Pharmaceutical Emulsions: A Drug Developer's Toolbag

This edition first published 2013 © 2013 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Sarker, Dipak K., author.

Pharmaceutical emulsions : a drug developer's toolbag / by Dipak K. Sarker.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-97683-8 (cloth)

I. Title.

[DNLM: 1. Emulsions– chemistry. 2. Biopharmaceutics– standards. 3. Chemistry, Pharmaceutical– methods. QV 786.5.C7]

RS420

615.1′9– dc23

2013018795

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Dedicated to my two fabulous sons

Hugh Callum Sarker

and

Noah Marcus Vesco Sarker

Mathematical symbols (with normal units)

Greek

Latin

Acronyms and abbreviations

Preface

The primary target audience for this text is students engaged in MPharm and professional practice modules, pharmacy technician or internal formulation and NPD courses and MScs in industrial pharmacy, PGDip industrial pharmaceutical studies and related themes. Most schools of pharmacy have about 40–160 of these students per cohort. Yet the book must simultaneously be pertinent to MRess, MScs, PhDs and postdocs (and BScs) in ‘pharmaceutical’ sciences. It is thus specialist yet generalist, to the point of not simply being a collection of research papers, but instead a teaching/training text. In light of this, the book is not targeted exclusively at either the undergraduate, the advanced researcher or the experienced industrialist. It will be seen by industrial pharmacists (pharmaceutical scientists, chemists, engineers, etc) as generalist, and for real subject experts it merely represents a referential ‘pocket guide’ and not an encyclopaedic reference manual. Unlike many colloid and dispersions books, this text is not generalist in the sense of application universality and it is exclusively written for those involved with pharmaceutical emulsions (a ‘hot’ topic, to quote one reviewer). In this sense, it has absolute value and novelty in terms of being rather specific. Many other books are available which elaborate theory and physics or physical chemistry background (e.g. Adamson, 1990; Hiemenz and Rajagopalan, 1997; Goodwin, 2000 and more recent editions). In principle, this book is primarily targeted at pharmacists, pharmaceuticists, medics and pharmacologists, and its form alludes to this in a significant manner.

I started my involvement with ‘colloids’ (now ‘nanotechnology’ in current ‘in-speak’) as an undergraduate dealing with industrial dispersions, then as a masters' chemical engineering student dealing with fabrication. During a physics PhD and numerous postdocs I had the pleasure to work with and in research groups in the UK, France, Germany and Italy, where dispersions (foams, thin liquid films and emulsions) were the mainstay of the target product or the vehicle for mechanistic elucidation. Dispersions investigated included model food foams and emulsions, liquid ion-exchange systems, theoretical and mechanistic models and industrial products of a food, automotive, petrochemical and medicinal nature. I have had the great luck to have worked and collaborated with some truly great thinkers and international colloid celebrities: Peter Wilde, David Clark, Jim Mingins, Vic Morris, Brian Robinson, Eric Dickinson, Monique Axelos, Yves Popineau, Daniel Bonn, Jacques Meunier, Vance Bergeron, Zdravko Lalchev, Reinhard Miller, Jürgen Krägel, Clive Washington, Seyed Moghimi, Vladimir Torchilin and Sandy Florence, to name but a few. Today, and for the last decade or more, most of my interest has been in pharmaceutical dispersions. Coarse emulsions (hereafter simply referred to as ‘emulsions’), nanoemulsions, micelles – simple, reverse and swollen – are the building blocks and centre points of nanomedicine, the pharmaceutical and therapeutic environment and modelling of drug encapsulation, new product design (nanoparticle drug delivery systems), increased efficacy and dosage miniaturisation, interfacial sculpting and molecular nanoengineering.

My research expertise, on which this book is founded, traverses areas of biophysics, material sciences, pharmaceutics and biopharmaceutics, food science, chemical engineering, physical chemistry, rheology and polymer science, medicinal chemistry, chemical biology, engineering, industrial product design and regulation and analytical chemistry. For teaching, I use a wide variety of books or chapters, and there are a number of really good pharmaceutics textbooks, but their main failings for pharmacy students is that they traverse year one to year four basic concepts such as pKa and log D and feature only one chapter (generalist) dealing with the pivotal role of ‘emulsions’ in medical products (therapeutics) sciences. I hope to expand on this information without providing a cost-restrictive or excessively detailed text and to focus entirely upon the dispersed particle or particle within matrix technologies, which is perhaps better suited for students with some basic primary experience or knowledge of pharmacy dispersions. Using many figures and tables is the chosen, I have attempted to provide a summary of the salient facts and thus keep the text short. As with all things, there is a compromise to be made between what we know and would like to say and the restrictions of time and the funds available in the student's pocket. I hope students and professionals alike will find the book useful, suitably informative and yet portable and readable.

Dipak K. Sarker

Brighton, 2013

Acknowledgements

Thanks to Ralitza, Hugh, Noah, Brenda, Anita, Dilip and Asis and the other members of family Sarker. I am what I am because of you. I have done what I have done with the aid of you.

‘To See a World in a Grain of Sand

And a Heaven in a Wild Flower,

Hold Infinity in the Palm of Your Hand

And Eternity in an Hour.’

‘Augeries of Innocence’: William Blake (1757–1827)

About the companion website

This book is accompanied by a companion website:

www.wiley.com/go/sarker/pharmaceuticalemulsions

The website includes:

Further case studies

Powerpoints of all figures from the book for downloading

PDFs of all tables from the book for downloading

Part I

Product considerations: medicinal formulations

All medicines and therapeutics formulated as ‘emulsions’ must typically and characteristically contain consistent amounts and specified polymorphic forms of the relevant drug (Mahato, 2007). Depending on the route of administration, some intervention may be required in order to pasteurise or sterilise the sample and thus reduce the risk of microbial growth and pathogenicity or the production of toxins. Unfortunately, most pharmaceutical dispersions, including emulsions, are thermodynamically unstable (metastable) and undergo significant change upon heating or irradiation as a consequence of changes in bulk and interfacial rheology (Sarker et al., 1999).

A patient receiving a cytotoxic drug intravenously in the form of a fine emulsion dispersion requires as a minimum that the product be suitably pure (P), suitably consistent (C) between batches and free from injurious elements, for example pathogenic microorganisms, spores and toxins, and thus of appropriate quality (Q). Acceptable PCQ is essential in any high-quality medicine (Sarker, 2008). Topical medicines (Sarker, 2006b) do not necessarily require the same degree of sterility (unless applied to broken skin), but it is worth striving for, as poor quality (Di Mattia et al., 2010) lessens product shelf life.

Shape, size, polydispersity and surface coverage (Sarker et al., 1999) all impact on the shelf life and efficacy (Sarker, 2005a, 2006b) of a drug delivery system (DDS). The most significant difficulty, industrially speaking, is the routine manufacture of a product and its profile, given variabilities and extremes of thermal and mechanical processing and resultant changes in surface chemistry and composition (Sarker et al., 1999; Sarker, 2005b).

An emulsion (derived from the Latin mulgeo and/or Ancient Greek αμ 1 λγω (amelgo): terms for milk, which is an emulsion) is a mixture of unmixable, immiscible or in principle unblendable fractions. It implies a discontinuity and heterogeneity on a microscopic (nanoscopic) scale. In classic terms, both phases are usually liquid, but this can be challenged in a plethora of common forms. The two phases can be entwined in the form of a crude ‘amalgam’, as in a depot (as with many liquid phases) of transdermal patches, of a colloidal particle (e.g. micelle), as in a microemulsion, or microheterogeneously, as in the case of a fine emulsion (cream, lotion, ointment). However, it is also the case that both the interior of a normal micelle and the bilayer leaflet of a vesicle represent a phase in which water is immiscible but apolar conjugated, aromatic or lipophilic molecules are miscible. The dispersion (see Section 2.1.1 and 2.3.1) is aided by inclusion of an emulsifier (emulgent, surfactant, etc.), which helps mixing and dispersion (Becher, 2001).

In order to make scholarly and industrial use of emulsions, the right level of background in physical chemistry and the theory of emulsion formation and stability are important, providing understanding of emulsion behaviour and the construction of effective DDSs. Critical considerations for medicinal formulations are: safety, efficacy, dose, hygiene, consistency, purity, quality, reproducibility, toxicity, effects, impurities and extraneous matter, cost, legal compliance, supplier reputation (for the fabrication) and the finished form.

All new emulsion products must pass through a regulatory process as just outlined. Figure I.1 shows a summary of the UK Medicines and Healthcare products Regulatory Agency (MHRA) regulation process for the approval of a new dispersion drug dosage form. Other regulators, such as the US Food and Drug Administration (FDA), also demand presentation of satisfactory safety and efficacy data (the presentation form may, however, change).

Figure I.1 Route for marketing authorisation (MA; product licence) of commercial pharmaceutical products. The schematic uses the MHRA as a template. Other regulators have a varied but generically similar approach.