Handbook of Polymers for
Pharmaceutical Technologies
Scrivener Publishing 100 Cummings Center, Suite 541J
Beverly, MA 01915-6106 Publishers at Scrivener
Martin Scrivener([email protected]) Phillip Carmical ([email protected])
Handbook of Polymers for Pharmaceutical Technologies
Edited by
Vijay Kumar Thakur and Manju Kumari Thakur
Volume 2
Processing and Applications
Copyright © 2015 by Scrivener Publishing LLC. All rights reserved.
Co-published by John Wiley & Sons, Inc. Hoboken, New Jersey, and Scrivener Publishing LLC, Salem, Massachusetts.
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Library of Congr ess Cataloging-in-Publication Data:
ISBN 978-1-119-04138-2
Printed in the United States of America 10 9 8 7 6 5 4 3 2 1
To my parents and teachers who helped me become what I am today.
Vijay Kumar Thakur
vii
Contents
Preface xvii 1 Particle Engineering of Polymers into Multifunctional Interactive Excipients 1
Sharad Mangal, Ian Larson, Felix Meiser and David AV Morton
1.1 Introduction 1
1.2 Polymers as Excipients 3
1.3 Material Properties Affecting Binder Activity 6
1.3.1 Particle Size 6
1.3.2 Deformation Mechanisms 7
1.3.3 Glass Transition Temperature (Tg) 8
1.4 Strategies for Improving Polymeric Filler-Binder Performance for
Direct Compression 8
1.4.1 Interactive Mixing 12
1.4.2 Challenges to Interactive Mixing 13
1.4.3 Controlling Interparticle Cohesion 14
1.5 Preparation and Characterization of Interactive Excipients 14 1.5.1 Particle Size and Size Distribution of Excipients 15 1.5.2 Effect of L-leucine on Surface Morphology 16 1.5.3 Effect of L-leucine on Surface Composition 16
1.5.4 Effect of L-leucine on Surface Energy 17
1.5.5 Effect of L-leucine on Interparticle Cohesion 18
1.6 Performance of Interactive Excipients 18
1.6.1 Blending Ability 18
1.6.2 Effect on Flow 20
1.6.3 Binder Activity 20
1.7 Investigation of the Effect of Polymer Mechanical Properties 23
1.8 Conclusion 25
References 26
2 The Art of Making Polymeric Membranes 33
K.C. Khulbe, T. Matsuura and C. Feng
2.1 Introduction 33
2.2 Types of Membranes 35
2.2.1 Porous Membranes 35
2.2.2 Nonporous Membranes 36
2.2.3 Liquid Membranes (Carrier Mediated Transport) 36
2.2.4 Asymmetric Membranes 36
2.3 Preparation of Membranes 36
2.3.1 Phase Inversion/Separation 37
2.3.2 Vapor-Induced Phase Separation (VIPS) 37
2.3.3 Thermally-Induced Phase Separation (TIPS) 37
2.3.4 Immersion Precipitation 38
2.3.5 Film/Dry Casting Technique 38
viii Contents
2.3.6 Track Etching 39
2.3.7 Electrospinning 39
2.3.7.1 Preparation of Electrospun Nanofiber Membranes
(ENMs) with Single Component 40
2.3.7.2 Preparation of Nanofibers with Two
Side-by-Side Components 40
2.3.7.3 Preparation of Core-Sheath and Hollow Nanofibers 41
2.3.8 Spraying 42
2.3.9 Foaming 42
2.3.10 Particle Leaching 43
2.3.11 Precipitation from the Vapor Phase 43
2.3.12 Emulsion Freeze-Drying 43
2.3.13 Sintering 44
2.3.14 Stretching 44
2.3.15 Composite/Supported 44
2.3.16 Mixed Matrix Membranes (MMMs) 45
2.3.17 Hollow Fiber Membranes 46
2.3.17.1 Methods for Spinning 46
2.3.18 Metal-Organic Frameworks (MOFs) 48
2.4 Modification of Membranes 49
2.4.1 Modification of Polymeric Membrane by Additives/Blending 49
2.4.2 Coating 50
2.4.3 Surface Modification by Chemical Reaction 50 2.4.4 Interfacial Polymerization (IP)/Copolymerization 50
2.4.5 Plasma Polymerization/Treatment 52
2.4.6 Surface Modification by Irradiation of High Energy Particles 52
2.4.7 UV Irradiation 53
2.4.8 Ion-Beam Irradiation 53
2.4.9 Surface Modification by Heat Treatment 53
2.4.10 Graft Polymerization/Grafting 53
2.4.11 Other Techniques 53
2.5 Characterization of Membrane by Different Techniques 54 2.5.1 Conventional Physical Methods to Determine Pore Size and
Pore Size Distribution 55
2.5.1.1 Bubble Gas Transport Method 55
2.5.1.2 Mercury Intrusion Porosimetry 56
2.5.1.3 Gas Liquid Equilibrium Method (Permporometry) 56 2.5.1.4 Adsorption-Desorption Method:
Barett-Joyner-Halenda (BJH) Method 57
2.5.1.5 Permeability Methods 57
2.5.2 Morphology 58
2.5.2.1 Microscopic Method 58
2.5.2.2 Spectroscopic Method 59
2.5.2.3 Positron Annihilation Spectroscopy (PAL) 59 2.5.2.4 X-Ray Analysis and Other Methods 59
2.5.3 Thermal Properties 60
Contents ix
2.5.4 Mechanical Properties 60
2.5.4.1 Tensile Strength 60
2.5.4.2 Young’s Modulus or Tensile Modulus of Elasticity 60
2.6 Summary 61
References 62 3 Development of Microstructuring Technologies of Polycarbonate
for Establishing Advanced Cell Cultivation Systems 67 Uta Fernekorn, Jörg Hampl, Frank Weise, Sukhdeep Singh,
Justyna Tobola and Andreas Schober
3.1 Introduction 67
3.2 Material Properties of Polycarbonate 71
3.2.1 Physical Properties 71
3.2.2 Chemical Properties 72
3.2.3 Biological Properties 72
3.3 Use of Polycarbonate Foils in Structuration Processes 75
3.3.1 Hot Embossing 75
3.3.2 Thermoforming 77
3.4 Simulation of Microstructuring of a Polycarbonate Foil 79
3.5 Chemical Functionalization of Polycarbonate 81
3.6 Surface Micropatterning of Polycarbonate 84
3.7 Application Examples 86
3.7.1 3D Liver Cell Cultivation in Polycarbonate Scaffolds 86 3.7.2 3D Lung Cell Cultivation in Semi-Actively Perfused Systems 87 3.7.3 Guiding 3D Cocultivation of Cells by
Micropatterning Techniques 87
3.8 Conclusion and Further Perspectives 88
Acknowledgements 89 References 89 4 In-Situ Gelling Thermosensitive Hydrogels for Protein Delivery Applications 95
Roberta Censi, Alessandra Dubbini and Piera Di Martino
4.1 Introduction 96
4.2 Polymers for the Design of Hydrogels 97
4.2.1 Polymer Architectures 97
4.2.2 Natural, Synthetic and Hybrid Hydrogels 97
4.2.3 Crosslinking Methods 99
4.2.4 Thermogelling Polymer Hydrogels 100
4.3 Pharmaceutical Applications of Hydrogels: Protein Delivery 107 4.3.1 Strategies for Protein Release from Hydrogels 109
4.3.1.1 Physical Entrapment of Proteins into Hydrogels: General
Principles and Release Mechanisms 109
4.3.1.2 Covalent Binding 112
4.3.1.3 Dual/Multiple Delivery Systems 112
4.4 Application of Hydrogels for Protein Delivery in Tissue Engineering 112
4.5 Conclusions 113
References 114
x Contents
5 Polymers as Formulation Excipients for Hot-Melt Extrusion Processing of
Pharmaceuticals 121 Kyriakos Kachrimanis and Ioannis Nikolakakis
5.1 Introduction 121
5.1.1 Overview of Hot-Melt Extrusion (HME) 121
5.1.2 Solubility/Dissolution Enhancement by Solid Dispersions 123
5.2 Polymers for HME Processing 127
5.2.1 Basic Requirements 127
5.2.2 Suitability – Examples 128
5.3 Polymer Selection for the HME Process 130
5.3.1 Thermodynamic Considerations – Drug-Polymer Solubility and
Miscibility 130
5.4 Processing of HME Formulations 135
5.4.1 Physical Properties of Feeding Material – Flowability,
Packing and Friction 135
5.4.1.1 Crystallinity 136
5.4.1.2 Molecular Weight and Viscosity 138
5.5 Improvements in Processing 141
5.5.1 Equipment Modifications 141
5.5.2 Plasticizers 142
5.5.2.1 Drugs Acting as Plasticizers 142
5.2.2.2 Extrusion Based on Use of Plasticizers 142
5.6 Conclusion and Future Perspective 144
References 144 6 Poly Lactic-Co-Glycolic Acid (PLGA) Copolymer and Its
Pharmaceutical Application 151
Abhijeet Pandey, Darshana S. Jain, Subhashis Chakraborty
6.1 Introduction 151
6.2 Physicochemical Properties 152
6.3 Biodegradation 153
6.4 Biocompatibiliy, Toxicty and Pharmacokinetics 154
6.5 Mechanism of Drug Release 155
6.6 PLGA-Based DDS 157
6.7 Bone Regeneration 158
6.8 Pulmonary Delivery 160
6.9 Gene Therapy 162
6.10 Tumor Trageting 162
6.11 Miscellaneous Drug Delivery Applications 164
6.12 Conclusion 165
References 165 7 Pharmaceutical Applications of Polymeric Membranes 173
Stefan Ioan Voicu
7.1 Introduction 173
7.2 Obtaining Pure and Ultrapure Water for
Pharmaceutical Usage 178
Contents xi
7.3 Wastewater Treatment for Pharmaceutics 180
7.4 Controlled Drug Delivery Devices Based on
Membrane Materials 183
7.5 Molecularly Imprinted Membranes 185
7.6 Conclusions 190
References 191 8 Application of PVC in Construction of Ion-Selective Electrodes
for Pharmaceutical Analysis: A Review of Polymer Electrodes for
Nonsteroidal, Anti-Inflammatory Drugs 195
Joanna Lenik
8.1 Introduction 195
8.2 Properties and Usage of Poly(vinyl)chloride (PVC) 197 8.3 PVC Application and Properties in Construction of
Potentiometric Sensors for Drug Detection 199
8.3.1 Role of Polymer Membrane Components 202
8.4 Ion-Selective, Classic, Liquid Electrodes (ISEs) 205
8.5 Ion-Selective Solid-State Electrodes 206
8.5.1 Ion-Selective Coated-Wire Electrodes (CWE) 206
8.5.2 Ion-Selective BMSA Electrodes 207
8.5.3 Electrodes Based on Conductive Polymers (SC-ISEs ) 208 8.6 Application of Polymer-Based ISEs for Determination of Analgetic,
Anti-Inflammatory and Antipyretic Drugs: Literature Review (2000-2014) 211 8.6.1 Electrodes for Determination of Narcotic Medicines 211 8.6.2 Electrode Sensitive to Dextromethorphan 211
8.6.3 Electrode Sensitive to Tramadol 212
8.6.4 Electrodes for Determination of Non-Narcotic Drugs 212
8.6.5 Salicylate Electrode 214
8.6.6 Ibuprofen Electrode 214
8.6.7 Ketoprofen Electrodes 216
8.6.8 Piroxicam Electrode 216
8.6.9 Tenoxicam Electrode 217
8.6.10 Naproxen Electrodes 217
8.6.11 Indomethacin Electrodes 217
8.6.12 Sulindac Electrode 218
8.6.13 Diclofenac Electrodes 218
8.7 Conclusion 218
References 222 9 Synthesis and Preservation of Polymer Nanoparticles for Pharmaceutical
Applications 229 Antonello A. Barresi, Marco Vanni, Davide Fissore and Tereza Zelenková
9.1 Introduction: Polymer Nanoparticles Production 229 9.2 Production of Polymer Nanoparticles by Solvent Displacement
Using Intensive Mixers 238
9.2.1 Influence of Polymer-Solvent Type and Hydrodynamics
on Particle Size 243
xii Contents
9.2.2 Dependence on Operating Conditions – Polymer and Drug
Concentration, Solvent/Antisolvent Ratio, Processing Conditions 248 9.2.3 Process Design: Selection of Mixing Device, Scale Up and
Process Transfer 256
9.3 Freeze-Drying of Nanoparticles 264
9.4 Conclusions and Perspectives 268
Acknowledgements 272 References 272 10 Pharmaceutical Applications of Maleic Anhydride/Acid Copolymers 281
Irina Popescu
10.1 Introduction 281
10.2 Maleic Copolymers as Macromolecular Drugs 283
10.3 Maleic Copolymer Conjugates 285
10.3.1 Polymer-Protein Conjugates 286
10.3.2 Polymer-Drug Conjugates 288
10.4 Noncovalent Drug Delivery Systems 291
10.4.1 Enteric Coatings 291
10.4.2 Solid Dispersions 292
10.4.3 Polymeric Films and Hydrogels 293
10.4.4 Microspheres and Microcapsules 294
10.4.5 Nanoparticles 295
10.4.6 Micelles 295
10.5 Conclusion 296
References 296 11 Stimuli-Sensitive Polymeric Nanomedicines for Cancer
Imaging and Therapy 311
F. Perche, S. Biswasand V. P. Torchilin
11.1 Introduction 311
11.2 Pathophysiological and Physical Triggers 314
11.2.1 Acidosis 314
11.2.1.1 pH-Sensitive Tumor Imaging 314
11.2.1.2 pH-Sensitive Prodrugs 315
11.2.1.3 pH-Dependent Change of Structure/Size or Shape 315 11.2.1.4 pH-Induced Exposure of an Internalization Moiety 315 11.2.1.5 pH-Sensitive Coordination Bonds 317 11.2.1.6 pH-Sensitive Dendrimer Nanoparticles 317 11.2.1.7 Drug Conjugated to Dendrimer via
pH-Sensitive Linkages 318
11.2.2 Reductive Stress 319
11.2.2.1 Reduction-Sensitive Prodrug 319 11.2.2.2 Reduction-Induced Exposure of an
Internalizing Moiety 320
11.2.2.3 Reduction-Sensitive Crosslinking 320
11.2.3 Tumor Hypoxia 320
11.2.3.1 Hypoxia-Induced Drug Release or Exposure of
Positive Charge 321
Contents xiii 11.2.4 Cancer Associated Extracellular Enzymes 322
11.2.4.1 Activatable Cell Penetrating Peptides for
Tumor Imaging 322
11.2.4.2 MMP-Induced Exposure of Internalization Moiety 322 11.2.4.3 MMP-Induced Exposure of Positive Charge 323
11.2.4.4 Combination Therapy 324
11.2.4.5 Enzyme-Sensitive Dendrimers 324
11.2.5 Magneto-Responsive Polymers 324
11.2.6 Temperature-Sensitive Dendrimers 325
11.2.7 Photoresponsive Polymers 326
11.2.7.1 Photodynamic Therapy 326
11.2.7.2 Photosensitive Dendrimers 327
11.2.7.3 Photoimmunotherapy 327
11.3 Stimuli-Responsive Polymers for Patient Selection and
Treatment Monitoring 327
11.3.1 Selection of Patients Amenable to Nanomedicine Treatment 328 11.3.2 Selection of Patients for pH-Sensitive Nanocarriers 329 11.3.3 Selection of Patients for Redox-Sensitive Nanocarriers 329 11.3.4 Mapping of Dominant Active Pathways Using
Enzyme-Sensitive Probes 330
11.3.5 Selection of Patients for Molecularly-Targeted Therapies 330
11.3.6 Evaluation of Response to Treatment 331
11.4 Conclusions and Future Perspectives 331
Acknowledgments 333 References 333 12 Artificial Intelligence Techniques Used for Modeling of Processes
Involving Polymers for Pharmaceutical Applications 345 Silvia Curteanu
12.1 Introduction 345
12.2 Artificial Neural Networks 347
12.2.1 Elements and Structure 347
12.2.2 Working Methodology 349
12.2.3 Variants of ANN Modeling 350
12.3 Support Vector Machines 352
12.3.1 General Aspects 352
12.3.2 SVM Modeling Methodology 353
12.4 Modeling of Processes Involving Polymers for
Pharmaceutical Applications 354
12.4.1 Neural Networks Used for Modeling of Processes Involving
Pharmaceutical Polymers 354
12.4.2 Support Vector Machines Used for Modeling of
Processes Involving Pharmaceutical Polymers 359
12.5 Conclusion and Future Perspective 360
References 361
xiv Contents
13 Review of Current Pharmaceutical Applications of Polysiloxanes (Silicones) 363 Krystyna Mojsiewicz-Pieńkowska
13.1 Introduction 363
13.2 Variety of Polysiloxane – Structure, Synthesis, Properties 364
13.2.1 Basic Silicone Chemistry 364
13.2.2 Properties of Silicones 364
13.3 Polysiloxanes as Active Pharmaceutical Ingredient (API) 368 13.3.1 Mechanism of Action of Dimethicone and Simethicone 370 13.3.2 Current Legislative Standards Related to Oral Application of
Dimethicone and Simethicone (PDMS) 370
13.3.3 Admissible Doses for Dimethicone and Simethicone (PDMS) 372
13.4 Polysiloxanes as Excipients 373
13.4.1 Skin Adhesive Patches 375
13.4.2 Carrier for Controlled-Release Drugs 375 13.4.2.1 Transdermal Drug Delivery System 377
13.5 Conclusion and Future Perspective 377
References 378 14 Polymer-Doped Nano-Optical Sensors for Pharmaceutical Analysis 383
M. S. Attia and M. S. A. Abdel-Mottaleb
14.1 Introduction 383
14.1.1 Sol-Gel Process 383
14.1.1.1 Mechanism of Sol-Gel Formation 384
14.1.1.2 Hybrid Nanomaterials 385
14.1.2 Molecular Imprinting Nanomaterial Polymer 386 14.1.2.1 Approach of Molecular Imprinted Polymer Formation 387 14.1.3 Poly(methyl methacrylate) Polymer (PMMA) 390
14.2 Processing 392
14.2.1 Sol-Gel Technique 392
14.2.1.1 Preparation of Optical Sensor Doped in TEOS 392 14.2.1.2 Preparation of Thin Film Nano-Optical Sensor
Doped in Sol-Gel Matrix 393
14.2.2 Molecular Imprinted Nanomaterials 394
14.2.2.1 Imprinted Nanoparticles (Imp-NPs) 394
14.2.2.2 Imprinted Nanospheres 394
14.2.2.3 Imprinted Nanoshells 395
14.2.2.4 Imprinted Nanofibers 396
14.2.3 Preparation of Optical Sensor Doped in PMMA Matrix 396 14.2.4 Determination of Pharmaceutical Drug in Pharmaceutical
Preparations 396 14.2.5 Determination of Pharmaceutical Drug in Serum Solution 397 14.3 Application of Optical Sensor for Pharmaceutical Drug Determination 397
14.3.1 TEOS-Doped Nano-Optical Sensor for Pharmaceutical
Determinations 397 14.3.1.1 Determination of Ramipril by Using
Sm3+-Doxycycline Doped in TEOS matrix 397
Contents xv 14.3.1.2 Determination of Metoclopramide Hydrochloride
by Using Europium Doped in TEOS Matrix 398 14.3.1.3 Nano-Optical Sensor for Chlorzoxazone and
Ibuprofen Determination 399
14.3.1.4 Nano-Optical Sensor for Norfloxacin and Gatifloxacin Determination 399
14.3.2 Molecular Imprinted Nano-Polymer 401
14.3.2.1 Hollow Molecular Imprinting Polymer for Ofloxacin Determination 401 14.3.2.2 Molecular Imprinted Solid-Phase Extraction for
Determination of Ofloxacin (OFL) and Lomefloxacin 401 14.3.2.3 Ofloxacin-Imprinted Polymer Using Poly(glycidyl
methacrylate-co-ethylenedimethacrylate) Particles
as a Support 402
14.3.2.4 Molecular Imprinted Polymer Nanoparticles for
Ofloxacin Determination 402
14.3.2.5 Molecular Imprinted Polymer for Ciprofloxacin
Determination 403 14.3.2.6 Molecular Imprinted Polymeric Membrane on a
Porous Silica-Gel for Norfloxacin Determination 403 14.3.2.7 Electrochemical Sensor Combined with Molecular
Imprinted Polymer for Paracetamol Determination 403 14.3.3 Sensor Embedded in Polymethymethacrylate 404
14.3.3.1 Metoclopramide Hydrochloride Determination by
Using an Optical Sensor Tb3+ Embedded in PMMA 404 14.3.3.2 Hydrochlorothiazide Determination by Using an
Optical Sensor Eu3+ Embedded in PMMA 404
14.4 Conclusion 405
References 405 15 Polymer-Based Augmentation of Immunosuppressive Formulations:
Application of Polymer Technology in Transplant Medicine 411 Ian C. Doyle and Ashim Malhotra
15.1 Introduction 411
15.2 Polymer-Based Immunosuppressive Formulations 414
15.2.1 Sirolimus 414
15.2.1.1 Oral and Injectable Formulations 414 15.2.1.2 Device Slow-Release Formulations 415
15.2.2 Cyclosporine A 424
15.2.2.1 CsA Delivery via Polymeric Micelles 425 15.2.2.2 CsA Delivery via Nanoparticles 426 15.2.2.3 CsA Delivery via Biodegradable Matrices 428 15.2.2.4 Ophthalmic CsA Delivery Systems 429
15.2.3 Tacrolimus 429
15.2.3.1 Polymer Applications for Oral
Tacrolimus Formulations 430
15.2.3.2 Other Polymer Applications for Tacrolimus 431
xvi Preface
15.2.4 Mycophenolic Acid 431
15.3 Conclusion and Future Perspective 433
References 434 16 Polymeric Materials in Ocular Drug Delivery Systems 439
M. E. Pina, P. Coimbra, P. Ferreira, P. Alves, A. I. Figueiredo and M. H. Gil
16.1 Introduction 439
16.2 A Brief Description of Ocular Anatomy and Physiology 440
16.2.1 Anatomy of the Human Eye 440
16.2.2 Routes of Ocular Drug Delivery 441
16.2.3 Barriers in Ocular Drug Delivery 444
16.2.3.1 Lacrimation, Drainage and Blood Vessels 444
16.2.3.2 Corneal–Aqueous Barrier 444
16.3 Polymeric Ocular Drug Delivery Systems 445
16.3.1 Non-Biodegradable Polymeric Ocular Drug Delivery Systems 446 16.3.1.1 Non-Biodegradable Synthetic Polymers 446 16.3.2 Biodegradable Polymeric Ocular Drug Delivery Systems 449 16.3.2.1 Biodegradable Synthetic Polymers 450
16.4 Conclusion and Future Perspective 455
References 455 Index 459
xvii
Preface
The modern pharmaceutical market is under relentless pressure from slowing new drug product approvals, blockbuster drug patent expiry, price pressure and global competi- tion. In addition, new opportunities exist due to an evolving patient population, numerous unmet medical needs and growing disease awareness. In order to sustain performance, the pharmaceutical industry must evolve and improve product development and processing efficiencies. Therefore, efficient and cost-effective product development and processing are continually being explored to meet the challenge of not only reducing cost, but also the risk of product recalls. In the last few decades, much importance has been given to the use of polymers in pharmaceutical systems. Huge opportunities in the design, synthesis and modification of the physical and chemical properties of polymers have made them the most rapidly growing group of materials with great importance and possible applications in pharmacy, medicine and cosmetology. Polymeric materials having biomedical applications can be classified into different groups depending upon the application. For example, they are generally divided into two major groups according to use: those employed in prosthetic devices such as cardiovascular and orthopedic prostheses; and those employed as thera- peutic systems such as drug carriers. Among the prosthetic systems, polymeric materials can be used as coatings or as cemented prostheses. Some of the major advantages in using polymeric materials for biomedical applications are their flexibility, biocompatibility, the possibility of tailoring their mechanical properties and their ability to incorporate thera- peutic agents into their matrix in order to allow drug administration at a specific site.
Both natural and man-made polymers have been widely utilized as tablet binders and filler-binders in the pharmaceutical industry. The physico-chemical and mechanical prop- erties such as particle size, shape and deformation behavior of polymeric binders are key to their effective use. Polymeric membranes are also becoming increasingly important in the field of separation processes in the pharmaceutical industry and artificial organs. Some polymers are obtained from natural sources (natural polymer) and then chemically modi- fied for various applications, while others are chemically synthesized (synthetic polymer).
Polymeric membranes can be fabricated in different configurations, such as flat sheet, tubu- lar hollow fibers, nanofibers, etc., via different techniques. Since the performance of the membrane is largely controlled by its surface (active layer), the design of membrane sur- face and its characterization, either by chemistry or morphology, are extremely important.
Hence, emphasis is being placed on the membrane surface. Hot-melt extrusion (HME) technique is used to create a dispersion of the active pharmaceutical ingredient (API) in a polymer matrix in order to achieve solubility enhancement, release rate modulation, mask taste, or to develop a new dosage form. However, polymers must fulfill a number of require- ments in order to be suitable for HME processing. The relatively recent introduction of
xviii Preface
HME in the pharmaceutical industry has opened new areas of applications for old and newly synthesized polymers, and enabled drug manufacturers to scale up the production of solid dispersions. A variety of chemically diverse polymers with different physico-chemical properties are available, which enable formulators to fine-tune the solid form of the extruded product by the selection of suitable polymer, drug-polymer ratio and operat- ing conditions. Scientists in collaboration with pharmaceutical industries are extensively developing new classes of pharmaceutical materials. This second volume of Handbook of Polymers for Pharmaceutical Technologies is primarily focused on the pharmaceutical poly- mers and deals with the processing and applications of these polymers. Numerous critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of pharmaceutical polymers.
The prime topics extensively described in this book include: particle engineering of poly- mers into multifunctional interactive excipients; the art of making polymeric membranes;
pharmaceutical applications of polymeric membranes; development of microstructuring technologies of polycarbonate for establishing advanced cell cultivation systems; in-situ gelling thermosensitive hydrogels for protein delivery applications; polymers as formula- tion excipients for the hot-melt extrusion processing of pharmaceuticals; poly lactic-co- glycolic acid (PLGA) copolymer and its pharmaceutical application; application of PVC in construction of ion-selective electrodes for pharmaceutical analysis; a review of polymer electrodes for nonsteroidal, anti-inflammatory drugs; synthesis and preservation of poly- mer nanoparticles for pharmaceutical applications; pharmaceutical applications of maleic anhydride/acid copolymers; stimuli-sensitive polymeric nanomedicines for cancer imag- ing and therapy; artificial intelligence techniques used for modeling of processes involving polymers for pharmaceutical applications; a review of current pharmaceutical applications of polysiloxanes (silicones); polymer-doped nano-optical sensors for pharmaceutical anal- ysis; and finally, polymer-based augmentation of immunosuppressive formulations – appli- cation of polymer technology in transplant medicine.
Several critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of processing and applications of pharmaceutical polymers. We would like to thank the publisher and Martin Scrivener for their invaluable help in the organization of the editing process. Finally, we would like to thank our parents for their continuous encouragement and support.
Vijay Kumar Thakur, PhD Washington State University, USA Manju Kumari Thakur, MSc, MPhil, PhD Himachal Pradesh University, Shimla, India May 2015
xix
About the Editors
Vijay Kumar Thakur, Ph.D.
Email: [email protected]
Dr. Vijay Kumar Thakur has been working as Research Faculty (staff scientist) in the School of Mechanical and Materials Engineering at Washington State University, USA, since September 2013. His for- mer appointments include being a research scientist in Temasek Laboratories at Nanyang Technological University, Singapore, and a visiting research fellow in the Department of Chemical and Materials Engineering at LHU- Taiwan. His research interests include the synthesis and processing of biobased polymers, nanomaterials, polymer micro/nanocomposites, nanoelectronic materials, novel high dielectric constant materials, electrochromic materials for energy storage, green synthesis of nanomaterials, and surface functionalization of polymers/nanomaterials. He did his post doctorate in Materials Science at Iowa State University and his PhD in Polymer Science (2009) at the National Institute of Technology. In his academic career, he has published more than 80 SCI journal research articles in the field of polymers/materials science and holds one United States patent. He has also published 15 books and thirty book chapters on the advanced state-of-the-art of polymers/materials science with numerous publishers.
Manju Kumari Thakur, M.Sc., M.Phil., Ph.D.
Email: [email protected]
Dr. Manju Kumar Thakur has been working as an Assistant Professor of Chemistry at the Division of Chemistry, Govt. Degree College Sarkaghat Himachal Pradesh University, Shimla, India, since June 2010. She received her BSc in Chemistry, Botany and Zoology; MSc, MPhil in Organic Chemistry and PhD in Polymer Chemistry from the Chemistry Department at Himachal Pradesh University, Shimla, India. She has rich experience in the field of organic chemistry, biopolymers, composites/nanocomposites, hydrogels, applications of hydrogels in the removal of toxic heavy metal ions, drug deliv- ery, etc. She has published more than 30 research papers in several international journals, co-authored five books and has also published 25 book chapters in the field of polymeric materials.
1
Vijay Kumar Thakur and Manju Kumari Thakur, Handbook of Polymers for Pharmaceutical Technologies, Volume 2 (1–32) © 2015 Scrivener Publishing LLC
*Corresponding author: [email protected]
1 Particle Engineering of Polymers into Multifunctional Interactive Excipients
Sharad Mangal, Ian Larson, Felix Meiser and David AV Morton*
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
Abstract
Both natural and man-made polymers are widely utilized as tablet binders and filler-binders.
The physicochemical and mechanical properties such as particle size, shape and deformation behavior of polymeric binders are key in their effective use. Many such binders are applied as solution in a wet granulation process, which facilitate its facile distribution leading to improved effectiveness as a binder. Direct compression and dry granulation are recognized as routes with reduced process complexity and cost. These processes require a binder to be employed in a dry form and it can be more difficult to obtain a homogeneous distribution of a dry binder in a powder formulation. Therefore, these binders are required in high proportions to generate mechanically strong tablets. At lower proportions, they often are insufficient to create mechani- cally strong tablets. Recently, innovations in the generation of co-processed excipients have been proposed. Co-processing is a popular means of improving excipient functionalities, where two or more existing excipients are combined by some suitable means to generate new structures with improved and often combined functionalities as compared to the component excipients.
Particle size reduction is known to improve the binder properties of an excipient, but also makes it highly cohesive and hard to blend. Via particle engineering, surface structure of smaller par- ticles can be tailored to optimize the cohesive-adhesive balance (CAB) of the powder, allowing formation of interactive mixtures. This chapter reviews recent efforts to engineer surface-modi- fied polymeric micro-excipient structures with the inherent ability to not only form an interac- tive mixture efficiently and provide flow enhancement, but also to create harder tablets at lower proportions. Hence, this approach represents a potential novel multifunctional prototype poly- meric micro-excipient for direct compression and dry granulation processes.
Keywords: Particle engineering, powder technology, interactive mixtures, tablets, binder, multifunctional excipients
1.1 Introduction
The modern pharmaceutical market is under relentless pressure from slowing new prod- uct approvals, patent expiries and global competition. In addition, new opportunities
2 Handbook of Polymers for Pharmaceutical Technologies
exist with an evolving patient population, numerous unmet medical needs and grow- ing disease awareness. The pharmaceutical industry must evolve and improve product developing and manufacturing efficiencies for sustainable performance. Efficient and cost-effective product development and manufacturing are continually being explored to meet the challenge of not only reducing cost but also reducing the risk of product recalls.
Tablets are the most commonly used pharmaceutical preparation, accounting for more than 80% of all dosage forms administered [1]. The principal reasons for their continued popularity include convenience of administration and patient preference, high-precision dosing, stability and cost effectiveness [2].
Tablets are typically manufactured by applying pressure to active pharmaceutical ingredient(s) (APIs) and excipients powder blends in a die using a punch, which com- presses the powder into a coherent compact. Under compression, bonds are established between the particles, thus conferring a certain mechanical strength to the compact.
A formulation must exhibit good flow and high compactability for an API to be trans- formed into tablets of satisfactory quality. Good flow is necessary to ascertain the rapid and reproducible filling of powder into the die to minimize weight variation; while high compactability is required to ensure that the tablets are sufficiently strong to withstand handling during manufacturing and transportation [3].
The majority of API(s) lack the requisite flow and compactability for direct tab- let manufacturing [4]. Therefore, the flow and compactability of the API(s) need to be adjusted to ensure formation of high-quality tablets. Typically, the flow and com- pactability of a tablet formulation is improved by a granulation step (wet or dry granu- lation) in which the particles of API(s) and excipients are agglomerated into larger particulate structures referred to as granules. Wet granulation of the input materials can improve the flow properties for further processing and can create non-segregating blends of powder ingredients [5]. However, it involves multiple manufacturing steps, which can add significant time and cost to the process. Conversely, direct compression
Wet granulation Dry granulation
Mixing
Mixing
Mixing Water
Binder Binder Binder
Diluent Diluent Diluent
API(s) API(s) API(s)
Wetting Granulation
Drying
Lubricant/Glidant
Lubricant/Glidant
Lubricant/Glidant
Disintegrant
Disintegrant Disintegrant
Mixing Mixing
Roller compaction
Compression
Direct compression
Compression Compression
Milling/Screening Milling/Screening
Figure 1.1 The various steps involved in wet granulation, dry granulation and direct compression tablet manufacturing. Adapted and modified from [6].
Particle Engineering of Polymers into Multifunctional Interactive 3 merely involves mixing of API(s) and excipients followed by immediate compression (Figure 1.1). Therefore, direct compression is an attractive manufacturing process, with fewer steps, for reducing cost and improving manufacturing output.
1.2 Polymers as Excipients
Excipients form an integral part of any pharmaceutical tablet formulation. They play the fundamental role in creation of robust tablet formulations by carrying out an exten- sive range of functions such as fillers, binders, disintegrants, lubricants, glidants, coat- ing agent and anti-adherents. Currently, a wide range of polymeric materials are used as excipients [6,7], and polymers are the largest overall consumed product segment for the global excipients market, accounting for over 30% [8]. The excipient market is expected to grow at an annual rate of 5.2% from 2013 to 2018, to reach around $7.35 billion by 2018 [8].
Polymers of natural, semi-synthetic and synthetic origin are used especially in the role of binder and filler-binder (see Table 1.1). Polymeric excipients are popular as they can be tailored for many applications by altering their chain length and by chemical functionalization. This can achieve new materials with various optimized physico- chemical and mechanical properties for such specific applications.
Table 1.1 List of polymeric excipients, their source and functionalities. This table is compiled from the information given in the Handbook of Pharmaceutical Excipients [9].
Polymeric Excipient Source Functionality
Natural
Zein Extracted from corn gluten Binder, Coating agent
Cellulose Extracted from fibrous plant material Diluent, Disintegrant Alginic acid Extracted from various species of
brown seaweed Binder, Disintegrant
Acacia Exudate from the stems and branches
of Acacia Senegal Binder
Guar gum Extracted from the endosperm of the
Cyamopsis tetragonolobus Binder, Disintegrant Inulin Extracted from the tubers of Dahlia
variabilis, Helianthus Binder
Chitosan Extracted from shells of crustaceans
such as shrimps and crabs Binder, Coating agent (Continued)
4 Handbook of Polymers for Pharmaceutical Technologies
Polymeric Excipient Source Functionality
Semi-synthetic
Sodium alginate By neutralized alginic acid with
sodium bicarbonate Binder, Disintegrant Calcium alginate By treating sodium alginate with
calcium salts Disintegrant
Methyl cellulose By treating wood pulp with alkali fol-
lowed by methylation Binder, Disintegrant, Coating agent Carboxymethyl
cellulose sodium By treating wood pulp with alkali followed by reaction with sodium monochloroacetate
Binder, Disintegrant
Carboxymethyl
cellulose calcium By treating wood pulp with alkali followed by methylation and then converting to calcium salt
Disintegrant
Cellulose acetate By treating cellulose with acid catalysis
and acetic anhydride Diluent, Coating agent
Cellulose acetate
phthalate By reacting cellulose acetate with
phthalic anhydride Coating agent
Microcrystalline
cellulose By controlled hydrolysis of
cellulose with mineral acid Binder, Diluent, Disintegrant Hydroxypropylmethyl
cellulose By treating alkali cellulose with chlo-
romethane and propylene oxide Binder, Coating agent Hydroxypropylmethyl
cellulose acetate succinate
By the esterification of hydroxypropylmethyl
cellulose with acetic anhydride and succinic anhydride
Film coating, Enteric coating
Hydroxypropylmethyl
cellulose phthalate By the esterification of
hydroxypropylmethyl cellulose with phthalic anhydride
Enteric coating
Ethylcellulose By ethylation of the alkali
cellulose with chloroethane Binder, Diluent, Coating agent Low substituted-
hydroxypropyl cellulose
By reacting alkaline cellulose with
propylene oxide Binder, Disintegrant
Ethyl cellulose By ethylation of the alkali cellulose
with chloroethane Binder, Diluent,
Coating agent Hydroxyethyl cellulose By reacting alkali cellulose with ethyl-
ene oxide Binder, Coating agent
Table 1.1 (Cont.)
(Continued)
Particle Engineering of Polymers into Multifunctional Interactive 5
Polymeric Excipient Source Functionality
Maltodextrin By heating starch with acid and/or
enzymes Binder, Diluent,
Coating agent Sodium starch
glycolate By reacting starch with sodium chloroacetate followed by acidic neutralization
Disintegrant
Hydroxypropyl starch By reacting starch with propylene
oxide in the presence of alkali Binder, Disintegrant Dextrates By controlled enzymatic hydrolysis of
starch Binder, Diluent
Dextrin By the incomplete hydrolysis of starch Binder, Diluent Lactose monohydrate By crystallization from supersaturated
lactose solutions Binder, Diluent
Spray-dried lactose By spray drying a suspension of
α-lactose monohydrate Binder, Diluent Pregelatinized starch By heating an aqueous slurry of starch
with salts or bases and surfactants Binder, Diluent, Disintegrant Synthetic
Poloxamer By reacting propylene oxide with propylene glycol followed by addition of ethylene oxide
Lubricant
Polyethylene oxide By polymerization of ethylene oxide Binder, Coating agent Polyethylene glycol By reacting ethylene oxide and water
under pressure Coating agent
Polyvinyl acetate
phthalate By reacting phthalic anhydride, sodium acetate, and a partially hydrolyzed polyvinyl alcohol
Coating agent
Polyvinyl alcohol By hydrolyzing of polyvinyl acetate Coating agent, Lubricant Polyvinylpyrrolidone
(PVP) By reacting acetylene and formalde- hyde followed by hydrogenation to form butyrolactone and reacting it with ammonia
Binder, Disintegrant
Copovidone PVP/VA By free-radical polymerization of vinylpyrrolidone and vinyl acetate in a ratio of 6 : 4
Binder
Crospovidone By polymerizing vinylpyrrolidone Disintegrant Polymethcrylate By the polymerization of acrylic and
methacrylic acids Binder, Diluent
Carbomer By crosslinking acrylic acid Binder
Table 1.1 (Cont.)
6 Handbook of Polymers for Pharmaceutical Technologies
In wet and dry granulation, the properties of the individual API and excipients par- ticles are significantly altered by their agglomeration into granules. Such structures can hide the undesirable properties of individual components (of both API(s) and excipi- ents) of the blend. In wet granulation, a binder can be sprayed into the powder as a solution, and so is easily distributed onto the particle interfaces, so facilitating the bind- ing action. For dry granulation, a binder must be added in dry particulate form. Tablet formulations involving a granulation step can be less sensitive to binder excipient per- formance and variation than for direct compression. In direct compression, the original particle’s structure remains largely unaltered, so individual particle properties (API(s) and excipient) have a more critical and direct impact on formulation properties, such as flow and compactability, and decide the success or otherwise of tablet formation.
Consequently, excipients, particularly filler-binders, which play a critical role in direct compression, can be very different in nature to the excipients used in wet/dry granula- tion. Therefore, there is a great interest in generating ready-made multifunctional filler- binders with improved flowability and binder activity (API uptake capacity) for robust tablet manufacturing using direct compression.
The main focus of this chapter is to examine the critical material properties that influence polymeric binder and filler-binder performance of directly compressible excipients, and how these material properties can be optimized and integrated with other functionalities via particle engineering.
1.3 Material Properties Affecting Binder Activity
The material properties such as particle size and deformation mechanism (elasticity- plasticity and fragmentation) and compressibility have been identified as affecting the ability of a binder to create strong tablets [10–14].
1.3.1 Particle Size
Previous studies have indicated that the optimal amount of binder corresponds to that providing a surface area ratio of unity to the corresponding API, i.e., the amount needed to form a monoparticulate layer of binder particles around the API particles [10]. This suggests that if the particle size of the binder and API is similar (as desir- able in direct compression powder blends to avoid segregation), higher proportions will be required to achieve monoparticulate layer of binder around the API particles.
However, if the binder particles are smaller than the API, lower proportions of binder particles can form a monoparticulate layer. This concept is illustrated in Figure 1.2.
The limited efficacy of the binders in direct compression formulations (and also in dry granulation) may partly be attributed to this concept, i.e., that the binder added in its dry state can be more difficult to disperse homogeneously than when added as a solution [10]. Other physical material properties such as shape and surface energy have also been demonstrated to have a significant impact on the tableting perfor- mance of the excipients [15–18].
Particle Engineering of Polymers into Multifunctional Interactive 7
1.3.2 Deformation Mechanisms
Polymers are typically considered to be as excellent binders owing to their good bond- ing properties [6,7]. The polymers such as PVP and PEG are also available in a vari- ety of molecular weights, and their deformation behavior under compression can be altered by altering their molecular weight [14]. However, the compaction of polymers is greatly affected by the speed of tableting. This has been attributed to the high elasticity of the excipients at high rates of strain [19]. Large stress relaxation yields porous and consequently weak tablets. Figure 1.3 schematically depicts relations between stress and strain for several materials. For a plastic solid, stress (σ) is directly proportional to deformation (strain, g):
s = E∗g (1.1)
The proportionality constant (E) is the elastic or Young’s modulus [20]. It is a mea- sure of the stiffness or resistance against deformation. The material behaves elastically up to the yield point (Py) at which the stress is called yield stress (σc). Beyond this point the material behaves as a plastic, rather than as an elastic solid. Brittle materials can be distinguished from plastic materials by the absence of the Py: stress increases propor- tionally with strain until the material breaks.
Figure 1.2 Effect of particle size on surface coverage of API particles with binder.
Brittle
Plastic
X: Fracture
Strain (g)
Stress (s)
Yield point (Py)
X X
Rubber X
Figure 1.3 Stress-strain behavior of brittle, plastic and rubbers. The point Py indicates the yield point with corresponding yield strength. Adapted and modified from [21].
8 Handbook of Polymers for Pharmaceutical Technologies 1.3.3 Glass Transition Temperature (Tg)
The amount of energy stored during densification is manifested as the stress relax- ation propensity of the material. Large stress relaxation yields porous and conse- quently weak tablets. At a high temperature difference (i.e., tableting temperature is much lower than the Tg), the polymer exhibits higher resistance to deformation and the amount of stored energy is large, resulting in highly porous and weak tablets. The Tg of amorphous polymeric materials appears to be a critical parameter with respect to mechanical properties (i.e., plastic/elastic character) of polymers [20]. At tempera- tures substantially below the Tg, an amorphous material is in the glassy state and its Young’s modulus is high, resulting in greater resistance to deformation. However, at temperature close to the Tg a material undergoes the change from a hard glassy form to a more plastic structure or a viscous fluid and the resistance against deformation decreases dramatically. This change is related to the onset of a certain degree of move- ment in the main chain and the rotation of side segments. Consequently, the perfor- mance of polymeric excipients during processes such as compaction strongly depends on their Tg [21].
It was reported that the compaction at a temperature of about 20 K under Tg yields circumstances for which the amount of stored energy has a minimum [21]. The Tg of the material depends on its chemical structure, the presence of a plasticizer and, in the case of polymers, on the molecular weight [22]. Therefore, it may be expected that using polymers with lower Tg (preferably near room temperature) would be advanta- geous for improved binder activity.
1.4 Strategies for Improving Polymeric Filler-Binder Performance for Direct Compression
The development of excipients of new chemical composition requires extensive toxi- cology tests. This is a costly preposition and so, in the last three decades, only a few such new excipients have been introduced in the market [23]. Therefore, improved filler-binders have mainly been generated via physical manipulation of existing excipi- ent materials, i.e., as the physical mixture of GRAS (generally regarded as safe) materi- als [24].
Particle size manipulation is a commonly used strategy to modify polymeric filler- binder performance. For example, microcrystalline cellulose, one of the most com- monly used polymeric multifunctional excipients, is commercially available in a variety of particle size ranges [25]. In addition, a wide range of multifunctional excipients are also available in different particle size grades (Table 1.2).
The main objective of excipient engineering is to improve both flow and binder activity of the excipients. Flow and compactability both depend on particle size, and these characteristics often compete, making it difficult to achieve an optimum excipi- ent performance [30]. For example, large particle size is typically associated with improved flow (Table 1.3). However, a smaller particle size is associated with improved compactability due to an increase in the surface area except for brittle materials (as shown in Figure 1.2) [31–33]. Hence there is a fundamental contradiction in designing
Particle Engineering of Polymers into Multifunctional Interactive 9
a multifunctional excipient where particle size reduction improves binder activity but compromises the flow. There are a number of commercially available polymeric excipi- ents with small particle size and better binder activity but these have relatively poor flow characteristics (Table 1.3).
Efforts have been made to engineer excipients which exhibit both good flow and compactability by co-processing materials. For example, combining excipients with Table 1.2 Particle size and flow specification of common commercially available fine-grade polymer powder excipients.
Excipient Grade Particle Size Flow description Ref.
Hydroxypropyl cellulose
Fine D10 = 16.6 ±5.1 µm D50 = 98.8 ±1.3 µm D90 = 341.8 ±31.7 µm
BD= 0.3 g/cm3, TD= 0.4 g/cm3,
CI= 19.9 [26]
Super fine D10 = 8 µm D50 =20 µm D90 =50 µm
AOR= 50˚, BD= 0.24 g/cm3,
TD= 0.41 g/cm3 [27]
Low-substituted hydroxypropyl cellulose
LH-11 D50= 50 µm
>150 µm (NMT 2 %)
AOR= 49˚, BD= 0.3 g/cm3,
TD= 0.6 g/cm3 [28]
LH-21 D50 = 40 µm
>75 µm (NMT 10 %)
AOR= 45, BD= 0.3 g/cm3,
TD= 0.6 g/cm3 [28]
LH-31 D50 = 25 µm
>40 µm (NMT 50 %)
AOR= 49, BD= 0.3 g/cm3,
TD= 0.6 g/cm3 [28]
Microcrystalline
cellulose Avicel PH 102 D10 =35.2 ±0.4 µm D50 = 109.2 ±0.8 µm D90 = 195.5 ±1.14 µm
AOR= 36˚, BD= 0.3 g/cm3, TD= 0.4 g/cm3, CI= 20.0
[26]
Ethylcellulose
7 FP Mean; 7–12 µm;
Max; 100 µm NA [27]
10 FP Mean; 3–8 µm;
Max;140 µm NA [27]
100 FP Mean; 30–60 µm;
Max; 150 µm NA [27]
Copovidone Kolidone VA- 64
fine <50 µm (>90%) BD= 0.1–0.2 g/cm3 [29]
BD = Bulk Density TD = Tapped Density AOR = Angle of Repose HR = Hausner's Ratio
10 Handbook of Polymers for Pharmaceutical Technologies
brittle and plastic compression behavior prevents storage of excessive elastic energy during the compression (Table 1.4) [42], which results in a reduced stress relaxation and a reduced tendency of capping and lamination. The brittle property also facil- itates fragmentation under compression to generate reduced particle sizes in situ.
Table 1.3 Particle size and flow specifications of typical commercially available directly compressible excipients.
Excipient Composition Particle Size Flow description Ref.
Ludipress
93% Lactose + 3.5%
Kollidon® 30 + 3.5 % Kollidon CL
<63 μm max. 15%
<200 μm 40 – 60%
<400 μm min. 90%
AOR = 34˚, BD = 0.6 g/cm3, TD = 0.7 g/cm3, HR = 1.2
[24,34]
Cellactose 80
75 % α-Lactose monohydrate + 25 % Cellulose powder
< 32 μm ≤ 20 %
< 160 μm = 35–65 %
< 250 μm ≥ 80 %
AOR =34˚, BD = 0.4 g/cm3, TD = 0.5 g/cm3, HR = 1.2
[24,35]
MicoceLac®100
75 % α-Lactose monohydrate + 25 %
Microcrystalline cellulose
< 32 µm: ≤ 15 %,
< 160 µm: 45–70 %,
< 250 µm: ≥ 90 %
AOR = 36.2˚, BD = 0.5 g/cm3 TD = 0.6 g/cm3, HR = 1.2
[24,36]
Pharmatose®
200M Lactose
monohydrate < 250 µm (100 %) NA [37]
Tablettose® 70 α-Lactose- monohydrate
< 63 µm: ≤ 6 %
< 200 µm: 30–70 %
< 500 µm: ≥ 98 %
BD = 0.5 g/cm3,
TD = 0.7 g/cm3 [38,39]
Avicel PH 200 Microcrystalline
cellulose 150 μm NLT 10 %
250 μm NLT 50% AOR = 36.2˚,
BD = 0.3 g/cm3 [40]
Starlac
85 % α-Lactose monohydrate + 15 % Maize starch
< 32 µm NLT 15%
< 160 µm 35 – 65%
< 250 µm NLT 80%
AOR = <30˚, BD = 0.6 g/cm3, TD = 0.7 g/cm3, HR = 1.2
[24]
Prosolv
98% Microcrystalline cellulose + 2 % Colloidal silicon dioxide
< 350 µm NLT 15%
AOR = <30˚, BD = 0.3 g/cm3, TD = 0.4 g/cm3, HR = 1.3
[24]
Advantose
FS 95 95 % Fructose + 5 %
Starch 170–450 µm AOR = <25˚,
BD = 0.6–0.8 g/cm3 TD = 0.7–0.8 g/cm3 [41]
BD = Bulk Density TD = Tapped Density AOR = Angle of Repose HR = Hausner's Ratio"
min. = Minimum proportion max. = maximum proportion
Particle Engineering of Polymers into Multifunctional Interactive 11
However, improvement in binder activity achieved using this approach is relatively limited and large proportions of such excipients are needed to create robust and mechanically stable tablets [43], so directly compressible excipients are only used where a low-dose of API is needed. At higher API loads (>500 mg), this may result in large tablets which are difficult to swallow. Therefore, tableting using these direct compression multifunctional excipients is only considered suitable for high/interme- diate potency APIs.
Another key aspect of particle size relates to powder segregation. The particle size and size distribution of excipients should also be able to generate a homogeneous and segregation-resistant blend with the API(s). This can be achieved via matching the particle sizes of API and excipients. A number of product recalls identified excipient variability as a contributor to failure of the pharmaceutical product [44], indicating the lack of understanding and control over excipient manufacturing and functionality.
With the US Food and Drug Administration’s (US-FDA) Quality in the 21st Century initiative, which includes the quality by design (QbD) and process analytical technolo- gies (PAT), it is becoming increasingly important to understand the impact of formula- tion process as well as material variability on the performance and manufacturability of new pharmaceutical products [45]. The variability in both APIs and excipients can have a significant impact on the critical quality attributes (CQAs), thereby the perfor- mance and manufacturability of the pharmaceutical product [23,46–51]. The intrin- sic lot-to-lot variability within a single grade of each excipient in a given formulation is dictated by the degree of process control implemented by each excipient vendor.
Managing excipient variability is an essential element in designing and manufacturing robust solid oral products and is an integral task when applying QbD principles. Tables 1.3 and 1.4 show excipients are provided with relatively wide particle size limits. In a QbD world such wide limits may not always be appropriate. This, therefore, presents an additional risk and cost to the overall product.
Table 1.4 List of co-processed excipients created by combining plastic and fragmenting excipients.
Excipient Component ingredients
Brittle excipient Plastic excipient
Ludipress α –Lactose monohydrate (93.4%) PVP (Kollidon 30) (3.2 %) and Crospovidone (Kollidon CL)
(3.4 %) Cellactose α –Lactose monohydrate (75 %) Cellulose (25%)
Prosolv Fumed colloidal silicon dioxide (2%) Microcrystalline cellulose (98%) Pharmatose Anhydrous lactose (95%) Lactitol (5%)
Xylitab Xylitol (>96.5%) Sodium caboxymethyl cellulose (<2 %)
Advantose Fructose (95%) Starch (5%)
Formaxx Calcium carbonate (70 %) Sorbitol (30 %)
Microcelac Lactose (75 %) Microcrystalline cellulose (25 %)
12 Handbook of Polymers for Pharmaceutical Technologies 1.4.1 Interactive Mixing
It was proposed that the knowledge and understanding of interactive mixing may be applied to create improved excipients. We proposed that binder with appropriate par- ticle size and surface properties can exhibit improved performance due to the ability to interactively blend with the API(s). Interactive mixing is a practical powder blending strategy to achieve the homogeneous distribution of small particles over relatively large particles. A fundamental principle of interactive mixing is that small particles with appropriate size and surface properties adhere to the coarse particles by interparticle interaction forces, which results in a uniform and segregation-resistant blend [52–55].
Such mixtures have wide application in the preparation of dosage forms containing relatively small doses of highly potent micronized API(s) in inhalation and tablet for- mulations [56–58]. As the particle becomes smaller their interactive ability increases and particles below 10 μm are considered to be highly interactive and tend to exhibit high degrees of adhesion to surfaces and cohesion to neighboring particles [59,60]. This is because the interparticle forces (cohesive forces arising from electrostatic, capillary or van der Waals interaction for particles in this larger size range) significantly exceed external forces such as gravity [61].
In an interactive mixture of components A (coarse) and B (fine), the interaction between fine particle and coarse particles (A-B) or between two fine particles (B-B) rep- resents the typical particle-particle interactions (Figure 1.4). However, if the coarse par- ticles are uniformly and sufficiently coated with fine particles, then the contacts between fine particles will represent the majority of particle-particle interactions. Thus, in such mixtures, the force of interparticle interactions between fine particles will determine the flow of the mixture. Since interparticle cohesion of fine particles depends heavily on their surface energy, it is also proposed that lowering the surface energy of fine particles may lower the overall forces of interparticle interaction and improve the flowability of an interactive mixture. However, this hypothesis is based on the assumption that the fine particles form a uniform surface coating regardless of the difference in their surface energy and interparticle cohesion. Thus, interactive excipients could also exert a flow additive action, as typically observed with benchmark flow aids such as silica [62,63].
We proposed that the interactive excipients with appropriate particle size and surface
Coarse particle Coarse particle
Fine particle
Fine particle Contact between
one fine particle and two coarse
particles
Contact between one fine particle
Figure 1.4 Interparticle contact models in an interactive mixture.
Particle Engineering of Polymers into Multifunctional Interactive 13 properties could be a practical solution to the complex problem of achieving excellent content uniformity, improved flow performance and high binder efficiency in directly compressible formulations.
1.4.2 Challenges to Interactive Mixing
To form an interactive mixture, mixing must overcome the cohesion forces acting between the individual components of an interactive mixture. Small particles (< 10 μm) are considered to be highly cohesive in nature, as the interparticle forces sig- nificantly exceed external forces such as gravity, resulting in agglomeration [55]. The ability of the mixing process to split agglomerates into individual particles decreases with increasing interparticle cohesion forces, which makes it difficult to break agglom- erates of particles during the mixing process [64]. This may compromise the ability of smaller excipient particles to form interactive mixture with larger API particles, affecting its functional performance as excipient. Therefore, controlling interparticle cohesion is considered to be a key aspect of designing such excipients, to facilitate easy de-agglomeration of interactive excipient, and thereby preferential adhesion to larger API particles.
Micronized particles usually interact with coarse particles via van der Waals forces in interactive mixtures [65,66]. Other attractive forces, such as capillary and electrostatic forces may also operate; but in general, they are smaller than the omnipresent van der Waals force in dry powders [66]. The magnitude of van der Waals force depends on the properties of both the fine and coarse components of an interactive mixture. It has been demonstrated that factors such as particle size, shape [67], particle size distribution [68,69], roughness [70–72] and surface energy [72] affect the phenomenon of particle adhesion in an interactive mixture. A change in any of these factors can change the magnitude of the van der Waals forces and hence the cohesion and adhesion strength of the particles [65].
The work of adhesion, Wad, is defined as the free energy required to separate unit areas of two different surfaces from contact to infinity in vacuum, whereas, the energy required to separate unit area of similar surfaces is referred to as the work of cohesion, Wco [65]. The adhesion between particles of different materials only occurs if the energy that is released during adhesion is larger than the energy that is required to break up the cohesion contacts of particles of individual material. Thus, adhesion will be an ener- getically favored phenomenon for such powders [60]. However, it only has importance for those powder mixtures which are classified as interactive, i.e., where one component is much smaller than the other. Also, this concept disregards the influence of other factors on adhesion such as surface roughness, hardness, elasticity, etc. Cohesion (i.e., agglomeration of fine micronized particles) can also be of energetic advantage and can explain why micronized powders are often heavily agglomerated. So, one can assume that the fine particles will only adhere to coarse particles when the energy of cohesion is lower than the energy of adhesion (Figure 1.5). Hence, the performance of interactive mixtures is a function of the relative magnitudes of cohesive and adhesive interparticu- late forces.
14 Handbook of Polymers for Pharmaceutical Technologies
1.4.3 Controlling Interparticle Cohesion
Engineering surface properties has evolved as one of the main strategies for reducing the interparticle cohesion of fine particles. The surface-altering excipients act as lubri- cants between surfaces, thus reducing cohesion and improving dispersibility [73,74].
These techniques were mainly explored in the area of dry powder inhalers, where par- ticles 1–5 µm with low cohesion and good dispersibility are desirable for their effi- cient delivery to the lungs [75,76]. Of these, the co-spraying with L-leucine has been previously employed as a remarkably effective strategy to improve the aerosolization of spray-dried micron-sized inhalation formulations [77–80]. In spray drying, the for- mation of a surface layer relies largely on the properties of excipient materials to accu- mulate at the air-solvent interface of droplets before drying takes place [81]. Therefore, a coating layer is formed during the drying of droplets and a uniform and coherent coating is easy to achieve [77].
1.5 Preparation and Characterization of Interactive Excipients
We spray dried PVP as a polymeric binder (6% w/v) with L-leucine (0.6 % w/v) as a surface modifying agent to control interparticle cohesion of fine spray-dried particles [82]. PVP was spray dried with and without L-leucine to generate small interactive excipients. The effect of L-leucine on the surface composition, surface energy and bulk cohesion of spray-dried formulation was assessed. The surface composition of these formulations was examined using state-of-the-art technique X-ray photoelec- tron spectroscopy (XPS). To then understand the bulk surface interactions, which may be influenced by molecular orientation at the surface, the surface energy was determined using inverse gas chromatography (IGC). The data obtained were used to explore how surface leucine concentration and molecular state affects morphology, surface energy, solid-state properties and the resulting change in bulk properties such as interparticle cohesion.
Coarse particles Work of cohesion (W∞) > Work of
adhesion (Wad) Work of cohesion (W∞) < Work of adhesion (Wad) Coarse particle Fine particles
Fine particle
Figure 1.5 Effect of cohesive and adhesive forces on particle distribution in interactive mixtures.
