Leena Peltonen is Adjunct Professor in the Division of Pharmaceutical Chemistry and Technology at the University of Helsinki, Finland. She holds two master's degrees, as well as a PhD in Pharmacy that she obtained in 2001.

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• List of Contributors xiiiSeries Preface xviiList of Abbreviations xix1 Selecting a Particle Sizer for the Pharmaceutical Industry 1Margarida Figueiredo, M. José Moura and Paulo J. Ferreira1.1 Introduction 11.1.1 Relevance of Particle Size in the Pharmaceutical Industry 11.1.2 Main Goals 21.1.3 Why it is So Difficult to Select a Particle Sizer 21.2 Particle Size Distribution 31.2.1 Equivalent Diameter 31.2.2 Reporting Particle Size 51.2.3 Distribution Statistics 71.3 Selecting a Particle Sizer 81.3.1 Classification 81.3.2 Selection Criteria 91.4 Aspects of Some Selected Methods 131.4.1 Optical Microscopy-based Methods 131.4.2 Laser Light-scattering Techniques 151.4.2.1 Laser Diffraction and Static Light Scattering 161.4.2.2 Dynamic Light Scattering 191.4.3 The Time-of-Flight Counter 201.4.4 Cascade Impactor 211.5 Conclusions 22Acknowledgements 22References 232 Spectroscopic Methods in Solid-state Characterization 27Clare Strachan, Jukka Saarinen, Tiina Lipiäinen, Elina Vuorimaa-Laukkanen, Kaisa Rautaniemi, Timo Laaksonen, Marcin Skotnicki and Martin Dračínský2.1 Solid-state Structure of Particulates 272.2 Spectroscopy Overview 282.3 Spectroscopic Data Analysis 302.3.1 Band Assignment 302.3.2 Statistical Analysis 302.4 Infrared Spectroscopy 352.4.1 Principle 352.4.2 MIR Applications 372.4.3 MIR Imaging 402.5 Near-infrared Spectroscopy 402.5.1 Principle 402.5.2 NIR Applications 412.5.3 NIR Imaging 452.6 Terahertz Spectroscopy 462.6.1 Principle 462.6.2 Terahertz Applications 482.6.3 Terahertz Imaging 502.7 Raman Spectroscopy 502.7.1 Principle 502.7.2 Raman Applications 532.7.3 Raman Imaging 572.8 Nonlinear Optics 592.8.1 Principle 592.8.2 Nonlinear Optics Applications 612.8.3 Nonlinear Optical Imaging 612.9 Fluorescence Spectroscopy 652.9.1 Principle 652.9.2 Fluorescence from Solid-state Samples 672.9.3 Intrinsic Fluorophores in Solid Samples 682.9.4 Fluorescence Imaging 692.9.5 Fluorescence Lifetime Imaging Microscopy 702.10 Solid-state Nuclear Magnetic Resonance 712.10.1 The Basic Theory of NMR Spectroscopy 712.10.2 Solid-state NMR Technique 722.10.2.1 Dipole–Dipole Interactions 722.10.2.2 Chemical Shift Anisotropy 722.10.2.3 Quadrupolar Coupling 732.10.2.4 Indirect Coupling 732.10.2.5 Magic-angle Spinning and High-power Proton Decoupling 732.10.3 Solid-state NMR Experiments 752.10.3.1 Sample Preparation 752.10.3.2 Cross-polarization 762.10.3.3 Heteronuclear Correlation Experiments 772.10.4 Pharmaceutical Applications of Solid-state NMR 772.11 Conclusions 82References 843 Microfluidic Analysis Techniques for Safety Assessment of Pharmaceutical Nano- and Microsystems 97Tiina M. Sikanen, Iiro Kiiski and Elisa Ollikainen3.1 Microfluidic Bioanalytical Platforms 973.2 Microfabrication Methods and Materials 983.3 Microfluidic Cell Cultures 1013.3.1 Selection of the Microfabrication Material by Design 1023.3.2 Additional Design Considerations 1043.3.3 Characterization of Pharmaceutical Nano- and Microsystems Using Organ-on-a-chip 1083.4 Immobilized Enzyme Microreactors for Hepatic Safety Assessment 1093.4.1 Nanoparticle Impacts on the Hepatic Clearance of Xenobiotics 1093.4.2 Cytochrome P450 Interaction Studies in Through-flow Conditions 1123.4.2.1 Immobilization Strategies for Cytochrome P450 Enzymes 1133.4.2.2 Microfabrication Materials and Design Considerations 1163.5 Microfluidic Total Analysis Systems 1203.5.1 Microfluidic Separation Systems 1213.5.2 Toward n-in-one Analytical Platforms 1243.6 Epilogue 126References 1264 In Vitro–In Vivo Correlation for Pharmaceutical Nano- and Microsystems 137Preshita P. Desai and Vandana B. Patravale4.1 Introduction 1374.2 In Vitro Dissolution and In Vivo Pharmacokinetics 1384.3 Levels of Correlation 1434.3.1 Level A Correlation 1434.3.2 Level B Correlation 1444.3.3 Level C Correlation 1454.3.4 Multiple Level C Correlation 1454.3.5 Level D Correlation 1454.4 Models of IVIVC 1454.4.1 Deconvolution Model 1464.4.2 Convolution Model 1494.4.3 Miscellaneous Models 1494.5 IVIVC Model Validation: Predictability Evaluation 1504.6 IVIVC Development Step-by-Step Approach 1514.7 Brief Introduction to Micro/Nanosystems and IVIVC Relevance 1524.7.1 Selection of Appropriate Dissolution Method 1534.7.2 Selection of Appropriate Dissolution Medium 1554.7.3 Selection of Appropriate IVIVC Mathematical Model 1574.8 Applications of IVIVC for Micro/nanoformulations 1584.8.1 Formulation Optimization 1624.8.2 Surrogate for Bioequivalence Studies and Biowaivers 1654.9 Softwares Used for IVIVC 1654.10 Conclusion and Future Prospects 166References 1665 Characterization of Bioadhesion, Mucin-interactions and Mucosal Permeability of Pharmaceutical Nano- and Microsystems 171Ellen Hagesaether, Malgorzata Iwona Adamczak, Marianne Hiorth and Ingunn Tho5.1 Introduction 1715.2 Background and Theory 1725.3 Mucosal Membranes 1745.3.1 Oral Mucosa 1745.3.2 Gastrointestinal Mucosa 1765.3.3 Pulmonary Mucosa 1765.3.4 Nasal Mucosa 1815.3.5 Ocular Mucosa 1825.3.6 Vaginal Mucosa 1825.4 Use of Mucosal Membranes in Studies of Micro- and Nanoparticles 1835.4.1 Diffusion Chambers 1835.4.2 Permeability Support for Cell-based Systems 1845.5 Selection of Biological Models 1855.5.1 Tissue-based Models 1855.5.2 Cell-based Models 1855.5.3 Mucus as Models 1875.5.4 Artificial Models 1885.6 Methods for Testing Biocompatibility 1895.6.1 Viability 1895.6.2 Cytotoxicity 1895.6.3 Paracellular Permeability 1895.7 Methods for Testing Mucoadhesion 1905.7.1 Atomic Force Microscopy (AFM) 1905.7.2 Quartz Crystal Microbalance (QCM) 1915.7.3 Rheology 1925.7.4 Rheology in Combination with Light Scattering (Rheo-SALS) 1925.7.5 Dynamic Light Scattering (DLS) and Zeta Potential Measurements 1935.7.6 Mechanical Methods 1945.7.7 Mucin Adsorption Study 1945.7.8 Wash-off Tests 1945.8 Methods for Testing Mucopenetration 1955.8.1 Fluorescent Recovery after Photobleaching (FRAP) and Multiple Image Photography (MIP) 1955.8.2 Permeability Studies 1955.8.3 Water-assisted Transport Through Mucus 1965.8.4 Particles with Dynamic Properties 1965.9 Methods for Assessing Cell Interactions 1975.9.1 Cell Adhesion 1975.9.2 Cellular Uptake 1975.9.3 Transcellular Transport 1995.10 Concluding Remarks 203References 2036 Cell–Nanoparticle Interactions: Toxicity and Safety Issues 207Flavia Fontana, Nazanin Zanjanizadeh Ezazi, Nayab Tahir and Helder A. Santos6.1 Introduction 2076.1.1 Role of Nanoparticles in Modern Medicine and Applications 2076.1.2 Cell–NP Interactions 2086.1.2.1 Size 2086.1.2.2 Shape 2086.1.2.3 Surface Charge 2096.1.2.4 Surface Functionalization and Hydrophobicity 2106.1.2.5 Protein Corona 2116.1.3 NP Toxicity 2116.2 Mechanisms of NP-Induced Cellular Toxicity 2116.2.1 Damage to the Plasma Membrane 2116.2.2 Alterations or Disruptions in the Cytoskeleton 2116.2.3 Mitochondrial Toxicity 2166.2.4 Nuclear Damage 2166.2.5 Reactive Oxygen Species (ROS) 2166.2.6 Interference in the Signaling Pathways 2166.3 In Vitro Assays to Evaluate Cell–NP Interactions 2166.3.1 Traditional Assays 2176.3.2 Innovative Assays 2176.4 Metal Oxide Nanoparticles 2176.4.1 Zinc Oxide 2176.4.2 Cerium Oxide 2206.4.3 Iron Oxide 2216.5 Non-metallic Nanoparticles 2236.5.1 Liposomes 2236.5.2 Polymeric Delivery Systems 2246.5.3 Dendrimers 2306.5.4 Silicon/Silica-based Drug Delivery Systems 2326.6 Conclusions and Future Perspectives 235Acknowledgements 235References 2367 Intestinal Mucosal Models to Validate Functionalized Nanosystems 243Cláudia Azevedo, Inês Pereira and Bruno Sarmento7.1 Introduction 2437.2 Intestinal Mucosal Characteristics 2447.2.1 Intestinal Morphology 2447.2.2 Transport Mechanisms 2467.3 In Vitro Models 2487.3.1 Monoculture Models 2497.3.2 Co-culture Models 2527.3.2.1 The Caco-2/HT29-MTX Model 2527.3.2.2 The Caco-2/Raji B Model 2537.3.2.3 The Caco-2/HT29-MTX/Raji B Model 2537.3.3 3D Co-culture Models 2537.3.4 Gut-on-a-Chip 2547.4 Ex Vivo Intestinal Models for In Vitro/In Vivo Correlation of Functionalized Nanosystems 2587.4.1 Diffusion Chambers 2587.4.1.1 Ussing Chamber 2587.4.1.2 Franz Cell 2587.4.2 Everted Intestinal Sac Model 2597.4.3 Non-everted Intestinal Sac Model 2607.4.4 Everted Intestinal Ring 2607.5 In Situ Models 2607.5.1 Intestinal Perfusion 2627.5.2 Intestinal Loop 2647.5.3 Intestinal Vascular Cannulation 2647.6 In Vivo Models 2647.7 Conclusion 265Acknowledgements 266References 2678 Biodistribution of Polymeric, Polysaccharide and Metallic Nanoparticles 275Nazl𝚤 Erdoğar, Gamze Varan, Cem Varan and Erem Bilensoy8.1 Introduction 2758.2 Biodistribution and Pharmacokinetics 2768.3 Mechanisms Affecting Biodistribution 2778.3.1 Nanoparticle Properties 2778.3.1.1 Effect of Particle Size 2778.3.1.2 Effect of Surface Charge 2798.3.1.3 Effect of Particle Shape 2808.3.2 Dosing and Toxicity 2818.3.3 Effect of Coating 2828.4 Conclusion 285References 2869 Opportunities and Challenges of Silicon-based Nanoparticles for Drug Delivery and Imaging 291Didem Şen Karaman, Martti Kaasalainen, Helene Kettiger and Jessica M. Rosenholm9.1 Synthesis and Characteristics of Silica-based Nanoparticles 2929.1.1 Nonporous Silica NPs 2929.1.2 Mesoporous Silica NPs 2959.1.3 Core@Shell Materials 2979.1.4 Hollow Silica Nanoparticles 2989.1.5 Porous Silicon (PSi) 3009.2 Solid-state Characterization 3039.2.1 Porosity and Morphology on the Nanoscale 3039.2.2 Structural Analysis 3059.2.3 Methods for Determination of Surface Functionalization 3069.3 Medium-dependent Characterization 3079.3.1 Hydrodynamic Size 3079.3.1.1 Dynamic Light Scattering 3099.3.2 Surface Charge and Zeta Potential 3099.3.3 Colloidal Stability 3119.3.4 Challenges in Particularly Porous Nanoparticle Characterization 3129.4 Incorporation of Active Molecules 3149.4.1 Drug Loading 3149.4.2 Labeling with Imaging Agents 3179.5 Biorelevant Physicochemical Characterization 3199.5.1 Biodegradation/Dissolution of Silica 3219.5.2 Biocompatibility and Nano–Bio Interactions 3239.5.3 Drug Release 3249.5.4 Label-free (Imaging) Technologies 3269.6 Conclusions 328References 32910 Statistical Analysis and Multidimensional Modeling in Research 339Osmo Antikainen10.1 Measurement in Research 33910.2 Mean and Sample Mean 33910.3 Correlation 34110.4 Modeling Relationships Between Series of Observations 34310.5 Quality of a Model 34410.5.1 The Meaning of R2 in Linear Regression 34410.5.2 Cross-validation 34510.6 Multivariate Data 35010.6.1 Screening Designs 35110.6.2 Full Factorial Designs 35210.6.2.1 Full Factorial Designs in Two Levels 35210.6.2.2 Full Factorial Designs in Three Levels (3n Design) 35510.7 Principal Component Analysis (PCA) 36210.8 Conclusions 366References 366Index 369

Leena Peltonen is Adjunct Professor in the Division of Pharmaceutical Chemistry and Technology at the University of Helsinki, Finland. She holds two master's degrees, as well as a PhD in Pharmacy that she obtained in 2001.

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• List of Contributors xiiiSeries Preface xviiList of Abbreviations xix1 Selecting a Particle Sizer for the Pharmaceutical Industry 1Margarida Figueiredo, M. José Moura and Paulo J. Ferreira1.1 Introduction 11.1.1 Relevance of Particle Size in the Pharmaceutical Industry 11.1.2 Main Goals 21.1.3 Why it is So Difficult to Select a Particle Sizer 21.2 Particle Size Distribution 31.2.1 Equivalent Diameter 31.2.2 Reporting Particle Size 51.2.3 Distribution Statistics 71.3 Selecting a Particle Sizer 81.3.1 Classification 81.3.2 Selection Criteria 91.4 Aspects of Some Selected Methods 131.4.1 Optical Microscopy-based Methods 131.4.2 Laser Light-scattering Techniques 151.4.2.1 Laser Diffraction and Static Light Scattering 161.4.2.2 Dynamic Light Scattering 191.4.3 The Time-of-Flight Counter 201.4.4 Cascade Impactor 211.5 Conclusions 22Acknowledgements 22References 232 Spectroscopic Methods in Solid-state Characterization 27Clare Strachan, Jukka Saarinen, Tiina Lipiäinen, Elina Vuorimaa-Laukkanen, Kaisa Rautaniemi, Timo Laaksonen, Marcin Skotnicki and Martin Dračínský2.1 Solid-state Structure of Particulates 272.2 Spectroscopy Overview 282.3 Spectroscopic Data Analysis 302.3.1 Band Assignment 302.3.2 Statistical Analysis 302.4 Infrared Spectroscopy 352.4.1 Principle 352.4.2 MIR Applications 372.4.3 MIR Imaging 402.5 Near-infrared Spectroscopy 402.5.1 Principle 402.5.2 NIR Applications 412.5.3 NIR Imaging 452.6 Terahertz Spectroscopy 462.6.1 Principle 462.6.2 Terahertz Applications 482.6.3 Terahertz Imaging 502.7 Raman Spectroscopy 502.7.1 Principle 502.7.2 Raman Applications 532.7.3 Raman Imaging 572.8 Nonlinear Optics 592.8.1 Principle 592.8.2 Nonlinear Optics Applications 612.8.3 Nonlinear Optical Imaging 612.9 Fluorescence Spectroscopy 652.9.1 Principle 652.9.2 Fluorescence from Solid-state Samples 672.9.3 Intrinsic Fluorophores in Solid Samples 682.9.4 Fluorescence Imaging 692.9.5 Fluorescence Lifetime Imaging Microscopy 702.10 Solid-state Nuclear Magnetic Resonance 712.10.1 The Basic Theory of NMR Spectroscopy 712.10.2 Solid-state NMR Technique 722.10.2.1 Dipole–Dipole Interactions 722.10.2.2 Chemical Shift Anisotropy 722.10.2.3 Quadrupolar Coupling 732.10.2.4 Indirect Coupling 732.10.2.5 Magic-angle Spinning and High-power Proton Decoupling 732.10.3 Solid-state NMR Experiments 752.10.3.1 Sample Preparation 752.10.3.2 Cross-polarization 762.10.3.3 Heteronuclear Correlation Experiments 772.10.4 Pharmaceutical Applications of Solid-state NMR 772.11 Conclusions 82References 843 Microfluidic Analysis Techniques for Safety Assessment of Pharmaceutical Nano- and Microsystems 97Tiina M. Sikanen, Iiro Kiiski and Elisa Ollikainen3.1 Microfluidic Bioanalytical Platforms 973.2 Microfabrication Methods and Materials 983.3 Microfluidic Cell Cultures 1013.3.1 Selection of the Microfabrication Material by Design 1023.3.2 Additional Design Considerations 1043.3.3 Characterization of Pharmaceutical Nano- and Microsystems Using Organ-on-a-chip 1083.4 Immobilized Enzyme Microreactors for Hepatic Safety Assessment 1093.4.1 Nanoparticle Impacts on the Hepatic Clearance of Xenobiotics 1093.4.2 Cytochrome P450 Interaction Studies in Through-flow Conditions 1123.4.2.1 Immobilization Strategies for Cytochrome P450 Enzymes 1133.4.2.2 Microfabrication Materials and Design Considerations 1163.5 Microfluidic Total Analysis Systems 1203.5.1 Microfluidic Separation Systems 1213.5.2 Toward n-in-one Analytical Platforms 1243.6 Epilogue 126References 1264 In Vitro–In Vivo Correlation for Pharmaceutical Nano- and Microsystems 137Preshita P. Desai and Vandana B. Patravale4.1 Introduction 1374.2 In Vitro Dissolution and In Vivo Pharmacokinetics 1384.3 Levels of Correlation 1434.3.1 Level A Correlation 1434.3.2 Level B Correlation 1444.3.3 Level C Correlation 1454.3.4 Multiple Level C Correlation 1454.3.5 Level D Correlation 1454.4 Models of IVIVC 1454.4.1 Deconvolution Model 1464.4.2 Convolution Model 1494.4.3 Miscellaneous Models 1494.5 IVIVC Model Validation: Predictability Evaluation 1504.6 IVIVC Development Step-by-Step Approach 1514.7 Brief Introduction to Micro/Nanosystems and IVIVC Relevance 1524.7.1 Selection of Appropriate Dissolution Method 1534.7.2 Selection of Appropriate Dissolution Medium 1554.7.3 Selection of Appropriate IVIVC Mathematical Model 1574.8 Applications of IVIVC for Micro/nanoformulations 1584.8.1 Formulation Optimization 1624.8.2 Surrogate for Bioequivalence Studies and Biowaivers 1654.9 Softwares Used for IVIVC 1654.10 Conclusion and Future Prospects 166References 1665 Characterization of Bioadhesion, Mucin-interactions and Mucosal Permeability of Pharmaceutical Nano- and Microsystems 171Ellen Hagesaether, Malgorzata Iwona Adamczak, Marianne Hiorth and Ingunn Tho5.1 Introduction 1715.2 Background and Theory 1725.3 Mucosal Membranes 1745.3.1 Oral Mucosa 1745.3.2 Gastrointestinal Mucosa 1765.3.3 Pulmonary Mucosa 1765.3.4 Nasal Mucosa 1815.3.5 Ocular Mucosa 1825.3.6 Vaginal Mucosa 1825.4 Use of Mucosal Membranes in Studies of Micro- and Nanoparticles 1835.4.1 Diffusion Chambers 1835.4.2 Permeability Support for Cell-based Systems 1845.5 Selection of Biological Models 1855.5.1 Tissue-based Models 1855.5.2 Cell-based Models 1855.5.3 Mucus as Models 1875.5.4 Artificial Models 1885.6 Methods for Testing Biocompatibility 1895.6.1 Viability 1895.6.2 Cytotoxicity 1895.6.3 Paracellular Permeability 1895.7 Methods for Testing Mucoadhesion 1905.7.1 Atomic Force Microscopy (AFM) 1905.7.2 Quartz Crystal Microbalance (QCM) 1915.7.3 Rheology 1925.7.4 Rheology in Combination with Light Scattering (Rheo-SALS) 1925.7.5 Dynamic Light Scattering (DLS) and Zeta Potential Measurements 1935.7.6 Mechanical Methods 1945.7.7 Mucin Adsorption Study 1945.7.8 Wash-off Tests 1945.8 Methods for Testing Mucopenetration 1955.8.1 Fluorescent Recovery after Photobleaching (FRAP) and Multiple Image Photography (MIP) 1955.8.2 Permeability Studies 1955.8.3 Water-assisted Transport Through Mucus 1965.8.4 Particles with Dynamic Properties 1965.9 Methods for Assessing Cell Interactions 1975.9.1 Cell Adhesion 1975.9.2 Cellular Uptake 1975.9.3 Transcellular Transport 1995.10 Concluding Remarks 203References 2036 Cell–Nanoparticle Interactions: Toxicity and Safety Issues 207Flavia Fontana, Nazanin Zanjanizadeh Ezazi, Nayab Tahir and Helder A. Santos6.1 Introduction 2076.1.1 Role of Nanoparticles in Modern Medicine and Applications 2076.1.2 Cell–NP Interactions 2086.1.2.1 Size 2086.1.2.2 Shape 2086.1.2.3 Surface Charge 2096.1.2.4 Surface Functionalization and Hydrophobicity 2106.1.2.5 Protein Corona 2116.1.3 NP Toxicity 2116.2 Mechanisms of NP-Induced Cellular Toxicity 2116.2.1 Damage to the Plasma Membrane 2116.2.2 Alterations or Disruptions in the Cytoskeleton 2116.2.3 Mitochondrial Toxicity 2166.2.4 Nuclear Damage 2166.2.5 Reactive Oxygen Species (ROS) 2166.2.6 Interference in the Signaling Pathways 2166.3 In Vitro Assays to Evaluate Cell–NP Interactions 2166.3.1 Traditional Assays 2176.3.2 Innovative Assays 2176.4 Metal Oxide Nanoparticles 2176.4.1 Zinc Oxide 2176.4.2 Cerium Oxide 2206.4.3 Iron Oxide 2216.5 Non-metallic Nanoparticles 2236.5.1 Liposomes 2236.5.2 Polymeric Delivery Systems 2246.5.3 Dendrimers 2306.5.4 Silicon/Silica-based Drug Delivery Systems 2326.6 Conclusions and Future Perspectives 235Acknowledgements 235References 2367 Intestinal Mucosal Models to Validate Functionalized Nanosystems 243Cláudia Azevedo, Inês Pereira and Bruno Sarmento7.1 Introduction 2437.2 Intestinal Mucosal Characteristics 2447.2.1 Intestinal Morphology 2447.2.2 Transport Mechanisms 2467.3 In Vitro Models 2487.3.1 Monoculture Models 2497.3.2 Co-culture Models 2527.3.2.1 The Caco-2/HT29-MTX Model 2527.3.2.2 The Caco-2/Raji B Model 2537.3.2.3 The Caco-2/HT29-MTX/Raji B Model 2537.3.3 3D Co-culture Models 2537.3.4 Gut-on-a-Chip 2547.4 Ex Vivo Intestinal Models for In Vitro/In Vivo Correlation of Functionalized Nanosystems 2587.4.1 Diffusion Chambers 2587.4.1.1 Ussing Chamber 2587.4.1.2 Franz Cell 2587.4.2 Everted Intestinal Sac Model 2597.4.3 Non-everted Intestinal Sac Model 2607.4.4 Everted Intestinal Ring 2607.5 In Situ Models 2607.5.1 Intestinal Perfusion 2627.5.2 Intestinal Loop 2647.5.3 Intestinal Vascular Cannulation 2647.6 In Vivo Models 2647.7 Conclusion 265Acknowledgements 266References 2678 Biodistribution of Polymeric, Polysaccharide and Metallic Nanoparticles 275Nazl𝚤 Erdoğar, Gamze Varan, Cem Varan and Erem Bilensoy8.1 Introduction 2758.2 Biodistribution and Pharmacokinetics 2768.3 Mechanisms Affecting Biodistribution 2778.3.1 Nanoparticle Properties 2778.3.1.1 Effect of Particle Size 2778.3.1.2 Effect of Surface Charge 2798.3.1.3 Effect of Particle Shape 2808.3.2 Dosing and Toxicity 2818.3.3 Effect of Coating 2828.4 Conclusion 285References 2869 Opportunities and Challenges of Silicon-based Nanoparticles for Drug Delivery and Imaging 291Didem Şen Karaman, Martti Kaasalainen, Helene Kettiger and Jessica M. Rosenholm9.1 Synthesis and Characteristics of Silica-based Nanoparticles 2929.1.1 Nonporous Silica NPs 2929.1.2 Mesoporous Silica NPs 2959.1.3 Core@Shell Materials 2979.1.4 Hollow Silica Nanoparticles 2989.1.5 Porous Silicon (PSi) 3009.2 Solid-state Characterization 3039.2.1 Porosity and Morphology on the Nanoscale 3039.2.2 Structural Analysis 3059.2.3 Methods for Determination of Surface Functionalization 3069.3 Medium-dependent Characterization 3079.3.1 Hydrodynamic Size 3079.3.1.1 Dynamic Light Scattering 3099.3.2 Surface Charge and Zeta Potential 3099.3.3 Colloidal Stability 3119.3.4 Challenges in Particularly Porous Nanoparticle Characterization 3129.4 Incorporation of Active Molecules 3149.4.1 Drug Loading 3149.4.2 Labeling with Imaging Agents 3179.5 Biorelevant Physicochemical Characterization 3199.5.1 Biodegradation/Dissolution of Silica 3219.5.2 Biocompatibility and Nano–Bio Interactions 3239.5.3 Drug Release 3249.5.4 Label-free (Imaging) Technologies 3269.6 Conclusions 328References 32910 Statistical Analysis and Multidimensional Modeling in Research 339Osmo Antikainen10.1 Measurement in Research 33910.2 Mean and Sample Mean 33910.3 Correlation 34110.4 Modeling Relationships Between Series of Observations 34310.5 Quality of a Model 34410.5.1 The Meaning of R2 in Linear Regression 34410.5.2 Cross-validation 34510.6 Multivariate Data 35010.6.1 Screening Designs 35110.6.2 Full Factorial Designs 35210.6.2.1 Full Factorial Designs in Two Levels 35210.6.2.2 Full Factorial Designs in Three Levels (3n Design) 35510.7 Principal Component Analysis (PCA) 36210.8 Conclusions 366References 366Index 369

Leena Peltonen is Adjunct Professor in the Division of Pharmaceutical Chemistry and Technology at the University of Helsinki, Finland. She holds two master's degrees, as well as a PhD in Pharmacy that she obtained in 2001.

Select Guide Rating

• List of Contributors xiiiSeries Preface xviiList of Abbreviations xix1 Selecting a Particle Sizer for the Pharmaceutical Industry 1Margarida Figueiredo, M. José Moura and Paulo J. Ferreira1.1 Introduction 11.1.1 Relevance of Particle Size in the Pharmaceutical Industry 11.1.2 Main Goals 21.1.3 Why it is So Difficult to Select a Particle Sizer 21.2 Particle Size Distribution 31.2.1 Equivalent Diameter 31.2.2 Reporting Particle Size 51.2.3 Distribution Statistics 71.3 Selecting a Particle Sizer 81.3.1 Classification 81.3.2 Selection Criteria 91.4 Aspects of Some Selected Methods 131.4.1 Optical Microscopy-based Methods 131.4.2 Laser Light-scattering Techniques 151.4.2.1 Laser Diffraction and Static Light Scattering 161.4.2.2 Dynamic Light Scattering 191.4.3 The Time-of-Flight Counter 201.4.4 Cascade Impactor 211.5 Conclusions 22Acknowledgements 22References 232 Spectroscopic Methods in Solid-state Characterization 27Clare Strachan, Jukka Saarinen, Tiina Lipiäinen, Elina Vuorimaa-Laukkanen, Kaisa Rautaniemi, Timo Laaksonen, Marcin Skotnicki and Martin Dračínský2.1 Solid-state Structure of Particulates 272.2 Spectroscopy Overview 282.3 Spectroscopic Data Analysis 302.3.1 Band Assignment 302.3.2 Statistical Analysis 302.4 Infrared Spectroscopy 352.4.1 Principle 352.4.2 MIR Applications 372.4.3 MIR Imaging 402.5 Near-infrared Spectroscopy 402.5.1 Principle 402.5.2 NIR Applications 412.5.3 NIR Imaging 452.6 Terahertz Spectroscopy 462.6.1 Principle 462.6.2 Terahertz Applications 482.6.3 Terahertz Imaging 502.7 Raman Spectroscopy 502.7.1 Principle 502.7.2 Raman Applications 532.7.3 Raman Imaging 572.8 Nonlinear Optics 592.8.1 Principle 592.8.2 Nonlinear Optics Applications 612.8.3 Nonlinear Optical Imaging 612.9 Fluorescence Spectroscopy 652.9.1 Principle 652.9.2 Fluorescence from Solid-state Samples 672.9.3 Intrinsic Fluorophores in Solid Samples 682.9.4 Fluorescence Imaging 692.9.5 Fluorescence Lifetime Imaging Microscopy 702.10 Solid-state Nuclear Magnetic Resonance 712.10.1 The Basic Theory of NMR Spectroscopy 712.10.2 Solid-state NMR Technique 722.10.2.1 Dipole–Dipole Interactions 722.10.2.2 Chemical Shift Anisotropy 722.10.2.3 Quadrupolar Coupling 732.10.2.4 Indirect Coupling 732.10.2.5 Magic-angle Spinning and High-power Proton Decoupling 732.10.3 Solid-state NMR Experiments 752.10.3.1 Sample Preparation 752.10.3.2 Cross-polarization 762.10.3.3 Heteronuclear Correlation Experiments 772.10.4 Pharmaceutical Applications of Solid-state NMR 772.11 Conclusions 82References 843 Microfluidic Analysis Techniques for Safety Assessment of Pharmaceutical Nano- and Microsystems 97Tiina M. Sikanen, Iiro Kiiski and Elisa Ollikainen3.1 Microfluidic Bioanalytical Platforms 973.2 Microfabrication Methods and Materials 983.3 Microfluidic Cell Cultures 1013.3.1 Selection of the Microfabrication Material by Design 1023.3.2 Additional Design Considerations 1043.3.3 Characterization of Pharmaceutical Nano- and Microsystems Using Organ-on-a-chip 1083.4 Immobilized Enzyme Microreactors for Hepatic Safety Assessment 1093.4.1 Nanoparticle Impacts on the Hepatic Clearance of Xenobiotics 1093.4.2 Cytochrome P450 Interaction Studies in Through-flow Conditions 1123.4.2.1 Immobilization Strategies for Cytochrome P450 Enzymes 1133.4.2.2 Microfabrication Materials and Design Considerations 1163.5 Microfluidic Total Analysis Systems 1203.5.1 Microfluidic Separation Systems 1213.5.2 Toward n-in-one Analytical Platforms 1243.6 Epilogue 126References 1264 In Vitro–In Vivo Correlation for Pharmaceutical Nano- and Microsystems 137Preshita P. Desai and Vandana B. Patravale4.1 Introduction 1374.2 In Vitro Dissolution and In Vivo Pharmacokinetics 1384.3 Levels of Correlation 1434.3.1 Level A Correlation 1434.3.2 Level B Correlation 1444.3.3 Level C Correlation 1454.3.4 Multiple Level C Correlation 1454.3.5 Level D Correlation 1454.4 Models of IVIVC 1454.4.1 Deconvolution Model 1464.4.2 Convolution Model 1494.4.3 Miscellaneous Models 1494.5 IVIVC Model Validation: Predictability Evaluation 1504.6 IVIVC Development Step-by-Step Approach 1514.7 Brief Introduction to Micro/Nanosystems and IVIVC Relevance 1524.7.1 Selection of Appropriate Dissolution Method 1534.7.2 Selection of Appropriate Dissolution Medium 1554.7.3 Selection of Appropriate IVIVC Mathematical Model 1574.8 Applications of IVIVC for Micro/nanoformulations 1584.8.1 Formulation Optimization 1624.8.2 Surrogate for Bioequivalence Studies and Biowaivers 1654.9 Softwares Used for IVIVC 1654.10 Conclusion and Future Prospects 166References 1665 Characterization of Bioadhesion, Mucin-interactions and Mucosal Permeability of Pharmaceutical Nano- and Microsystems 171Ellen Hagesaether, Malgorzata Iwona Adamczak, Marianne Hiorth and Ingunn Tho5.1 Introduction 1715.2 Background and Theory 1725.3 Mucosal Membranes 1745.3.1 Oral Mucosa 1745.3.2 Gastrointestinal Mucosa 1765.3.3 Pulmonary Mucosa 1765.3.4 Nasal Mucosa 1815.3.5 Ocular Mucosa 1825.3.6 Vaginal Mucosa 1825.4 Use of Mucosal Membranes in Studies of Micro- and Nanoparticles 1835.4.1 Diffusion Chambers 1835.4.2 Permeability Support for Cell-based Systems 1845.5 Selection of Biological Models 1855.5.1 Tissue-based Models 1855.5.2 Cell-based Models 1855.5.3 Mucus as Models 1875.5.4 Artificial Models 1885.6 Methods for Testing Biocompatibility 1895.6.1 Viability 1895.6.2 Cytotoxicity 1895.6.3 Paracellular Permeability 1895.7 Methods for Testing Mucoadhesion 1905.7.1 Atomic Force Microscopy (AFM) 1905.7.2 Quartz Crystal Microbalance (QCM) 1915.7.3 Rheology 1925.7.4 Rheology in Combination with Light Scattering (Rheo-SALS) 1925.7.5 Dynamic Light Scattering (DLS) and Zeta Potential Measurements 1935.7.6 Mechanical Methods 1945.7.7 Mucin Adsorption Study 1945.7.8 Wash-off Tests 1945.8 Methods for Testing Mucopenetration 1955.8.1 Fluorescent Recovery after Photobleaching (FRAP) and Multiple Image Photography (MIP) 1955.8.2 Permeability Studies 1955.8.3 Water-assisted Transport Through Mucus 1965.8.4 Particles with Dynamic Properties 1965.9 Methods for Assessing Cell Interactions 1975.9.1 Cell Adhesion 1975.9.2 Cellular Uptake 1975.9.3 Transcellular Transport 1995.10 Concluding Remarks 203References 2036 Cell–Nanoparticle Interactions: Toxicity and Safety Issues 207Flavia Fontana, Nazanin Zanjanizadeh Ezazi, Nayab Tahir and Helder A. Santos6.1 Introduction 2076.1.1 Role of Nanoparticles in Modern Medicine and Applications 2076.1.2 Cell–NP Interactions 2086.1.2.1 Size 2086.1.2.2 Shape 2086.1.2.3 Surface Charge 2096.1.2.4 Surface Functionalization and Hydrophobicity 2106.1.2.5 Protein Corona 2116.1.3 NP Toxicity 2116.2 Mechanisms of NP-Induced Cellular Toxicity 2116.2.1 Damage to the Plasma Membrane 2116.2.2 Alterations or Disruptions in the Cytoskeleton 2116.2.3 Mitochondrial Toxicity 2166.2.4 Nuclear Damage 2166.2.5 Reactive Oxygen Species (ROS) 2166.2.6 Interference in the Signaling Pathways 2166.3 In Vitro Assays to Evaluate Cell–NP Interactions 2166.3.1 Traditional Assays 2176.3.2 Innovative Assays 2176.4 Metal Oxide Nanoparticles 2176.4.1 Zinc Oxide 2176.4.2 Cerium Oxide 2206.4.3 Iron Oxide 2216.5 Non-metallic Nanoparticles 2236.5.1 Liposomes 2236.5.2 Polymeric Delivery Systems 2246.5.3 Dendrimers 2306.5.4 Silicon/Silica-based Drug Delivery Systems 2326.6 Conclusions and Future Perspectives 235Acknowledgements 235References 2367 Intestinal Mucosal Models to Validate Functionalized Nanosystems 243Cláudia Azevedo, Inês Pereira and Bruno Sarmento7.1 Introduction 2437.2 Intestinal Mucosal Characteristics 2447.2.1 Intestinal Morphology 2447.2.2 Transport Mechanisms 2467.3 In Vitro Models 2487.3.1 Monoculture Models 2497.3.2 Co-culture Models 2527.3.2.1 The Caco-2/HT29-MTX Model 2527.3.2.2 The Caco-2/Raji B Model 2537.3.2.3 The Caco-2/HT29-MTX/Raji B Model 2537.3.3 3D Co-culture Models 2537.3.4 Gut-on-a-Chip 2547.4 Ex Vivo Intestinal Models for In Vitro/In Vivo Correlation of Functionalized Nanosystems 2587.4.1 Diffusion Chambers 2587.4.1.1 Ussing Chamber 2587.4.1.2 Franz Cell 2587.4.2 Everted Intestinal Sac Model 2597.4.3 Non-everted Intestinal Sac Model 2607.4.4 Everted Intestinal Ring 2607.5 In Situ Models 2607.5.1 Intestinal Perfusion 2627.5.2 Intestinal Loop 2647.5.3 Intestinal Vascular Cannulation 2647.6 In Vivo Models 2647.7 Conclusion 265Acknowledgements 266References 2678 Biodistribution of Polymeric, Polysaccharide and Metallic Nanoparticles 275Nazl𝚤 Erdoğar, Gamze Varan, Cem Varan and Erem Bilensoy8.1 Introduction 2758.2 Biodistribution and Pharmacokinetics 2768.3 Mechanisms Affecting Biodistribution 2778.3.1 Nanoparticle Properties 2778.3.1.1 Effect of Particle Size 2778.3.1.2 Effect of Surface Charge 2798.3.1.3 Effect of Particle Shape 2808.3.2 Dosing and Toxicity 2818.3.3 Effect of Coating 2828.4 Conclusion 285References 2869 Opportunities and Challenges of Silicon-based Nanoparticles for Drug Delivery and Imaging 291Didem Şen Karaman, Martti Kaasalainen, Helene Kettiger and Jessica M. Rosenholm9.1 Synthesis and Characteristics of Silica-based Nanoparticles 2929.1.1 Nonporous Silica NPs 2929.1.2 Mesoporous Silica NPs 2959.1.3 Core@Shell Materials 2979.1.4 Hollow Silica Nanoparticles 2989.1.5 Porous Silicon (PSi) 3009.2 Solid-state Characterization 3039.2.1 Porosity and Morphology on the Nanoscale 3039.2.2 Structural Analysis 3059.2.3 Methods for Determination of Surface Functionalization 3069.3 Medium-dependent Characterization 3079.3.1 Hydrodynamic Size 3079.3.1.1 Dynamic Light Scattering 3099.3.2 Surface Charge and Zeta Potential 3099.3.3 Colloidal Stability 3119.3.4 Challenges in Particularly Porous Nanoparticle Characterization 3129.4 Incorporation of Active Molecules 3149.4.1 Drug Loading 3149.4.2 Labeling with Imaging Agents 3179.5 Biorelevant Physicochemical Characterization 3199.5.1 Biodegradation/Dissolution of Silica 3219.5.2 Biocompatibility and Nano–Bio Interactions 3239.5.3 Drug Release 3249.5.4 Label-free (Imaging) Technologies 3269.6 Conclusions 328References 32910 Statistical Analysis and Multidimensional Modeling in Research 339Osmo Antikainen10.1 Measurement in Research 33910.2 Mean and Sample Mean 33910.3 Correlation 34110.4 Modeling Relationships Between Series of Observations 34310.5 Quality of a Model 34410.5.1 The Meaning of R2 in Linear Regression 34410.5.2 Cross-validation 34510.6 Multivariate Data 35010.6.1 Screening Designs 35110.6.2 Full Factorial Designs 35210.6.2.1 Full Factorial Designs in Two Levels 35210.6.2.2 Full Factorial Designs in Three Levels (3n Design) 35510.7 Principal Component Analysis (PCA) 36210.8 Conclusions 366References 366Index 369