Pharmaceutical Emulsions

PharmaceuticalEmulsionsA Drug Developer’s Toolbag

Dipak K. SarkerSchool of Pharmacy and Biomolecular SciencesUniversity of BrightonUK

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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]RS420615.1′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 maynot be available in electronic books.

Set in 10.5/13pt Times by Laserwords Private Limited, Chennai, India.

1 2013

Dedicated to my two fabulous sons

Hugh Callum Sarker

and

Noah Marcus Vesco Sarker

Contents

Mathematical symbols (with normal units) xi

Acronyms and abbreviations xiii

Preface xv

Acknowledgements xvii

About the companion website xix

I Product considerations: medicinal formulations 1

1 Historical perspective 5

1.1 Landmarks 51.2 Significant discoveries 71.3 Difficulties 81.4 Traditional uses 101.5 Product regulation 13

2 What is an emulsion? 15

2.1 States of matter 242.2 Summary thermodynamics 342.3 Interfacial tension and wetting 362.4 Shear and size reduction 462.5 Raw materials 47

3 Stability, metastability and instability 49

3.1 Stokes’ law 513.2 Derjaguin–Landau–Verwey–Overbeek (DLVO) theory 523.3 Interfacial rheology 56

4 Manufacture 63

4.1 Premixing 634.2 High-shear mixers and size reduction 644.3 Multiple and microemulsions 65

viii CONTENTS

4.4 Hot melt (steriles) 654.5 Filling 66

II Forms, uses and applications: biopharmaceutics 67

5 Creams and ointments 69

5.1 Nutraceuticals and cosmeceuticals 715.2 Medicinals 71

6 Pastes and bases 77

6.1 Emolliency 776.2 Suppositories 786.3 Pessaries 79

7 IV colloids 81

7.1 Needle free 867.2 Ocular therapy 877.3 Cancer 887.4 Antimicrobials 907.5 Temperature-sensitive matrices and release forms 937.6 Targeted endosomal use 947.7 Solid lipid nanoparticles 957.8 Diagnostic emulsions 98

8 Transdermal patches: semisolids 99

8.1 Hormones 1048.2 Analgesia 1048.3 Anaesthesia 1048.4 Nicotine 1058.5 Inserts: vaginal rings 105

9 Gels 107

9.1 Micro- and nanogels 1079.2 Semisolids 107

10 Implants 109

10.1 Plastics and glasses 10910.2 Thermoresponsive materials 110

11 De novo science, sustainable novel products and platformapplications 111

11.1 Tablets 11311.2 Metered-dose inhalers 11311.3 Blood substitutes 114

CONTENTS ix

III Tests: chemistry to control the quality, efficacy andfitness for purpose of a product 117

12 Physicochemical properties 119

12.1 Thermal evaluation (differential scanning calorimetry) and lipidpolymorphs 124

12.2 Drug form, log P and Lipinski rules 12912.3 Skin and epithelial models 13312.4 Drug delivery routes 134

13 Sizing and microscopy 137

13.1 ζ -potential 13713.2 Hydrodynamic diameter 139

14 Rheology, texture, consistency and spreadability 141

14.1 Bulk properties 14114.2 Solid-state and nanorheological properties 14414.3 Interfacial properties 144

15 Quality control, process analytical technologyand accelerated testing 149

15.1 Preformulation, high-throughput screening 15015.2 Industrial concerns 15115.3 Rancimat and other methods 152

Questions 155

Guide for readers 155Specimen ‘test’ questions 155Answers 168

References 173

Index 181

Mathematical symbols(with normal units)

Greek

σ stress (Pa)τ shear stress (Pa), decay time (s−1), delay time (s−1)γ dot shear rate (Hz, s−1)� surface excess concentration (mol/m2)κ Debye length (m)μ micron (10−6 m), ionic strength (mol/dm3, M)η bulk viscosity, coefficient of viscosity (mPa s, cP, cSt)η* complex bulk viscosity (Pas)ηd surface (dilational) viscosity (mN s/m)ηs surface (shear) viscosity (N/s/m)ε dielectric constant (dimensionless), permittivity (8.854 × 10−10 C2/N/m2)ε strain (L/L, where L is length)ζ zeta potential (mV)ρ density, bulk phase (g/cm3)ρ density difference (medium minus dispersed phase) (g/cm3)γ surface tension (mN/m)φ phase volume (dimensionless)ψ surface potential (mV)θ contact angle (◦)π surface pressure (mN/m)λ wavelength (nm)N frequency, wavenumber (cm)

Latin

H Hamaker constant for constants based on interaction of oil and water[(oil–oil)0.5 − (water–water)0.5]2 (1 × 10−20 J)

Na Avogadro’s number (6.022 × 1023)R gas constant (8.314 J/K/mol)Rg radius of gyration (m)g acceleration due to gravity (9.81 m/s2)

xii MATHEMATICAL SYMBOLS (WITH NORMAL UNITS)

G Young’s modulus (Pa)G* complex modulus (Pa)G’ storage modulus (Pa)G’’ loss modulus (Pa)P Laplace pressure (Pa, N/m2)K dissociation constant of ionisationP partition coefficient ([octanol]/[water])kB Boltzmann constant (1.381 × 10−23 J/K)k rate constant (s−1)T temperature (◦C, K)t time (s)Ed dilational modulus (mN/m)E complex elastic modulus (mN/m)D4,3 usual hydrodynamic particle diameter (by volume) (nm)D3,2 Sauter hydrodynamic particle diameter (by area) (nm)D diffusion coefficient (cm2/s)exp or e exponent, exponential

Other symbols are explained at their point of use.

Acronyms and abbreviations

A/W air–water systemADME adsorption, distribution, metabolism and excretion (of a drug)AFM atomic force microscopyCMC critical micelle concentrationDDS drug delivery systemDLS dynamic light scatteringDLVO a theory from Derjaguin, Landau, Verwey and OverbeekDSC differential scanning calorimetryEMEA European Medicines Agency (a.k.a. EMA)EPR enhanced permeability and retention (effect)FDA Food and Drug Administration (USA)FDG 2-fluoro-2-deoxy-d-glucoseGCP good clinical practiceGI tract gastrointestinal tractGLP good laboratory practiceGMP good manufacturing practiceHLB hydrophile–lipophile balanceICH International Conference on HarmonisationISO International Standards Organization (Geneva)IV intravenousLCST/HCST lower or higher critical solution temperatureLNC lipid nanocapsuleLNP lipid nanoparticleMHRA Medicines Health and Regulatory (products) Agency (UK)NPD new (medicinal) product developmentO/W oil-in-water systemPCL poly(caprolactone)PCS photon correlation spectroscopyPEG poly(ethylene glycol)PIT phase-inversion temperaturePLA poly(lactic acid)PLGA poly(lactic–glycolic acid)PMMA polymethyl(methacrylate)QA quality assuranceQC quality controlQMS quality management system

xiv ACRONYMS AND ABBREVIATIONS

RES/MPS reticuloendothelial system/monocyte–phagocyte systemSC stratum corneum (skin)SEM scanning electron microscopySLC solid lipid capsuleSLN solid lipid nanoparticleTD transdermalTLF thin liquid filmTQMS total quality management systemW/O water-in-oilW/O/W water-in-oil-in-waterWHO World Health Organization

Other abbreviations are explained at their point of use.

Preface

The primary target audience for this text is students engaged in MPharm andprofessional practice modules, pharmacy technician or internal formulation andNPD courses and MScs in industrial pharmacy, PGDip industrial pharmaceuti-cal studies and related themes. Most schools of pharmacy have about 40–160of these students per cohort. Yet the book must simultaneously be pertinent toMRess, MScs, PhDs and postdocs (and BScs) in ‘pharmaceutical’ sciences. Itis thus specialist yet generalist, to the point of not simply being a collection ofresearch papers, but instead a teaching/training text. In light of this, the bookis not targeted exclusively at either the undergraduate, the advanced researcheror the experienced industrialist. It will be seen by industrial pharmacists (phar-maceutical scientists, chemists, engineers, etc) as generalist, and for real subjectexperts it merely represents a referential ‘pocket guide’ and not an encyclopaedicreference manual. Unlike many colloid and dispersions books, this text is notgeneralist in the sense of application universality and it is exclusively writtenfor those involved with pharmaceutical emulsions (a ‘hot’ topic, to quote onereviewer). In this sense, it has absolute value and novelty in terms of being ratherspecific. Many other books are available which elaborate theory and physics orphysical chemistry background (e.g. Adamson, 1990; Hiemenz and Rajagopalan,1997; Goodwin, 2000 and more recent editions). In principle, this book is primar-ily targeted at pharmacists, pharmaceuticists, medics and pharmacologists, and itsform 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 mas-ters’ chemical engineering student dealing with fabrication. During a physics PhDand numerous postdocs I had the pleasure to work with and in research groups inthe UK, France, Germany and Italy, where dispersions (foams, thin liquid films andemulsions) were the mainstay of the target product or the vehicle for mechanisticelucidation. Dispersions investigated included model food foams and emulsions,liquid ion-exchange systems, theoretical and mechanistic models and industrialproducts of a food, automotive, petrochemical and medicinal nature. I have hadthe great luck to have worked and collaborated with some truly great thinkersand international colloid celebrities: Peter Wilde, David Clark, Jim Mingins, VicMorris, Brian Robinson, Eric Dickinson, Monique Axelos, Yves Popineau, DanielBonn, Jacques Meunier, Vance Bergeron, Zdravko Lalchev, Reinhard Miller,Jurgen Kragel, Clive Washington, Seyed Moghimi, Vladimir Torchilin and SandyFlorence, to name but a few. Today, and for the last decade or more, most of

xvi PREFACE

my interest has been in pharmaceutical dispersions. Coarse emulsions (hereaftersimply referred to as ‘emulsions’), nanoemulsions, micelles – simple, reverse andswollen – are the building blocks and centre points of nanomedicine, the pharma-ceutical and therapeutic environment and modelling of drug encapsulation, newproduct design (nanoparticle drug delivery systems), increased efficacy and dosageminiaturisation, interfacial sculpting and molecular nanoengineering.

My research expertise, on which this book is founded, traverses areas of bio-physics, material sciences, pharmaceutics and biopharmaceutics, food science,chemical engineering, physical chemistry, rheology and polymer science, medic-inal chemistry, chemical biology, engineering, industrial product design and reg-ulation and analytical chemistry. For teaching, I use a wide variety of books orchapters, and there are a number of really good pharmaceutics textbooks, but theirmain failings for pharmacy students is that they traverse year one to year four basicconcepts such as pKa and log D and feature only one chapter (generalist) dealingwith the pivotal role of ‘emulsions’ in medical products (therapeutics) sciences.I hope to expand on this information without providing a cost-restrictive or exces-sively detailed text and to focus entirely upon the dispersed particle or particlewithin matrix technologies, which is perhaps better suited for students with somebasic primary experience or knowledge of pharmacy dispersions. Using manyfigures and tables is the chosen, I have attempted to provide a summary of thesalient facts and thus keep the text short. As with all things, there is a compromiseto be made between what we know and would like to say and the restrictions oftime and the funds available in the student’s pocket. I hope students and profes-sionals alike will find the book useful, suitably informative and yet portable andreadable.

Dipak K. SarkerBrighton, 2013

Acknowledgements

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

‘To See a World in a Grain of SandAnd a Heaven in a Wild Flower,Hold Infinity in the Palm of Your HandAnd 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