WM), 141 Wowtab, 304 Xanthan SM, 241 Xylan, 241 Xylitol, 366 Yellow phenolphthalein, 205–207 Zer-OsÔ, 499 Zinc lozenges, 366 ZOFRANÒ (ondansetron), 293 ZydisÒ technology, 296 .. .Pharmaceutical Dosage Forms: TABLETS Pharmaceutical Dosage Forms: TABLETS Third Edition Volume 2: Rational Design and Formulation Edited by Larry L Augsburger University of Maryland Baltimore,... Botanicals and Their Formulation into Oral Solid Dosage Forms Susan H Kopelman, Ping Jin and Larry L Augsburger 12 Formulation of Specialty Tablets for Slow Oral Dissolution Loyd V Allen, Jr... only has to work until the tablet is swallowed This can be achieved with a number of materials Typical examples are cellulose–esters (such as hydroxypropyl methylcellulose or methylcellulose) and