Aulton's Pharmaceutics: The Design and Manufacture of Medicines 5th Edition PDF

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Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2015v1.0 www.konkur.in Aulton’s Pharmaceutics The Design and Manufacture of Medicines www.konkur.in This page intentionally left blank www.konkur.in Aulton’s Pharmaceutics The Design and Manufacture of Medicines FIFTH EDITION Edited by Michael E. Aulton BPharm PhD FAAPS FSP FRPharmS Emeritus Professor, De Montfort University, Leicester, UK Kevin M. G. Taylor BPharm PhD FRPharmS Professor of Clinical Pharmaceutics, UCL School of Pharmacy, London, UK Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2018 www.konkur.in © 2018 Elsevier Ltd. All rights reserved. First edition 1988 Second edition 2002 Third edition 2007 Fourth edition 2013 Fifth edition 2018 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the publisher’s permissions policies, and the publisher’s arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at https://www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods, they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (1) on procedures featured or (2) by the manufacturer of each product to be administered to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of product liability, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN 978-0-7020-7005-1 International Edition 978-0-7020-7003-7 Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 Content Strategist: Pauline Graham Content Development Specialist: Fiona Conn Project Manager: Andrew Riley Design: Christian Bilbow Illustration Manager: Amy Faith Heyden Marketing Manager: Deborah Watkins The publisher’s policy is to use paper manufactured from sustainable forests www.konkur.in Contents Preface................................................................ vii Contributors............................................................ viii Acknowledgements...................................................... xi What is pharmaceutics? Michael E. Aulton and Kevin M. G. Taylor.......1 1. Design of dosage forms Peter York.......................6 PART 1 Scientific principles of dosage form design 2. Dissolution and solubility Michael E. Aulton.................. 18 3. Properties of solutions Michael E. Aulton................... 37 4. Surfaces and interfaces Graham Buckton................... 47 5. Disperse systems David Attwood....................... 60 6. Rheology Christopher Marriott......................... 93 7. Kinetics Gareth R. Williams.......................... 114 PART 2 Particle science and powder technology 8. Solid-state properties Graham Buckton................... 128 9. Particle size analysis Kevin M. G. Taylor................... 140 10. Particle size reduction and size separation Michael E. Aulton....... 158 11. Mixing Andrew M. Twitchell.......................... 172 12. Powder flow Michael E. Aulton........................ 189 PART 3 Pharmaceutical microbiology and sterilization 13. Fundamentals of microbiology Geoffrey W. Hanlon............. 201 14. Pharmaceutical applications of microbiological techniques Norman A. Hodges............................... 227 15. Action of physical and chemical agents on microorganisms Geoffrey W. Hanlon and Norman A. Hodges.................. 250 16. Principles of sterilization Susannah E. Walsh and Jean-Yves Maillard... 268 17. Sterilization in practice Jean-Yves Maillard and Susannah E. Walsh.... 278 PART 4 Biopharmaceutical principles of drug delivery 18. Introduction to biopharmaceutics Marianne Ashford............ 296 19. Gastrointestinal tract – physiology and drug absorption Marianne Ashford................................ 300 20. Bioavailability – physicochemical and dosage form factors Marianne Ashford................................ 319 v www.konkur.in Contents 21. Assessment of biopharmaceutical properties Marianne Ashford..... 339 22. Dosage regimens Soraya Dhillon, Nkiruka Umaru and John H. Collett... 363 PART 5 Dosage form design and manufacture 23. Pharmaceutical preformulation Simon Gaisford............... 380 24. Solutions Sudaxshina Murdan......................... 407 25. Clarification Andrew M. Twitchell....................... 417 26. Suspensions Susan A. Barker......................... 427 27. Emulsions and creams Gillian M. Eccleston................. 446 28. Powders, granules and granulation Michael E. Aulton........... 476 29. Drying Michael E. Aulton and Satyanarayana Somavarapu.......... 498 30. Tablets and compaction Göran Alderborn and Göran Frenning....... 517 31. Modified-release oral drug delivery Emma L. McConnell and Abdul W. Basit................................. 564 32. Coating of tablets and multiparticulates Stuart C. Porter.......... 580 33. Hard capsules Brian E. Jones......................... 597 34. Soft capsules Keith G. Hutchison and Josephine Ferdinando........ 612 35. Dissolution testing of solid dosage forms Ana Cristina Freire and Abdul W. Basit................................. 626 36. Parenteral drug delivery Robert Lowe.................... 638 37. Pulmonary drug delivery Kevin M. G. Taylor................. 653 38. Nasal drug delivery Gary P. Martin and Alison B. Lansley.......... 671 39. Ocular drug delivery Hala Fadda, Ashkan Khalili, Peng Tee Khaw, and Steve Brocchini............................... 690 40. Topical and transdermal drug delivery Adrian C. Williams......... 715 41. Rectal and vaginal drug delivery Kalliopi Dodou............... 739 42. The formulation and manufacture of plant medicines G. Brian Lockwood............................... 758 43. Delivery of biopharmaceuticals Ijeoma F. Uchegbu and Andreas G. Schätzlein.............................. 769 44. Pharmaceutical nanotechnology and nanomedicines Yvonne Perrie... 784 45. Design and administration of medicines for paediatric and geriatric patients Catherine Tuleu, Mine Orlu and David Wright............ 804 Part 6 Packaging and stability of pharmaceutical products 46. Packaging Sudaxshina Murdan........................ 820 47. Chemical stability in dosage forms Andrew R. Barnes........... 836 48. Microbial contamination, spoilage and preservation of medicines Norman A. Hodges............................... 850 49. Product stability and stability testing Paul Marshall............. 862 Self Assessment Please check your eBook at https://studentconsult.inkling. com/ for self-assessment questions. See inside cover for registration details. Index................................................................ 886 vi www.konkur.in Preface This is the fifth edition of Aulton’s Pharmaceutics: written by a new generation of experts. The new The Design and Manufacture of Medicines. The first authorship reflects contemporary knowledge and edition was published in 1988, the second in 2002, thinking in pharmaceutics. the third in 2007 and the fourth in 2013. The pedigree The fourth edition of this book saw major restruc- of the book is, however, actually much older. It was turing and revision of the text, with the addition of originally known as Tutorial Pharmacy (which itself many new chapters and deletion of others. In this went to six editions) and was initially edited by John edition, the changes have been less radical, but neces- Cooper and Colin Gunn, and later by Sidney Carter. sary and important nonetheless. Every chapter has Professor Mike Aulton and Professor Kevin Taylor received detailed attention and has been revised and continue their editing role and have identified new updated appropriately to reflect modern thinking and authors and fresh subject matter for this new edition. current university curricula worldwide. Some of the The philosophy of this fifth edition remains basic science remains virtually unchanged – and will unchanged from that of previous editions, i.e. it is always do so – but other areas, particularly biophar- intentionally designed and written for newcomers to maceutics and some areas of drug delivery, have the design of dosage forms (drug products). Other changed significantly in recent years. Several new expert texts can take you into much greater detail authors have been included in this edition to ensure for each of the subject areas considered here, once the comprehensive nature and currency of this text. you have mastered these basics. The subject matter All purchasers of the print version of this new of the book remains, in essence, the same but the edition receive the enhanced ebook, which can be detail has changed significantly, because pharmaceutics used online or downloaded to their mobile device has changed. Since the last edition there have been for convenient, any time access. The ebook includes changes in the way that dosage forms are designed more than 400 self-assessment questions, based on and manufactured and drugs are delivered. These the book, to check understanding and to help with developments are reflected in this new edition. any examination preparation. The involvement of a wide range of authors We wish you well in your studies if you are an continues in this edition, all authors being a recognized undergraduate student, or with your career if you expert in the field on which they have written. Just are working in industry, medicines regulation or the as importantly, each author has experience of impart- hospital service. We sincerely hope that this book ing that information to undergraduate pharmacy and helps you with your understanding of pharmaceutics pharmaceutical science students, and to practitioners – the science of the design and manufacture of in the pharmaceutical and associated industries and medicines. those working in technical services within hospital M. E. Aulton pharmacy who are new to the subject. Many authors K. M. G. Taylor from the previous edition remain as they are still world leaders in their field. Other chapters have been vii www.konkur.in Contributors Göran Alderborn PhD Soraya Dhillon BPharm, PhD Professor in Pharmaceutical Technology, Uppsala Professor and Dean, Life and Medical Sciences, University, Uppsala, Sweden University of Hertfordshire, Hatfield, UK Marianne Ashford BSc (Pharm), PhD Kalliopi Dodou BSc (Pharm), PhD Associate Principal Scientist Drug Delivery, AstraZeneca, Reader, Pharmacy Health and Wellbeing, University of Macclesfield, UK Sunderland, Sunderland, UK David Attwood BPharm, PhD, DSc, CChem, FRSC Gillian M. Eccleston BSc, PhD Emeritus Professor, University of Manchester, Professor of Pharmacy, University of Strathclyde, Manchester, UK Glasgow, UK Michael E. Aulton BPharm, PhD, FAAPS, FSP, FRPharmS Hala Fadda MPharm, PhD Emeritus Professor, De Montfort University, Leicester, Associate Professor of Pharmaceutics, College of UK Pharmacy and Health Sciences, Butler University, Indianapolis, USA Susan A. Barker BPharm, PhD Senior Lecturer in Pharmaceutics, UCL School of Josephine Ferdinando BSc, MSc, PhD Pharmacy, London, UK Senior Vice President, Nonclinical Development, Shire Research and Development, Basingstoke, UK Andrew R. Barnes BSc (Pharm), PhD Quality Assurance Specialist, Pharmacy Quality Ana Cristina Freire PhD Assurance Specialist Services, Hellesdon Hospital, Development Manager, Kuecept, Potters Bar, UK Norwich, UK Göran Frenning Abdul W. Basit BPharm, PhD Professor in Pharmaceutical Physics, Uppsala University, Professor of Pharmaceutics, UCL School of Pharmacy, Uppsala, Sweden London, UK Simon Gaisford BSc, MSc, PhD Steve Brocchini BA, PhD Professor in Pharmaceutics, UCL School of Pharmacy, Professor of Chemical Pharmaceutics, UCL School of London, UK Pharmacy, London, UK Geoffrey W. Hanlon BSc, PhD Graham Buckton BPharm, PhD, DSc Emeritus Professor of Pharmaceutical Microbiology, Emeritus Professor of Pharmaceutics, UCL School of University of Brighton, Brighton, UK Pharmacy, London, UK Norman A. Hodges MPharm, PhD John H. Collett PhD, DSC, FRPharmS Principal Lecturer in Pharmaceutical Microbiology, Professor of Pharmaceutics, University of Manchester, School of Pharmacy and Biomolecular Sciences, Manchester, UK University of Brighton, Brighton, UK viii www.konkur.in Contributors Keith G. Hutchison BSc (Pharm), PhD Emma L. McConnell MPharm, PhD, MRPharmS Senior Vice President Research and Development, Medical Writer, KnowledgePoint360 Group, Capsugel, Bornem, Belgium Macclesfield, UK Brian E. Jones BPharm, MPharm Sudaxshina Murdan BPharm, PhD Scientific Advisor, Qualicaps Europe, Alcobendas, Spain Reader in Pharmaceutics, UCL School of Pharmacy, Honorary Senior Lecturer, Welsh School of Pharmacy, London, UK Cardiff University, Cardiff, UK Mine Orlu BD, MSc, PhD Ashkan Khalili MD, PhD Lecturer, UCL School of Pharmacy, London, UK Research Fellow, UCL School of Pharmacy, London, UK NIHR Biomedical Research Centre, Moorfields Eye Yvonne Perrie BSc (Pharm), PhD Hospital and UCL Institute of Ophthalmology, London, Professor of Drug Delivery, University of Strathclyde, UK Glasgow, UK Peng Tee Khaw PhD, FRCP, FRCS, FRCOphth, FRCPath, Stuart C. Porter BPharm, PhD FSB, FMedSci Director and Senior Research Fellow Pharmaceutical Professor of Ophthalmology, NIHR Biomedical Research Research and Development, Ashland Specialty Centre, Moorfields Eye Hospital and UCL Institute of Chemicals, Wilmington, USA Ophthalmology, London, UK Andreas G. Schätzlein BVMS, DrMedVet Alison B. Lansley BSc (Pharm), PhD Professor of Translational Therapeutics, UCL School of Principal Lecturer, School of Pharmacy and Pharmacy, London, UK Biomolecular Sciences, University of Brighton, Brighton, UK Satyanarayana Somavarapu MPharm, PhD Lecturer in Pharmaceutics, UCL School of Pharmacy, G. Brian Lockwood BPharm, PhD, MRPharmS London, UK Professor of Pharmaceutical Sciences, University of Manchester, Manchester, UK Kevin M. G. Taylor BPharm, PhD, FRPharmS Professor of Clinical Pharmaceutics, UCL School of Robert Lowe BPharm Pharmacy, London, UK Director of Pharmacy, Quality Assurance Specialist Services, East of England and Northamptonshire NHS Catherine Tuleu DPharm, MSc, PhD England, Norwich, UK Reader, UCL School of Pharmacy, London, UK Jean-Yves Maillard BSc, PhD Andrew M. Twitchell BSc, PhD Professor of Pharmaceutical Microbiology, School of Pharmaceutical Assessor, Licensing, Medicines and Pharmacy and Pharmaceutical Sciences, Cardiff Healthcare products Regulatory Agency, London, UK University, Cardiff, UK Ijeoma F. Uchegbu PhD Christopher Marriott PhD, DSc Professor of Pharmaceutical Nanoscience, UCL School Emeritus Professor of Pharmaceutics, King’s College of Pharmacy, London, UK London, London, UK Nkiruka Umaru MPharm, PhD Paul Marshall BPharm, PhD Principal Lecturer in Clinical Pharmacy, School of Life Principal Consultant, Integrated Product Development, and Medical Sciences Pharmacy, University of PAREXEL International, London, UK Hertfordshire, Hatfield, UK Gary P. Martin BPharm, PhD, FRPharmS Susannah E. Walsh BSc, PhD, MBA Emeritus Professor of Formulation Science, King’s Principal Lecturer School of Pharmacy, De Montfort College London, London, UK University, Leicester, UK ix www.konkur.in Contributors Adrian C. Williams BSc, PhD David Wright BPharm, PhD, PGCHE Professor of Pharmaceutics, University of Reading, Professor of Pharmacy, University of East Anglia, Reading, UK Norwich, UK Gareth R. Williams MChem, DPhil Peter York BSc, PhD, DSc Lecturer in Pharmaceutics, UCL School of Pharmacy, Emeritus Professor, School of Pharmacy, University of London, UK Bradford, Bradford, UK x www.konkur.in Acknowledgements The editors wish to take this opportunity to thank Catherine Baumber (Pharmaceutics Department, those who have assisted with the preparation of this UCL School of Pharmacy) for her considerable text. We are extremely indebted to the following: secretarial and administrative support The authors for the time and quality of effort that throughout this book’s preparation. they have put into their texts; always under John Malkinson (UCL School of Pharmacy) for pressure from numerous other commitments, assistance in the checking of Chapter 7. and also from us. Modern life has few spare Fiona Conn (of Elsevier) for being efficient, moments and so the time that they have spent pleasant and extremely helpful to the editors in contributing so knowledgeably and and authors during the chapter-creation and professionally to this text is warmly chapter-submission phases. appreciated. Andrew Riley of Elsevier Production. The many academic and industrial pharmaceutical On reaching the milestone of the fifth edition of scientists who helped during the design of the Aulton’s Pharmaceutics, the editors acknowledge the contents and organization of this edition to contribution of all previous authors to earlier editions. ensure that it corresponds as closely as possible Each of the following has left their mark on the book with modern practice and with the curricula of today, and elements of their earlier contributions still current pharmacy and pharmaceutical science remain. courses internationally. Dr John Richards (Chapters 2 and 3) The publishing companies who have given their Dr John Pugh (Chapter 7) permission to reproduce material in this edition. The late Professor John Staniforth (Chapters 9, The many secretaries and artists who have 10, 12) assisted the authors, editors and publishers in The late Dr Stuart Proudfoot (Chapters 18–22) the preparation of their work. Dr Malcolm Summers (Chapter 28) Christine Aulton for typing and other secretarial Dr Josef Tukker (Chapter 41) assistance, and for help in countless other ways Professor Sanjay Garg (Chapter 41) that has enabled time to be spent on this Mike Aulton edition of the book. Kevin Taylor Pauline Taylor for her support and forbearance during the evenings, weekends and holidays spent in the preparation of this book. xi www.konkur.in This page intentionally left blank www.konkur.in What is ‘pharmaceutics’? Welcome to ‘Ceutics! ‘pharmacological agent’, ‘active principle’, ‘active One of the earliest impressions that many new ingredient’, or increasingly ‘active pharmaceutical pharmacy and pharmaceutical science students have ingredient (API)’, etc. The book uses the simpler of their chosen subject is the large number of long and still correct word, ‘drug’. Phrases like ‘active and sometimes unusual-sounding names that are used ingredient’ can suggest that the other ingredients of to describe the various subject areas within pharmacy a medicine have no function at all. This book will and the pharmaceutical sciences. The aim of this teach you loud and clear that this is not the case. section is to explain to the reader what is meant by Pharmaceutics, and therefore this book, is concerned just one of them – ‘pharmaceutics’. It describes how with the scientific and technological aspects of the the term has been interpreted for the purpose of design and manufacture of dosage forms. Arguably, this book and how pharmaceutics fits into the overall it is the most diverse of all the subject areas in the scheme of pharmaceutical science and the process pharmaceutical sciences and encompasses: of designing and manufacturing a new medicine. This an understanding of the basic physical chemistry note also leads the reader through the organization necessary for the effective design of dosage of this book and explains the reasons why an under- forms (physical pharmaceutics) standing of the material contained in its chapters is an understanding of relevant body systems and important in the design of modern drug delivery how drugs arrive there following administration systems. (biopharmaceutics) The word ‘pharmaceutics’ is used in pharmacy the design and formulation of medicines and the pharmaceutical sciences to encompass a wide (dosage form design) range of subject areas that are all associated with the the manufacture of these medicines on a small steps to which a drug is subjected towards the end (compounding), intermediate (pilot-scale) and of its development. It encompasses the stages that large (manufacturing) scale follow on from the discovery or synthesis of the drug, its isolation and purification, and its testing for the avoidance and elimination of beneficial pharmacological effects and absence of microorganisms in medicines (pharmaceutical serious toxicological problems. Put at its simplest microbiology, sterilization), and – pharmaceutics converts a drug into a medicine. product performance testing (physical testing, Just a comment here about the word ‘drug’. This drug release, stability testing). is the pharmacologically active ingredient in a Medicines are drug-delivery systems. That is, they medicine. ‘Drug’ is the correct word, but because are a means of administering drugs to the body in a the word has been somewhat hijacked as the safe, effective, accurate, reproducible and convenient common term for a substance of misuse, alternatives manner. The book discusses the overall considerations are frequently used, such as ‘medicinal agent’, that must be made so that the conversion of a drug 1 www.konkur.in What is ‘pharmaceutics’? to a medicine can take place. It emphasizes the fact of these solutions. The reader will see later in the that medicines are very rarely drugs alone but require book how drug release from the dosage form and additives (termed excipients) to make them into absorption of the drug into the body across biological dosage forms, and this in turn introduces the concept barriers are strongly dependent on the properties of of formulation. The book explains that there are three the drug in solution, such as the degree of ionisation major considerations in the design of dosage forms: and speed of diffusion of the drug molecules. The properties of surfaces and interfaces are 1. the physicochemical properties of the drug described next. These are important to an understand- itself ing of adsorption onto solid surfaces, and are involved 2. biopharmaceutical considerations, such as how in the dissolution of solid particles and the study of the administration route and formulation of a disperse systems, such as colloids, suspensions and dosage form affect the rate and extent of drug emulsions. The scientific background to the systems absorption into the body, and mentioned is also discussed. Knowledge of the flow 3. therapeutic considerations of the disease state properties of liquids (whether solutions, suspensions and patient to be treated, which in turn or emulsions) and semisolids is useful in solving certain determine the most suitable type of dosage problems relating to the manufacture, performance form, possible routes of administration and the and stability of liquid and semi-solid dosage forms. most suitable duration of action and dose This Part ends with an explanation of the kinetics frequency for the drug in question. of many different processes. As the chapter explains, The first chapter provides an excellent introduction the mathematics of these processes has importance to the subject matter of the book as a whole and in a large number of areas of product design, manu- clearly justifies the need for the pharmacist and facture, storage and drug delivery. Relevant processes formulation scientist to understand the science include: dissolution, microbiological growth and contained in this text. New readers are encouraged destruction, biopharmaceutics (including drug absorp- to read this chapter first, thoroughly and carefully, tion, distribution, metabolism and excretion), pre- so that they can grasp the basics of the subject before formulation, the rate of drug release from dosage proceeding onto the more detailed information that forms, and the decomposition of medicinal compounds follows. and products. The book is then divided into various Parts that Part 2 collects together those aspects of pharma- group together chapters into related subject areas. ceutics associated with powdered materials. By far Part 1 collects some of the more important physico- the majority of drugs are solid (mainly crystalline) chemical knowledge that is required to design and powders and, unfortunately, most of these particulate prepare dosage forms. The chapters have been solids have numerous adverse characteristics that designed to give the reader an insight into those must be overcome or controlled during the design scientific and physicochemical principles that are of medicines to enable their satisfactory manufacture important to the formulation scientist. These chapters and subsequent performance in dosage forms. are not intended as a substitute for a thorough The book therefore explains the concept of the understanding of physical chemistry and many specific, solid state and how the internal and surface properties more detailed, texts are available containing this of solids are important and need to be characterized. information. This is followed by an explanation of the more For many reasons, which are discussed in the book, macroscopic properties of powders that influence the vast majority of dosage forms are administered their performance during the design and manufacture via the mouth in the form of solid products, such as of dosage forms – particle size and its measurement, tablets and capsules. This means that one of the most size reduction, and the separation of powders with important stages in drug administration is the dis- the desired size characteristics from those of other solution of solid particles to form a solution in the sizes. There follows an explanation of the many gastrointestinal tract. The formulation scientist problems associated with the mixing and flow of therefore needs knowledge of both liquid and solid powders. In large-scale tablet and capsule production, materials, in particular the properties of drugs in for example, powders must contain a satisfactory solution and the factors influencing their dissolution mix of all the ingredients in order to achieve uniform- from solid particles. Once solutions are formed, the ity of dosage in every dosage unit manufactured. The formulation scientist must understand the properties powder must have fast and uniform powder flow in 2 www.konkur.in What is ‘pharmaceutics’? high-speed tableting and encapsulation machines. For a small synthetic molecule, a plant extract or a convenience, the mixing of liquids and semisolids is biotechnology product can only be achieved by the also discussed here as the basic theory is the same. involvement of the formulation scientist. Good Another extremely important area that must be formulation can enhance therapeutic efficacy and/or understood before a satisfactory dosage form can be limit adverse effects. A couple of examples illustrate designed and manufactured is the microbiological this: aspects of medicines development and production. Whilst an immediate-release capsule of It is necessary to control or eliminate viable micro- nifedipine has a dosing frequency of three times organisms from the product both before and during a day, formulation of the drug in a manufacture. Microbiology is a very wide-ranging modified-release capsule permits once-daily subject. This book concentrates only on those aspects dosing, with an improved drug plasma profile of microbiology that are directly relevant to the design, and increased patient convenience and production and distribution of dosage forms. This adherence. mainly involves avoiding (asepsis) and eliminating A cream formulation of a sunscreen applied to (sterilization) the presence (contamination) of viable the skin restricts the active component(s) to microorganisms in medicines, and preventing the the skin surface, whilst a gel formulation of growth of any microorganism which might enter the estradiol, also applied to the skin surface, is product during storage and use of the medicine formulated so as to ensure effective penetration (preservation). Techniques for testing that these of drug through the skin and into the systemic intentions have been achieved are also described. circulation. The principles and practice of sterilization are also discussed. The relevant aspects of pharmaceutical The first stage of designing and manufacturing a microbiology and sterilization are considered in Part dosage form is known as preformulation. This, as 3 of this book. the name implies, is a consideration of the steps It is not possible to begin to design a satisfactory that need to be performed before formulation proper dosage form without knowledge and understanding can begin. Preformulation involves a full understanding of how drugs are absorbed into the body, the various of the physicochemical properties of drugs and routes that can be used for this purpose and the fate other ingredients (excipients) in a dosage form and of the drugs once they enter the body and reach how they may interact. An early grasp of this knowl- their site(s) of action. The terms ‘bioavailability’ and edge is of great use to the formulation scientist ‘biopharmaceutics’ are defined and explained in Part as the data gathered in these early stages will influence 4. The factors influencing the bioavailability of a drug strongly the design of the future dosage form. Results and methods of its assessment are described. This is of tests carried out at this stage of development can followed by a consideration of the manner in which give a much clearer indication of the possible (and the frequency of drug administration and the rate at indeed impossible) dosage forms for a new drug which drug is released from a dosage form affect its candidate. concentration in the blood plasma at any given time. Following, consideration of preformulation, the This book concentrates on the preparation, administra- remaining chapters of Part 5 cover the formulation, tion, release and absorption of drugs but stops there. small and large scale manufacture, and the advantages, It leaves to other texts the detail of how drugs enter disadvantages and characterization of the wide range individual cells, how they act and how they are of available dosage forms. The properties of these metabolized and eliminated from the body. dosage forms can be modified dependent on the Having gathered this understanding of the basics properties of the drug, excipients included, the route of pharmaceutics, the formulation scientist should of drug administration and specific patient needs. now be equipped to begin a consideration of the Early chapters consider liquid dosage forms, namely design and manufacture of the most suitable dosage solutions (drug dispersed as molecules or ions), forms for the drug in question. suspensions (drug dispersed as particles) and emul- Superficially, the formulation and manufacture of sions (one liquid phase dispersed in another, with dosage forms containing drugs may seem relatively drug present in either phase, dependent upon its straightforward. The chapters in Part 5 will demon- relative solubility). Appropriate formulation of emul- strate that this is not the case. The full potential of sions results in more structured semi-solid creams, the active pharmaceutical ingredient, whether it is most frequently used for application to the skin. 3 www.konkur.in What is ‘pharmaceutics’? These dosage forms may be administered by a number for delivering drugs by each route are outlined and of routes, and their formulation requirements will particular aspects regarding their formulation and vary dependent on the route of administration. manufacture are highlighted. The methods used to Whilst drugs in the solid state can be administered characterize and test these dosage forms, for formula- as simple powders, they are more usually formulated tion development and quality assurance purposes are as solid dosage forms, namely tablets (currently the also detailed. most commonly encountered solid dosage form) and The final chapters of Part 5 reflect special consid- capsules. Several chapters in this Part describe the erations in dosage form design and manufacture. Drugs various stages in the processing of a powder required of natural (plant) origin are discussed. Unlike con- to manufacture tablets: granulation (formation of ventional dosage forms these comprise plant extracts drug-excipient aggregates), drying, compaction and that have many complex components with potentially coating. Tablet formulation and manufacture requires variable composition. inclusion of several excipients, including fillers, Certain biotechnology products, for instance disintegrants, binders, glidants, lubricants and anti- insulin, are long established, whilst others such as adherents. The purposes of these are described, nucleic acids for gene therapy offer exciting thera- together with their impact on product quality and peutic possibilities for the future. All are relatively performance. The strategies to modify the release large macromolecules and present particular formula- of drug from solid dosage forms include: production tion and drug delivery challenges. To meet some of of monolithic matrix systems, the use of a rate- the challenges associated with delivery of biotechnol- controlling membrane or osmotic pump systems. ogy products, pharmaceutical nanotechnology has These are described in a separate chapter, as are become established in recent years as a means of other solid dosage forms: hard and soft capsules. For improving solubility and dissolution rate, protecting all dosage forms, drug must be released at an appropri- drugs from hostile environments, minimizing adverse ate rate at the appropriate site for drug action and/ effects and delivering drugs to specific therapeutic or absorption to occur. This is particularly pertinent targets. The preparation and properties of various for solid peroral dosage forms, which must permit nanomedicines, including antibodies, polymer-drug dissolution of drug at an appropriate rate and at an conjugates, liposomes, nanoparticles and dendrimers appropriate site within the gastrointestinal tract. are considered. Bioavailability (i.e. the amount of drug that is absorbed Some specific patient groups (in particular the into the bloodstream) may be limited by the rate of elderly and young children) have particular needs drug dissolution, whilst the pH range in the (difficulty swallowing, subdivision of commercially gastrointestinal tract (pH 1–8) may adversely affect available doses, etc.) and the formulation consequences the absorption of ionizable drugs. Consequently, are discussed. dissolution testing is a key quality control test and Before finalizing the formulation and packaging of is considered in detail here. the dosage form, there must be a clear understanding Solid dosage forms are administered predominantly of the stability of the drug(s) and other additives in (though not exclusively) by the oral route. Whilst a pharmaceutical product with respect to the reasons the oral route is the most common way of administer- why, and the rates at which, they may degrade during ing drugs, many other routes for administration exist storage. Aspects of product stability, stability testing and are necessary. Each of these is considered in and the selection of appropriate packaging to minimize detail. Such routes include parenteral administration deterioration during storage are considered in Part (injections, infusions, implants), pulmonary (aerosols), 6. nasal (sprays, drops, semisolids, powders), ocular The product pack and any possible interactions (drops, semisolids, injection, implants), topical and between it and the drug or medicine it contains are transdermal (semisolids, patches, liquids, powders), so vitally linked that the final pack should not be ungual (nail lacquers, liquids), rectal (suppositories, considered as an afterthought. Instead, packaging tablets, capsules, semisolids, liquids, foams) and considerations should be uppermost in the minds of vaginal (pessaries, semisolids, films, rings, tampons). formulators as soon as they receive the drug substance For each route, consideration is given to the nature on which to work. The technology of packaging and of the administration site and the formulation require- filling of products is discussed. ments either to localize drug action, or to control No product will be stable indefinitely, and so absorption, as appropriate. The dosage forms available mechanisms (i.e. the fundamental chemistry) and 4 www.konkur.in What is ‘pharmaceutics’? kinetics of degradation must be understood so that Finally, the book explains how packaging considera- a safe and realistic shelf-life for every product can tions, chemical degradation and microbial contamina- be determined. tion influence the stability of the final drug product. Possible routes of microbiological contamination At this point the product is considered to be of of medicines and the ways in which this can be appropriate quality for patient use and, once approved prevented or minimized are discussed. It is shown by regulatory authorities, the pharmaceutical technolo- how the presence of antimicrobial preservatives in gist passes the product on to another aspect of the medicine can minimize the consequences of such pharmacy – the interface with the patient, i.e. dispens- contamination. However, such preservatives must be ing and pharmacy practice. These disciplines are dealt nontoxic by the route of administration and should with in other texts. not interact with components of the drug product or its packaging. 5 www.konkur.in 1 Design of dosage forms Peter York CHAPTER CONTENTS of drug substances to form various medicines or Principles of dosage form design...... 6 dosage forms. The principal objective of dosage form design is to Biopharmaceutical aspects of dosage form design................. 8 achieve a predictable therapeutic response to a drug Routes of drug administration.......... 9 included in a formulation which can be manufactured on a large scale with reproducible product quality. To Drug factors in dosage form design.... 11 ensure product quality, numerous features are required: Particle size and surface area......... 12 chemical and physical stability, with suitable preserva- Solubility.................... 12 tion against microbial contamination if appropriate, Dissolution................... 13 uniformity of the dose of the drug, acceptability to Partition coefficient and pKa.......... 14 users, including both prescriber and patient, and suitable Crystal properties: polymorphism....... 14 packaging and labelling. Ideally, dosage forms should Stability.................... 15 also be independent of patient-to-patient variation, Organoleptic properties............ 15 although in practice this feature remains difficult to Other drug properties............. 16 achieve. However, recent developments are beginning Therapeutic considerations in dosage to accommodate this requirement. These include drug form design.................16 delivery systems that rely on the specific metabolic Summary.................. 17 activity of individual patients and implants that respond, Bibliography.................17 for example, to externally applied sound or magnetic fields to trigger a drug delivery function. Consideration should be given to differences in Principles of dosage the bioavailability of drugs (the rate and extent to form design which they are absorbed) and their biological fate in patients between apparently similar formulations and Drugs are rarely administered as pure chemical possible causative reasons. In recent years, increasing substances alone and are almost always given as attention has therefore been directed towards elimina- formulated preparations or medicines. These can tion of variation in bioavailability characteristics, range from relatively simple solutions to complex particularly for medicinal products containing an drug delivery systems through the use of appropri- equivalent dose of a drug substance, as it is recognized ate additives or excipients in the formulations. The that formulation factors can influence their therapeutic excipients provide varied and specialized pharma- performance. To optimize the bioavailability of drug ceutical functions. It is the formulation additives substances, it is often necessary to carefully select that, amongst other things, solubilize, suspend, the most appropriate chemical form of the drug. For thicken, preserve, emulsify, modify dissolution, example, such selection should address solubility increase the compactability and improve the flavour requirements, drug particle size and drug physical 6 www.konkur.in Design of dosage forms CHAPTER 1 Table 1.1 Dosage forms available for different chemical forms and formulation additives, a range of administration routes effective anti-inflammatory preparations are available, including tablets, gastro-resistant coated tablets, Administration Dosage forms injections, eye drops and enemas. The extremely route low aqueous solubility of the base prednisolone and Oral Solutions, syrups, suspensions, emulsions, its acetate salt makes these forms useful in tablet and gels, powders, granules, capsules, tablets slowly absorbed intramuscular suspension injection Rectal Suppositories, ointments, creams, forms, whilst the soluble sodium phosphate salt enables powders, solutions preparation of a soluble tablet form and solutions for eye and ear drops, enemas and intravenous injections. Topical Ointments, creams, pastes, lotions, gels, The analgesic paracetamol is also available in a range solutions, topical aerosols, foams, transdermal patches of dosage forms and strengths to meet the specific needs of the user, including tablets, dispersible tablets, Parenteral Injections (solution, suspension, emulsion paediatric soluble tablets, paediatric oral solution, forms), implants, irrigation and dialysis sugar-free oral solution, oral suspension, double- solutions strength oral suspension and suppositories. Respiratory Aerosols (solution, suspension, emulsion, In addition, whilst many new drugs based on low powder forms), inhalations, sprays, gases molecular weight organic compounds continue to be Nasal Solutions, inhalations discovered and transformed into medicinal products, Eye Solutions, ointments, creams the development of drugs from biotechnology is increasing and the importance of these therapeutic Ear Solutions, suspensions, ointments, creams agents is growing. Such active compounds are mac- romolecular and of relatively high molecular weight, form and should consider appropriate additives and and include materials such as peptides, proteins and manufacturing aids coupled with selection of the most viral components. These drug substances present appropriate administration route(s) and dosage different and complex challenges in their formulation form(s). Additionally, suitable manufacturing pro- and processing into medicines because of their alterna- cesses, labelling and packaging are required. tive biological, chemical and structural properties. There are numerous dosage forms into which a Nevertheless, the underlying principles of dosage drug substance can be incorporated for the convenient form design remain applicable. and efficacious treatment of a disease. Dosage forms At present, these therapeutic agents are principally can be designed for administration by a variety of formulated into parenteral and respiratory dosage delivery routes to maximize therapeutic response. forms, although other routes of administration are Preparations can be taken orally or injected, as well being considered and researched. Delivery of these as being applied to the skin or inhaled; Table 1.1 lists biotechnologically based drug substances via these the range of dosage forms which can be used to routes of administration imposes additional con- deliver drugs by the various administration routes. straints on the selection of appropriate formulation However, it is necessary to relate the drug substance excipients. to the clinical indication being treated before the Another growing area of clinically important correct combination of drug and dosage form can be medicines is that of polymer therapeutics. These agents made, as each disease or illness often requires a include designed macromolecular drugs, polymer–drug specific type of drug therapy. In addition, factors and polymer–protein conjugates as nanomedicines, governing the choice of administration route and the generally in injection form. These agents can also provide specific requirements of that route which affect drug drug-targeting features (e.g. treating specific cancers) absorption need to be taken into account when dosage as well as modified pharmacokinetic profiles (e.g. forms are being designed. changed drug metabolism and elimination kinetics). Many drugs are formulated into several dosage It is therefore apparent that before a drug substance forms of various strengths, each having selected can be successfully formulated into a dosage form, pharmaceutical characteristics which are suitable for a many factors must be considered. These can be specific application. One such drug is the glucocorticoid broadly grouped into three categories: prednisolone used in the suppression of inflammatory 1. biopharmaceutical considerations, including and allergic disorders. Through the use of different factors affecting the absorption of the drug 7 www.konkur.in CHAPTER 1 substance from different administration as drug distribution, metabolism and excretion. In routes; general, a drug substance must be in solution before 2. drug factors, such as the physical and chemical it can be absorbed via absorbing membranes and properties of the drug substance; and epithelia of the skin, gastrointestinal tract and lungs 3. therapeutic considerations, including into body fluids. Drugs are absorbed in two general consideration of the clinical indication to be ways: by passive diffusion and by carrier-mediated treated and patient factors. transport mechanisms. In passive diffusion, which is thought to control the absorption of many drugs, the High-quality and efficacious medicines will be for- process is driven by the concentration gradient existing mulated and prepared only when all these factors across the cellular barrier, with drug molecules passing are considered and related to each other. This is the from regions of high concentration to regions of low underlying principle of dosage form design. concentration. Lipid solubility and the degree of ionization of the drug at the absorbing site influence Biopharmaceutical aspects the rate of diffusion. Recent research into carrier- mediated transport mechanisms has provided much of dosage form design information and knowledge, providing guidance in some cases for the design of new drug molecules. Biopharmaceutics can be regarded as the study of Several specialized transport mechanisms are postu- the relationship between the physical, chemical and lated, including active and facilitated transport. Once biological sciences applied to drugs, dosage forms absorbed, the drug can exert a therapeutic effect and drug action. Clearly, understanding the principles either locally or at a site of action remote from the of this subject is important in dosage form design, site of administration. In the latter case the drug has particularly with regard to drug absorption, as well to be transported in body fluids (Fig. 1.1). Gastrointestinal Skin tract Oral Buccal Topical Vascular Mouth system preparations Subcutaneous injection Direct Intramuscular injection Vascular system or Stomach hepato- Circulatory enteric system Respiratory Small (drug or tract intestine metabolites) Vascular Aerosols system Large Gases intestine Intravenous injection Rectal Rectal Rectum preparations Drug or metabolite in tissues, extracellular Drug in fluids and faeces Kidneys lymphatics Drug or metabolites Drug or metabolites in in urine saliva, exhaled air, etc. Excretion Elimination Fig. 1.1 Pathways a drug may take following the administration of a dosage form by different routes. 8 www.konkur.in Design of dosage forms CHAPTER 1 When the dosage form is designed to deliver drugs since they will be dealt with in greater detail later via the buccal, respiratory, rectal, intramuscular or in this book. subcutaneous routes, the drug passes directly into the circulating blood from absorbing tissues, whilst the intravenous route provides the most direct route Oral route of all. When a drug is delivered by the oral route, The oral route is the most frequently used route for onset of drug action will be delayed because of drug administration. Oral dosage forms are intended the required transit time in the gastrointestinal usually for systemic effects resulting from drug tract before absorption, the absorption process and absorption through the various epithelia and mucosa factors associated with hepatoenteric blood circula- of the gastrointestinal tract. A few drugs, however, tion. The physical form of the oral dosage form will are intended to dissolve in the mouth for rapid also influence the absorption rate and onset of action, absorption or for local effect in the gastrointestinal with solutions acting faster than suspensions, which tract because of poor absorption by this route or low in turn generally act faster than capsules and tablets. aqueous solubility. Compared with other routes, the Dosage forms can thus be listed in order of the time oral route is the simplest, most convenient and safest of onset of the therapeutic effect (Table 1.2). means of drug administration. However, disadvantages However, all drugs irrespective of their delivery route include the relatively slow onset of action and pos- remain foreign to the human body, and distribution, sibilities of irregular absorption and destruction of metabolic and elimination processes commence certain drugs by the enzymes and secretions of the immediately following drug absorption until the gastrointestinal tract. For example, insulin-containing drug is eliminated from the body via the urine, preparations are inactivated by the action of stomach faeces, saliva, skin or lungs in unchanged or metabo- fluids. lized form. Whilst drug absorption from the gastrointestinal tract follows the general principles described later in this book, several specific features should be Routes of drug administration emphasized. Changes in drug solubility can result from reactions with other materials present in the The absorption pattern of drugs differs considerably gastrointestinal tract; for example, interference with between individual drug substances, as well as between absorption of tetracyclines through the formation of the different administration routes. Dosage forms insoluble complexes with calcium, which can be are designed to provide the drug in a suitable form available from foodstuffs or formulation additives. for absorption from each selected route of administra- Gastric emptying time is an important factor for tion. The following discussion considers briefly the effective drug absorption from the intestine. Slow routes of drug administration and, whilst dosage forms gastric emptying can be detrimental to drugs inacti- are mentioned, this is intended only as an introduction vated by the gastric juices and can delay absorption of drugs more effectively absorbed from the intestine. In addition, since environmental pH can influence Table 1.2 Variation in time of onset of action for the ionization and lipid solubility of drugs, the pH different dosage forms change occurring along the gastrointestinal tract, from Time of onset Dosage forms a pH as low as 1 in the stomach to approximately 7 of action or 8 in the large intestine, is important for both the degree and the site of drug absorption. Since mem- Seconds Intravenous injections branes are more permeable to un-ionized forms than Minutes Intramuscular and subcutaneous to ionized forms and since most drugs are weak acids injections, buccal tablets, aerosols, gases or bases, it can be shown that weak acids, being Minutes to Short-term depot injections, solutions, largely un-ionized, are well absorbed from the hours suspensions, powders, granules, stomach. In the small intestine (pH from approxi- capsules, tablets, modified-release tablets mately 4 to 6.5), with its extremely large absorbing Several hours Gastro-resistant coated formulations surface, both weak acids and weak bases are well Days to weeks Depot injections, implants absorbed. The most popular oral dosage forms are tablets, Varied Topical preparations capsules, suspensions, solutions and emulsions. Tablets 9 www.konkur.in CHAPTER 1 are prepared by compaction and contain drugs and than solid dosage forms or suspensions since drug formulation additives which are included for specific dissolution is not required. functions, such as disintegrants, which promote tablet break-up into granules and powder particles in the gastrointestinal tract, facilitating drug dissolution and Rectal route absorption. Tablets are often coated, either to provide Drugs given rectally in solution, suppository or emul- a protective barrier to environmental factors for drug sion form are generally administered for local rather stability purposes or to mask unpleasant drug taste, than systemic effects. Suppositories are solid forms as well as to protect drugs from the acid conditions intended for introduction into body cavities (usually of the stomach (gastro-resistant coating). Increasing rectal but also vaginal and urethral), where they melt, use is being made of modified-release tablet products releasing the drug. The choice of suppository base such as fast-dissolving systems and controlled-release, or drug carrier can greatly influence the degree and delayed-release or sustained-release formulations. The rate of drug release. This route of drug administration benefits of controlled-release tablet formulations, is also indicated for drugs inactivated by the achieved, for example, by the use of polymeric-based gastrointestinal fluids when given orally or when the tablet cores or coating membranes, include reduced oral route is precluded, for example when a patient frequency of drug-related side effects and maintenance is vomiting or unconscious. Drugs administered of steady levels of drug in the plasma for extended rectally enter the systemic circulation without passing periods, which are important when medications are through the liver, an advantage for drugs significantly delivered for chronic conditions or where constant inactivated by the liver following oral route absorption. levels are required to achieve optimal efficacy, as in Disadvantageously, the rectal route is inconvenient treatment of angina and hypertension. and drug absorption is often irregular and difficult Capsules are solid dosage forms containing the to predict. drug and, usually, appropriate filler(s), enclosed in a hard or soft shell composed primarily of gelatin or other suitable polymeric material. As with tablets, Parenteral routes uniformity of dose can be readily achieved, and A drug administered parenterally is one injected via various sizes, shapes and colours of the shell are a hollow needle into the body at various sites and to commercially available. The capsule shell readily various depths. The three main parenteral routes are ruptures and dissolves following oral administration, subcutaneous, intramuscular and intravenous. Other and in most cases drugs are released from capsules routes, such as intracardiac and intrathecal, are used faster than from tablets. Recently, increased interest less frequently. The parenteral route is preferred when has been shown in the filling of hard capsules with rapid absorption is essential, as in emergency situations semisolid and microemulsion formulations to provide or when patients are unconscious or unable to accept rapidly dispersing dosage forms for poorly soluble oral medication, and in cases when drugs are drugs. destroyed, inactivated or poorly absorbed following Suspensions, which contain finely divided drugs oral administration. In general, the blood levels suspended in a suitable vehicle, are a useful means attained are more predictable than those achieved of administering large amounts of drugs that would by oral dosage forms. be inconvenient if they were taken in tablet or capsule Injectable preparations are usually sterile solutions form. They are also useful for patients who experience or suspensions of drugs in water or other suitable difficulty in swallowing tablets and capsules and physiologically acceptable vehicles. As referred to for paediatric use. Whilst dissolution of drugs is previously, drugs in solution are rapidly absorbed, required before absorption, the fine solid particles and thus suspension injections act more slowly than in a suspension have a large surface area to present solution injections. In addition, since body to the gastrointestinal fluids, and this facilitates drug fluids are aqueous, by use of drugs suspended in oily dissolution, thus aiding absorption and thereby the vehicles, a preparation exhibiting slower absorption onset of drug action. Not all oral suspensions, however, characteristics can be formulated to give a depot are formulated for systemic effects, and several are preparation, providing a reservoir of the drug, which designed for local effects in the gastrointestinal tract. is released slowly into the systemic circulation. Such On the other hand, solutions, including formulations preparations are administered by intramuscular such as syrups and linctuses, are absorbed more rapidly injection deep into skeletal muscles (e.g. several 10 www.konkur.in Design of dosage forms CHAPTER 1 penicillin-containing injections). Alternatively, depot determining the character of drug release from the preparations can be achieved by subcutaneous implants formulation. Ointments are hydrophobic, oleaginous- or pellets, which are compacted or moulded discs based dosage forms, whereas creams are semisolid of drug placed in loose subcutaneous tissue under emulsions. Pastes contain more solids than ointments the outer layers of the skin. Such systems include and thus are stiffer. For topical application in liquid solid microspheres and biodegradable polymeric form other than solution, lotions, suspensions of solids microspheres (e.g. lactide and glycolic acid homopoly- in aqueous solution or emulsions are used. mers and copolymers) containing proteins or peptides Application of drugs to other topical surfaces such (e.g. human growth hormone and leuprolide). More as the eye, ear and nose is common, and ointments, generally, subcutaneous injections are aqueous solutions creams, suspensions and solutions are used. Oph- or suspensions which allow the drug to be placed in thalmic preparations are required, amongst other the immediate vicinity of blood capillaries. The drug features, to be sterile. Nasal dosage forms include then diffuses into the capillaries. Inclusion of vaso- solutions or suspensions delivered by drops or fine constrictors or vasodilators in subcutaneous injections aerosol from a spray. Ear formulations, in general, will clearly influence blood flow through the capillaries, are viscous to prolong contact with affected areas. thereby modifying the capacity for absorption. This principle is often used in the administration of local Respiratory route anaesthetics with the vasoconstrictor adrenaline, which delays drug absorption. Conversely, increased drug The lungs provide an excellent surface for absorption absorption can result when vasodilators are included. when the drug is delivered in gaseous, aerosol mist Intravenous administration involves injection of sterile or ultrafine solid particle form. For drug particles aqueous solutions directly into a vein at an appropriate presented to the lungs as an aerosol, particle size rate. The volumes delivered can range from a few largely determines the extent to which they penetrate millilitres, as in emergency treatment or for hypnotics, the alveolar region, the zone of rapid absorption. to litre quantities, as in replacement fluid treatment Drug particles that have diameters in the region of or parenteral nutrition. 1 µm to 5 µm reach the deep lung. Particles smaller Given the generally negative patient acceptance than 1 µm are largely exhaled, and particles larger of this important route of drug delivery, primarily than 5 µm are deposited on larger bronchial airways. associated with pain and inconvenience, recent This delivery route is particularly useful for the direct developments to help with self-injection by patients treatment of asthma, with use of both powder aerosols have focused on ‘needle-free’ injection systems and (e.g. salmeterol xinafoate) and pressurized metered- devices which propel the drug in aqueous solution dose inhalers containing the drug in liquefied inert or powder form at high velocity directly through the propellant (e.g. salbutamol sulfate inhaler). Impor- external layers of the skin. tantly, this delivery route is being increasingly rec- ognized as a useful means of administering the therapeutic agents emerging from biotechnology Topical route requiring systemic distribution and targeted delivery, Drugs are applied topically (i.e. to the skin) mainly such as peptides and proteins. for local action. Whilst this route can also be used for systemic drug delivery, percutaneous absorp- tion is often poor and erratic, although several Drug factors in dosage transdermal patches delivering drugs for systemic form design distribution (e.g. fentanyl patches for severe pain management and nicotine patches for cessation of Each type of dosage form requires careful study smoking) are available. The drugs applied to the skin of the physical and chemical properties of drug for local effect include antiseptics, antifungals and substances to achieve a stable, efficacious product. anti-inflammatory agents, as well as skin emollients These properties, such as dissolution, crystal size and for protective effects. polymorphic form, solid-state stability and drug– Pharmaceutical topical formulations – ointments, additive interaction, can have profound effects on creams and pastes – are composed of the drug in a the physiological availability and physical and chemical suitable semisolid base which is either hydrophobic stability of the drug. Through combination of or hydrophilic. The bases play an important role in such information and knowledge with that from 11 www.konkur.in CHAPTER 1 pharmacological and biochemical studies, the most of powders. Drug dissolution rate, drug absorption suitable drug form and additives can be selected for rate, drug content uniformity in dosage forms and the formulation of chosen dosage forms. stability are all dependent to various degrees on Whilst comprehensive property evaluation will not particle size, particle size distribution and particle be required for all types of formulations, those interaction with solid surfaces. In many cases, for properties which are recognized as important in dosage both drugs and additives, particle size reduction is form design and processing are listed in Table 1.3. required to achieve the desired physicochemical The stresses to which the formulation might be characteristics. exposed during processing and manipulation into It is now generally recognized that poorly water- dosage forms, as well as the procedures involved are soluble drugs showing a dissolution-rate-limiting step also list

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