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Book Details
Abstract
From a review of the previous edition:
‘For all the pharmacy students out there part of your pharmacy degree will be to study formulation design and pharmaceutics. This is the holy grail of pharmaceutical technology books. The text reads well and introduces difficult concepts in a more easy-to-understand way, it is definitely worth the money to help you get through the module, if you’re doing a research project in pharmaceutical design then this would also be an excellent buy…This is essential for passing exams and developing professional competence.’
This is the best known text on pharmaceutics. Its strength lies mainly in being a complete course in one book. Reviewers consistently praise its comprehensiveness and its extremely high quality-quality content. Pharmaceutics is one of the most diverse subject areas in pharmaceutical science and an understanding of it is vital for all pharmacists and scientists involved in converting drugs to medicines that can be safely delivered to a patient. The editorial and author team deliver a tour de force of accessibility, coverage and currency in this new edition of a world-class textbook.
- Relevant chemistry covered throughout
- Reflects current and future use of biotechnology products throughout
- Covers ongoing changes in our understanding of biopharmaceutics, certain areas of drug delivery and the significance of the solid state
- Includes the science of formulation and drug delivery
- Designed and written for newcomers to the design of dosage forms
- Key points boxes throughout
- Summaries at the end of each chapter
- Fully updated throughout, with particular focus on delivery of biopharmaceuticals, nanotechnology and nanomedicines, parenteral and ocular drug delivery mechanisms.
- Now comes with online access on StudentConsult.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | cover | ||
| IFC_Student Consult PIN Page | ifc1 | ||
| Aulton's Pharmaceutics | i | ||
| Copyright Page | iv | ||
| Table Of Contents | v | ||
| Preface | vii | ||
| Contributors | viii | ||
| Acknowledgements | xi | ||
| What is ‘pharmaceutics’? | 1 | ||
| 1 Design of dosage forms | 6 | ||
| Chapter contents | 6 | ||
| Principles of dosage form design | 6 | ||
| Biopharmaceutical aspects of dosage form design | 8 | ||
| Routes of drug administration | 9 | ||
| Oral route | 9 | ||
| Rectal route | 10 | ||
| Parenteral routes | 10 | ||
| Topical route | 11 | ||
| Respiratory route | 11 | ||
| Drug factors in dosage form design | 11 | ||
| Particle size and surface area | 12 | ||
| Solubility | 12 | ||
| Dissolution | 13 | ||
| Partition coefficient and pKa | 14 | ||
| Crystal properties: polymorphism | 14 | ||
| Stability | 15 | ||
| Organoleptic properties | 15 | ||
| Other drug properties | 16 | ||
| Therapeutic considerations in dosage form design | 16 | ||
| Summary | 17 | ||
| Bibliography | 17 | ||
| 1 Scientific principles of dosage form design | 18 | ||
| 2 Dissolution and solubility | 18 | ||
| Chapter contents | 18 | ||
| Key points | 18 | ||
| Introduction | 18 | ||
| Definition of terms | 19 | ||
| Solution, solubility and dissolution | 19 | ||
| Process of dissolution | 19 | ||
| Dissolution mechanisms | 19 | ||
| Interfacial reaction | 20 | ||
| Leaving the surface. | 20 | ||
| Moving into the liquid. | 20 | ||
| Diffusion through the boundary layer | 20 | ||
| Energy/work changes during dissolution | 20 | ||
| Dissolution rates of solids in liquids | 21 | ||
| Interface-controlled dissolution rate | 21 | ||
| Diffusion-controlled dissolution rate | 21 | ||
| Noyes–Whitney equation | 21 | ||
| Factors affecting the rate of dissolution of diffusion- controlled systems | 22 | ||
| Surface area of undissolved solid (A) | 22 | ||
| Size of solid particles. | 22 | ||
| Dispersibility of powdered solid in dissolution medium. | 23 | ||
| Porosity of solid particles. | 24 | ||
| Changing area during dissolution. | 24 | ||
| Solubility of solid in dissolution medium (CS) | 24 | ||
| Temperature. | 24 | ||
| Nature of dissolution medium. | 24 | ||
| Molecular structure of solute. | 24 | ||
| Crystalline form of solid. | 24 | ||
| Presence of other compounds. | 24 | ||
| Concentration of solute in solution at time t (C) | 24 | ||
| Volume of dissolution medium. | 24 | ||
| Any process that removes dissolved solute from the dissolution medium. | 24 | ||
| Dissolution rate constant (k) | 24 | ||
| Thickness of the boundary layer. | 24 | ||
| Diffusion coefficient of solute in the dissolution medium. | 25 | ||
| Intrinsic dissolution rate | 25 | ||
| Techniques for measuring the IDR | 25 | ||
| Measurement of dissolution rates of drugs from dosage forms | 25 | ||
| Solubility | 26 | ||
| Methods of expressing solubility and concentration | 26 | ||
| Expressions of concentration | 26 | ||
| Quantity per quantity | 26 | ||
| Percentage | 26 | ||
| Parts | 26 | ||
| Molarity | 26 | ||
| Molality | 26 | ||
| Mole fraction | 26 | ||
| Milliequivalents and normal solutions | 27 | ||
| Qualitative descriptions of solubility | 27 | ||
| Prediction of solubility | 27 | ||
| Physicochemical prediction of solubility | 28 | ||
| Solubility parameters. | 28 | ||
| Solubility of solids in liquids | 28 | ||
| Determination of the solubility of a solid in a liquid | 28 | ||
| Factors affecting the solubility of solids in liquids | 29 | ||
| Temperature and heat input | 29 | ||
| Molecular structure of solute | 30 | ||
| Nature of solvent: cosolvents | 30 | ||
| Crystal characteristics: polymorphism and solvation | 30 | ||
| Particle size of the solid | 31 | ||
| pH | 31 | ||
| Common-ion effect | 31 | ||
| Effect of different electrolytes on the solubility product. | 32 | ||
| Effective concentration of ions. | 32 | ||
| Effect of nonelectrolytes on the solubility of electrolytes. | 32 | ||
| Effect of electrolytes on the solubility of nonelectrolytes. | 32 | ||
| Complex formation. | 32 | ||
| Solubilizing agents. | 32 | ||
| Solubility of gases in liquids | 32 | ||
| Solubility of liquids in liquids | 33 | ||
| Systems showing an increase in miscibility with rise in temperature | 33 | ||
| Systems showing a decrease in miscibility with rise in temperature | 33 | ||
| Systems showing upper and lower critical solution temperatures | 33 | ||
| Effects of added substances on critical solution temperatures | 34 | ||
| Blending | 34 | ||
| Distribution of solutes between immiscible liquids | 34 | ||
| Partition coefficients | 34 | ||
| Solubility of solids in solids | 35 | ||
| Summary | 36 | ||
| Reference | 36 | ||
| Bibliography | 36 | ||
| 3 Properties of solutions | 37 | ||
| Chapter contents | 37 | ||
| Key points | 37 | ||
| Introduction | 37 | ||
| Types of solution | 37 | ||
| Vapour pressures of solids, liquids and solutions | 38 | ||
| Ideal solutions: Raoult’s law | 38 | ||
| Real or nonideal solutions | 39 | ||
| Ionization of solutes | 40 | ||
| Hydrogen ion concentration and pH | 40 | ||
| Dissociation (or ionization) constants; pKa and pKb | 41 | ||
| Link between pH, pKa, degree of ionization and solubility of weakly acidic or basic drugs | 42 | ||
| Use of the Henderson–Hasselbalch equations to calculate the degree of ionization of weakly acidic or basic drugs | 42 | ||
| Buffer solutions and buffer capacity | 42 | ||
| Colligative properties | 44 | ||
| Osmotic pressure | 44 | ||
| Osmolality and osmolarity | 45 | ||
| Isoosmotic solutions | 45 | ||
| Isotonic solutions | 45 | ||
| Diffusion in solution | 45 | ||
| Summary | 46 | ||
| Bibliography | 46 | ||
| 4 Surfaces and interfaces | 47 | ||
| Chapter contents | 47 | ||
| Key points | 47 | ||
| Introduction | 47 | ||
| Surface tension | 48 | ||
| Measurement of surface tension | 49 | ||
| Solid wettability | 50 | ||
| Contact angle | 50 | ||
| Adsorption at interfaces | 52 | ||
| Solid–liquid interfaces | 52 | ||
| Solid–vapour interfaces | 53 | ||
| Solid–vapour adsorption isotherms | 53 | ||
| Langmuir (type I) isotherm | 53 | ||
| Type II isotherms | 54 | ||
| Type III isotherms | 54 | ||
| Brunauer, Emmett and Teller isotherm | 54 | ||
| Interpretation of isotherm plots | 55 | ||
| Interactions between powders and water vapour | 55 | ||
| Water adsorption | 56 | ||
| Water absorption | 56 | ||
| Deliquescence | 58 | ||
| Inverse phase gas chromatography (IGC) | 58 | ||
| References | 59 | ||
| 5 Disperse systems | 60 | ||
| Chapter contents | 60 | ||
| Key points | 60 | ||
| Introduction | 61 | ||
| Colloids | 61 | ||
| Preparation of colloidal systems | 61 | ||
| Lyophilic colloids | 61 | ||
| Lyophobic colloids | 61 | ||
| Dispersion methods | 62 | ||
| Colloid mills. | 62 | ||
| Ultrasonic treatment. | 62 | ||
| Condensation methods | 62 | ||
| Purification of colloidal systems | 62 | ||
| Dialysis | 62 | ||
| Ultrafiltration | 62 | ||
| Electrodialysis | 62 | ||
| Properties of colloids | 62 | ||
| Size and shape of colloidal particles | 62 | ||
| Size distribution | 62 | ||
| Shape | 63 | ||
| Kinetic properties | 63 | ||
| Brownian motion | 63 | ||
| Diffusion | 63 | ||
| Sedimentation | 64 | ||
| Sedimentation velocity. | 64 | ||
| Sedimentation equilibrium. | 64 | ||
| Osmotic pressure | 64 | ||
| Viscosity | 65 | ||
| Optical properties | 66 | ||
| Light scattering | 66 | ||
| Dynamic light scattering (photon correlation spectroscopy) | 67 | ||
| Ultramicroscopy | 67 | ||
| Electron microscopy | 67 | ||
| Electrical properties | 67 | ||
| Electrical properties of interfaces | 67 | ||
| Ion dissolution. | 68 | ||
| Ionization. | 68 | ||
| Ion adsorption. | 68 | ||
| The electrical double layer | 68 | ||
| Electrokinetic phenomena | 69 | ||
| Electrophoresis. | 69 | ||
| Other electrokinetic phenomena. | 70 | ||
| Physical stability of colloidal systems | 70 | ||
| Stability of lyophobic systems (DLVO theory) | 71 | ||
| Repulsive forces between particles. | 72 | ||
| Attractive forces between particles. | 72 | ||
| Total potential energy of interaction. | 72 | ||
| Stability of lyophilic systems | 73 | ||
| Coacervation and microencapsulation. | 73 | ||
| Effect of addition of macromolecular material to lyophobic colloidal sols. | 74 | ||
| Steric stabilization (protective colloid action) | 74 | ||
| Gels | 76 | ||
| Types of gel | 76 | ||
| Gelation of lyophobic sols | 76 | ||
| Gelation of lyophilic sols | 76 | ||
| Surface-active agents | 77 | ||
| Surface activity | 77 | ||
| Micelle formation | 79 | ||
| Solubilization | 81 | ||
| Pharmaceutical applications of solubilization | 81 | ||
| Solubilization and drug stability | 82 | ||
| Detergency | 82 | ||
| Coarse disperse systems | 82 | ||
| Suspensions | 82 | ||
| Controlled flocculation | 83 | ||
| Steric stabilization of suspensions | 84 | ||
| Wetting problems | 84 | ||
| Rheological properties of suspensions | 85 | ||
| Emulsions | 85 | ||
| Microemulsions | 85 | ||
| Theory of emulsion stabilization | 86 | ||
| Interfacial films | 86 | ||
| Hydrophilic colloids as emulsion stabilizers | 87 | ||
| Solid particles in emulsion stabilization | 87 | ||
| Emulsion type | 87 | ||
| Hydrophile–lipophile balance | 88 | ||
| Phase viscosity | 89 | ||
| Stability of emulsions | 89 | ||
| Flocculation | 89 | ||
| Phase inversion | 90 | ||
| Creaming | 90 | ||
| Assessment of emulsion stability | 91 | ||
| Foams | 91 | ||
| Aerosols | 91 | ||
| Preparation of aerosols | 92 | ||
| Application of aerosols in pharmacy | 92 | ||
| References | 92 | ||
| Bibliography | 92 | ||
| 6 Rheology | 93 | ||
| Chapter contents | 93 | ||
| Key points | 93 | ||
| Viscosity, rheology and the flow of fluids | 93 | ||
| Newtonian fluids | 94 | ||
| Viscosity coefficients for Newtonian fluids | 94 | ||
| Dynamic viscosity | 94 | ||
| Kinematic viscosity | 95 | ||
| Relative and specific viscosities | 95 | ||
| Intrinsic viscosity | 95 | ||
| Huggins constant | 96 | ||
| Boundary layers | 96 | ||
| Laminar, transitional and turbulent flow | 97 | ||
| Determination of the flow properties of simple fluids | 98 | ||
| Capillary viscometers | 98 | ||
| Ostwald U-tube viscometer. | 98 | ||
| Suspended-level viscometer. | 99 | ||
| Calculation of viscosity from capillary viscometers | 99 | ||
| Falling-sphere viscometer | 100 | ||
| Non-Newtonian fluids | 101 | ||
| Types of non-Newtonian behaviour | 101 | ||
| Plastic (or Bingham) flow | 102 | ||
| Pseudoplastic flow | 102 | ||
| Dilatant flow | 103 | ||
| Time-dependent behaviour | 104 | ||
| Determination of the flow properties of non-Newtonian fluids | 105 | ||
| Rotational viscometers | 105 | ||
| Concentric cylinder geometry. | 106 | ||
| Cone–plate geometry. | 106 | ||
| Parallel-plate geometry. | 107 | ||
| Rheometers | 107 | ||
| Viscoelasticity | 109 | ||
| Creep testing | 110 | ||
| Dynamic testing | 111 | ||
| The applications of rheology in pharmaceutical formulation | 112 | ||
| References | 113 | ||
| Bibliography | 113 | ||
| 7 Kinetics | 114 | ||
| Chapter contents | 114 | ||
| Key points | 114 | ||
| Introduction | 115 | ||
| Energetics | 115 | ||
| Homogeneous and heterogeneous processes | 116 | ||
| Molecularity | 116 | ||
| Rate laws and order of reaction | 116 | ||
| Zero-order processes | 117 | ||
| First-order processes | 118 | ||
| Pseudo-first-order processes | 118 | ||
| Second-order processes | 120 | ||
| Half-life, t1/2 | 121 | ||
| Summary of parameters | 121 | ||
| Determination of order and rate constant | 121 | ||
| Complex reactions | 122 | ||
| Consecutive reactions | 123 | ||
| Parallel (side) reactions | 123 | ||
| Reversible reactions | 123 | ||
| The Michaelis–Menten equation | 123 | ||
| Effect of temperature on reaction rate | 126 | ||
| Summary | 127 | ||
| Bibliography | 127 | ||
| 2 Particle science and powder technology | 128 | ||
| 8 Solid-state properties | 128 | ||
| Chapter contents | 128 | ||
| Key points | 128 | ||
| Solid state | 128 | ||
| Crystallization | 129 | ||
| Polymorphism | 130 | ||
| Polymorphism and bioavailability | 131 | ||
| Hydrates and solvates | 132 | ||
| Amorphous state | 133 | ||
| Crystal habit | 136 | ||
| Surface nature of particles | 137 | ||
| Dry powder inhalers | 137 | ||
| Surface energy | 138 | ||
| Vapour sorption | 138 | ||
| References | 139 | ||
| Bibliography | 139 | ||
| 9 Particle size analysis | 140 | ||
| Chapter contents | 140 | ||
| Key points | 140 | ||
| Introduction | 140 | ||
| Particle size | 141 | ||
| Dimensions | 141 | ||
| Equivalent sphere diameters | 142 | ||
| Particle size distribution | 142 | ||
| Summarizing size distribution data | 144 | ||
| Mean particle sizes | 146 | ||
| Interconversion of mean sizes | 147 | ||
| Influence of particle shape | 147 | ||
| Particle size analysis methods | 148 | ||
| Sieve methods | 148 | ||
| Equivalent sphere diameter | 148 | ||
| Range of analysis | 148 | ||
| Sample preparation and analysis conditions | 148 | ||
| Principles of measurement | 148 | ||
| Alternative techniques | 149 | ||
| Microscope methods | 149 | ||
| Equivalent sphere diameters | 149 | ||
| Range of analysis | 149 | ||
| Sample preparation and analysis conditions | 149 | ||
| Light microscopy | 149 | ||
| Principles of measurement | 149 | ||
| Electron microscopy | 150 | ||
| Image analysis | 150 | ||
| Sedimentation methods | 150 | ||
| Equivalent sphere diameters | 150 | ||
| Range of analysis | 150 | ||
| Sample preparation and analysis conditions | 150 | ||
| Principles of measurement | 150 | ||
| Alternative techniques | 151 | ||
| Electrical sensing zone (electrozone sensing) method (Coulter Counter®) | 152 | ||
| Equivalent sphere diameter | 152 | ||
| Range of analysis | 152 | ||
| Sample preparation and analysis conditions | 152 | ||
| Principles of measurement | 152 | ||
| Laser diffraction (low-angle laser light scattering) | 153 | ||
| Equivalent sphere diameters | 153 | ||
| Range of analysis | 153 | ||
| Sample preparation and analysis conditions | 153 | ||
| Principles of measurement | 153 | ||
| Fraunhofer diffraction and Mie theory | 153 | ||
| Dynamic light scattering (photon correlation spectroscopy) | 154 | ||
| Equivalent sphere diameter | 154 | ||
| Range of analysis | 154 | ||
| Sample preparation and analysis conditions | 154 | ||
| Principles of measurement | 154 | ||
| Particle counting | 155 | ||
| Selection of a particle size analysis method | 155 | ||
| Reference | 156 | ||
| Bibliography | 156 | ||
| 10 Particle size reduction and size separation | 158 | ||
| Chapter contents | 158 | ||
| Key points | 158 | ||
| Introduction to size reduction | 159 | ||
| Influence of material properties on size reduction | 159 | ||
| Crack propagation and toughness | 159 | ||
| Surface hardness | 159 | ||
| Energy requirements of the size reduction process | 160 | ||
| Influence of size reduction on size distribution | 161 | ||
| Size reduction methods | 162 | ||
| Cutting methods | 162 | ||
| 3 Pharmaceutical microbiology and sterilization | 201 | ||
| 13 Fundamentals of microbiology | 201 | ||
| Chapter contents | 201 | ||
| Key points | 201 | ||
| Introduction | 201 | ||
| Viruses | 202 | ||
| Reproduction of viruses | 203 | ||
| Adsorption to the host cell | 203 | ||
| Penetration | 204 | ||
| Uncoating | 204 | ||
| Nucleic acid and protein synthesis | 204 | ||
| Assembly of new virions | 204 | ||
| Release of virus progeny | 204 | ||
| Latent infections | 204 | ||
| Oncogenic viruses | 204 | ||
| Bacteriophages | 204 | ||
| Archaea | 205 | ||
| Eubacteria | 205 | ||
| Atypical bacteria | 205 | ||
| Rickettsiaceae, Coxiellaceae and Bartonellaceae | 205 | ||
| Chlamydiae | 205 | ||
| Mycoplasmas | 206 | ||
| Actinomycetes | 206 | ||
| Typical bacteria | 206 | ||
| Shape, size and aggregation | 206 | ||
| Anatomy | 207 | ||
| Capsule | 207 | ||
| Cell wall | 208 | ||
| Cytoplasmic membrane | 209 | ||
| Nuclear material | 209 | ||
| Mesosomes | 209 | ||
| Ribosomes | 209 | ||
| Inclusion granules | 209 | ||
| Flagella | 210 | ||
| Pili and fimbriae | 210 | ||
| Endospores | 210 | ||
| Microscopy and staining of bacteria | 211 | ||
| Differential stains | 212 | ||
| Gram stain. | 212 | ||
| Ziehl–Neelsen acid-fast stain. | 212 | ||
| Fluorescence microscopy | 212 | ||
| Dark-ground microscopy | 212 | ||
| Phase-contrast microscopy | 212 | ||
| Differential-interference contrast microscopy | 213 | ||
| Electron microscopy | 213 | ||
| Growth and reproduction of bacteria | 213 | ||
| Genetic exchange | 214 | ||
| Transformation. | 214 | ||
| Transduction. | 214 | ||
| Conjugation. | 214 | ||
| Bacterial nutrition | 214 | ||
| Lithotrophs (synonym: autotrophs). | 214 | ||
| Organotrophs (synonym: heterotrophs). | 214 | ||
| Oxygen requirements | 214 | ||
| Influence of environmental factors on the growth of bacteria | 215 | ||
| Temperature. | 215 | ||
| pH. | 215 | ||
| Osmotic pressure. | 215 | ||
| Handling and storage of microorganisms | 215 | ||
| Inoculation of agar surfaces by streaking | 216 | ||
| Inoculation of slopes | 216 | ||
| Transference of liquids | 217 | ||
| Release of infectious aerosols | 217 | ||
| Cultivation of anaerobes | 217 | ||
| Counting bacteria | 218 | ||
| Total counts | 218 | ||
| Microscope methods. | 218 | ||
| Spectroscopic methods. | 218 | ||
| Electronic methods. | 218 | ||
| Other methods. | 219 | ||
| Viable counts | 219 | ||
| Spread plates. | 219 | ||
| Pour plates. | 219 | ||
| Membrane filtration. | 219 | ||
| ATP determination. | 220 | ||
| Isolation of pure bacterial cultures | 220 | ||
| Classification and identification | 220 | ||
| Nomenclature | 220 | ||
| Identification | 221 | ||
| Biochemical tests | 221 | ||
| Rapid identification systems | 222 | ||
| Serological tests | 222 | ||
| Phage typing. | 223 | ||
| Fungi | 223 | ||
| Fungal morphology | 223 | ||
| Yeasts | 223 | ||
| Yeast-like fungi | 223 | ||
| Dimorphic fungi | 223 | ||
| Filamentous fungi | 224 | ||
| Mushrooms and toadstools | 224 | ||
| Reproduction of fungi | 224 | ||
| Asexual reproduction | 224 | ||
| Sexual reproduction | 224 | ||
| Fungal classification | 225 | ||
| Zygomycetes | 225 | ||
| Ascomycetes | 225 | ||
| Deuteromycetes | 225 | ||
| Basidiomycetes | 225 | ||
| Bibliography | 226 | ||
| 14 Pharmaceutical applications of microbiological techniques | 227 | ||
| Chapter contents | 227 | ||
| Key points | 227 | ||
| Introduction | 227 | ||
| Measurement of antimicrobial activity | 228 | ||
| Factors to be controlled in the measurement of antimicrobial activity | 228 | ||
| Origin of the test organism | 228 | ||
| Composition and pH of the culture medium | 228 | ||
| Exposure and incubation conditions | 229 | ||
| Inoculum concentration and physiological state | 230 | ||
| Antibiotic assays | 230 | ||
| Agar diffusion assays | 231 | ||
| Practical aspects of the conduct of agar diffusion assays | 233 | ||
| Turbidimetric assays | 233 | ||
| Practical aspects of the conduct of turbidimetric assays | 234 | ||
| Minimum inhibitory concentration determinations | 234 | ||
| MIC test methods | 234 | ||
| Distinction between MICs determined in agar and the assessment of sensitivity using agar diffusion methods | 235 | ||
| Preservative efficacy tests (or challenge tests) | 236 | ||
| Choice of test organisms and inoculum concentration | 237 | ||
| Inactivation of preservative | 237 | ||
| Interpretation of results | 238 | ||
| Disinfectant evaluation | 239 | ||
| Microbiological quality of pharmaceutical materials | 240 | ||
| Nonsterile products | 240 | ||
| Environmental monitoring | 241 | ||
| Counting of microorganisms in pharmaceutical products | 242 | ||
| Very low concentrations of microorganisms in aqueous solutions. | 242 | ||
| Insoluble solids. | 242 | ||
| Oils and hydrophobic ointments. | 243 | ||
| Creams and lotions. | 243 | ||
| Detection of specific hazardous organisms | 243 | ||
| Microbiological assays of B-group vitamins | 244 | ||
| Sterile products | 245 | ||
| Sterilization monitoring | 245 | ||
| Tests for sterility | 246 | ||
| Endotoxin and pyrogen testing | 248 | ||
| References | 248 | ||
| 15 Action of physical and chemical agents on microorganisms | 250 | ||
| Chapter contents | 250 | ||
| Key points | 250 | ||
| Introduction | 251 | ||
| Kinetics of cell inactivation | 251 | ||
| D value, or decimal reduction time | 252 | ||
| Z value | 252 | ||
| Alternative survivor plots | 253 | ||
| Antimicrobial effects of moist and dry heat | 254 | ||
| Resistance of microorganisms to moist and dry heat | 254 | ||
| Factors affecting heat resistance and its measurement | 256 | ||
| Species and strain differences | 256 | ||
| Cell form | 256 | ||
| Culture conditions | 256 | ||
| pH and composition of heating menstruum | 257 | ||
| Recovery of heat-treated cells | 257 | ||
| Ionizing radiation | 257 | ||
| Particulate radiation | 258 | ||
| Electromagnetic radiation | 258 | ||
| Units of radioactivity | 258 | ||
| Effect of ionizing radiation on materials | 258 | ||
| Factors affecting the radiation resistance of microorganisms | 259 | ||
| Ultraviolet radiation | 259 | ||
| Factors affecting resistance to UV light | 260 | ||
| Gases | 260 | ||
| Ethylene oxide | 260 | ||
| Factors affecting the activity of ethylene oxide | 261 | ||
| Formaldehyde | 261 | ||
| Peracetic acid | 261 | ||
| Hydrogen peroxide | 261 | ||
| Chlorine dioxide | 261 | ||
| Propylene oxide | 262 | ||
| Methyl bromide | 262 | ||
| Gas plasmas | 262 | ||
| Antimicrobial effects of chemical agents | 262 | ||
| Principal factors affecting activity | 263 | ||
| Range of chemical agents | 263 | ||
| Phenolics | 263 | ||
| Alcohols, aldehydes, acids and esters | 265 | ||
| Quaternary ammonium compounds | 265 | ||
| Biguanides and amidines | 266 | ||
| Halogens and their compounds | 266 | ||
| Metals | 267 | ||
| The acridines | 267 | ||
| References | 267 | ||
| 16 Principles of sterilization | 268 | ||
| Chapter contents | 268 | ||
| Key points | 268 | ||
| Introduction | 268 | ||
| Need for sterility | 269 | ||
| Sterilization parameters | 269 | ||
| D value and Z value | 269 | ||
| Inactivation factor and most probable effective dose | 270 | ||
| F value | 270 | ||
| Principles of sterilization processes | 270 | ||
| Heat sterilization | 270 | ||
| Principles of steam sterilization | 271 | ||
| Principles of dry heat sterilization | 271 | ||
| Combination treatments | 272 | ||
| Alternative means for heat delivery and control | 272 | ||
| Gaseous sterilization | 272 | ||
| Alkylating gases | 273 | ||
| Oxidizing gases | 273 | ||
| Radiation sterilization | 273 | ||
| Filtration sterilization | 274 | ||
| High-level disinfection | 274 | ||
| New technologies | 275 | ||
| Ultrahigh pressure | 275 | ||
| High-intensity light pulses | 275 | ||
| Ultrasonication | 276 | ||
| Gas plasma | 276 | ||
| Summary | 276 | ||
| References | 277 | ||
| Bibliography | 277 | ||
| 17 Sterilization in practice | 278 | ||
| Chapter contents | 278 | ||
| Key points | 278 | ||
| Sterile products | 278 | ||
| Determination of sterilization protocols | 280 | ||
| Recommended pharmacopoeial sterilization processes | 281 | ||
| Steam (under pressure) sterilization | 282 | ||
| Dry heat sterilization | 284 | ||
| Integrated lethality in sterilization practice | 285 | ||
| Gaseous sterilization | 286 | ||
| Radiation sterilization | 286 | ||
| Filtration | 287 | ||
| High-level disinfection | 288 | ||
| Statistical considerations of sterility testing and sterility assurance level | 288 | ||
| Test for sterility of the product | 289 | ||
| Validation of a sterilization process | 289 | ||
| Process indicators | 290 | ||
| Testing filtration efficacy | 292 | ||
| Monitoring decontamination | 292 | ||
| Limitations of sterilization methods | 294 | ||
| Summary | 294 | ||
| References | 294 | ||
| Bibliography | 295 | ||
| 4 Biopharmaceutical principles of drug delivery | 296 | ||
| 18 Introduction to biopharmaceutics | 296 | ||
| Chapter contents | 296 | ||
| Key points | 296 | ||
| What is biopharmaceutics? | 296 | ||
| Background | 296 | ||
| Concept of bioavailability | 298 | ||
| Concept of biopharmaceutics | 298 | ||
| Summary | 299 | ||
| Bibliography | 299 | ||
| 19 Gastrointestinal tract – physiology and drug absorption | 300 | ||
| Chapter contents | 300 | ||
| Key points | 300 | ||
| Introduction | 300 | ||
| Physiological factors influencing oral drug absorption | 301 | ||
| Physiology of the gastrointestinal tract | 301 | ||
| Oesophagus | 302 | ||
| Stomach | 303 | ||
| Small intestine | 303 | ||
| Colon | 305 | ||
| Transit of pharmaceuticals in the gastrointestinal tract | 305 | ||
| Gastric emptying | 306 | ||
| Small intestinal transit | 306 | ||
| Colonic transit | 307 | ||
| Barriers to drug absorption | 307 | ||
| Environment within the lumen | 307 | ||
| Gastrointestinal pH | 307 | ||
| Luminal enzymes | 308 | ||
| Influence of food in the gastrointestinal tract | 308 | ||
| Complexation of drugs with components in the diet. | 308 | ||
| Alteration of pH. | 309 | ||
| Alteration of gastric emptying. | 309 | ||
| Stimulation of gastrointestinal secretions. | 309 | ||
| Competition between food components and drugs for specialized absorption mechanisms. | 309 | ||
| Increased viscosity of gastrointestinal tract contents. | 309 | ||
| Food-induced changes in presystemic metabolism. | 309 | ||
| Food-induced changes in blood flow. | 309 | ||
| Disease state and physiological disorders | 309 | ||
| Mucus and the unstirred water layer | 310 | ||
| Gastrointestinal membrane | 310 | ||
| Structure of the membrane | 310 | ||
| Mechanisms of transport across the gastrointestinal membrane | 311 | ||
| Transcellular transport | 311 | ||
| Passive diffusion | 311 | ||
| Membrane transporters | 313 | ||
| Transcytosis | 316 | ||
| Paracellular pathway | 317 | ||
| Presystemic metabolism | 317 | ||
| Gut wall metabolism | 317 | ||
| Hepatic metabolism | 317 | ||
| Summary | 318 | ||
| References | 318 | ||
| Bibliography | 318 | ||
| 20 Bioavailability – physicochemical and dosage form factors | 319 | ||
| Chapter contents | 319 | ||
| Key points | 319 | ||
| Introduction | 319 | ||
| Physicochemical factors influencing bioavailability | 319 | ||
| Dissolution and solubility | 319 | ||
| Physiological factors affecting the dissolution rate of drugs | 320 | ||
| Drug factors affecting the dissolution rate | 321 | ||
| Surface area and particle size | 321 | ||
| Solubility in the diffusion layer, Cs | 322 | ||
| Salts | 323 | ||
| Crystal form | 324 | ||
| Polymorphism | 324 | ||
| Amorphous solids | 324 | ||
| Solvates | 324 | ||
| Factors affecting the concentration of a drug in solution in the gastrointestinal fluids | 325 | ||
| Complexation. | 325 | ||
| Micellar solubilization. | 325 | ||
| Adsorption. | 325 | ||
| Chemical stability of the drug in the gastrointestinal fluids. | 326 | ||
| Poorly soluble drugs | 326 | ||
| Drug absorption | 326 | ||
| Drug dissociation and lipid solubility | 326 | ||
| pH-partition hypothesis of drug absorption | 327 | ||
| Limitations of the pH-partition hypothesis | 327 | ||
| Lipid solubility | 328 | ||
| Molecular size and hydrogen bonding | 329 | ||
| Summary | 329 | ||
| Dosage form factors influencing bioavailability | 329 | ||
| Introduction | 329 | ||
| Influence of the type of dosage form | 329 | ||
| Aqueous solutions | 330 | ||
| Aqueous suspensions | 331 | ||
| Liquid-filled capsules | 331 | ||
| Powder-filled capsules | 332 | ||
| Tablets | 333 | ||
| Uncoated tablets | 333 | ||
| Coated tablets | 334 | ||
| Gastro-resistant tablets | 335 | ||
| Influence of excipients for conventional dosage forms | 335 | ||
| Diluents | 336 | ||
| Surfactants | 336 | ||
| Lubricants | 337 | ||
| Disintegrants | 337 | ||
| Viscosity-enhancing agents | 337 | ||
| Summary | 337 | ||
| Reference | 338 | ||
| Bibliography | 338 | ||
| 21 Assessment of biopharmaceutical properties | 339 | ||
| Chapter contents | 339 | ||
| Key points | 339 | ||
| Introduction | 339 | ||
| Measurement of key biopharmaceutical properties | 340 | ||
| Release of a drug from its dosage form into solution | 340 | ||
| Stability in physiological fluids | 341 | ||
| Permeability | 342 | ||
| Partition coefficients | 342 | ||
| Cell culture techniques | 343 | ||
| Tissue techniques | 345 | ||
| Perfusion studies | 346 | ||
| Assessment of permeability in humans | 348 | ||
| Intestinal perfusion studies | 348 | ||
| Noninvasive approaches | 348 | ||
| Presystemic metabolism | 348 | ||
| Mechanistic physiologically based pharmacokinetic models | 349 | ||
| Assessment of bioavailability | 349 | ||
| Plasma concentration–time curves | 350 | ||
| Minimum effective (or therapeutic) plasma concentration. | 350 | ||
| Maximum safe concentration. | 351 | ||
| Therapeutic range or window. | 351 | ||
| Onset. | 351 | ||
| Duration. | 351 | ||
| Peak concentration. | 351 | ||
| Time to peak concentration. | 351 | ||
| Area under the plasma concentration–time curve. | 351 | ||
| Use of plasma concentration–time curves in bioavailability studies | 351 | ||
| Cumulative urinary drug excretion curves | 352 | ||
| Use of urinary drug excretion curves in bioavailability studies | 353 | ||
| Absolute and relative bioavailability | 354 | ||
| Absolute bioavailability | 354 | ||
| Relative bioavailability | 355 | ||
| Bioequivalence | 356 | ||
| Regulatory requirements for bioequivalence | 357 | ||
| Pharmacokinetic studies to assess bioequivalence | 357 | ||
| Other methods of determining bioequivalence | 359 | ||
| Assessment of site of release in vivo | 360 | ||
| Biopharmaceutics classification system | 360 | ||
| Class I drugs. | 361 | ||
| Class II drugs. | 361 | ||
| Class III drugs. | 361 | ||
| Class IV drugs. | 361 | ||
| Biopharmaceutical drug disposition classification system | 361 | ||
| Summary | 361 | ||
| References | 362 | ||
| Bibliography | 362 | ||
| 22 Dosage regimens | 363 | ||
| Chapter contents | 363 | ||
| Key points | 363 | ||
| Dosage regimens: influence on the plasma concentration-time profile of a drug in the body | 364 | ||
| Rates of ADME processes | 364 | ||
| One-compartment open model of drug disposition in the body | 365 | ||
| Rate of drug input versus rate of drug output | 365 | ||
| Elimination rate constant and biological half-life of a drug | 366 | ||
| Concentration–time curve of a drug in the body following the oral administration of equal doses of a drug at fixed time intervals | 369 | ||
| Important factors influencing steady-state plasma concentrations of a drug | 371 | ||
| Dose size and frequency of administration | 371 | ||
| Size of dose | 371 | ||
| Time interval between successive equal doses | 371 | ||
| Summary of the effects of dose size and frequency of administration | 374 | ||
| Concept of loading doses | 375 | ||
| Population data and basic pharmacokinetic parameters | 377 | ||
| Influence of changes in the apparent elimination rate constant of a drug: patients with renal impairment | 377 | ||
| Summary | 378 | ||
| Bibliography | 379 | ||
| 5 Dosage form design and manufacture | 380 | ||
| 23 Pharmaceutical preformulation | 380 | ||
| Chapter contents | 380 | ||
| Key points | 380 | ||
| The concept of preformulation | 381 | ||
| Assay development | 381 | ||
| Solubility | 382 | ||
| Ideal solubility | 383 | ||
| Determination of melting point and enthalpy of fusion using DSC | 383 | ||
| Solubility as a function of temperature | 385 | ||
| Solubility and physical form | 386 | ||
| Measurement of intrinsic solubility | 386 | ||
| Effect of impurities on intrinsic solubility | 387 | ||
| Molecular dissociation | 389 | ||
| Measurement of pKa | 390 | ||
| Partitioning | 390 | ||
| Determination of log P | 391 | ||
| Shake-flask method | 391 | ||
| Chromatographic methods | 392 | ||
| Dissolution rate | 393 | ||
| Intrinsic dissolution rate | 393 | ||
| IDR as a function of pH | 394 | ||
| IDR and the common-ion effect | 394 | ||
| Salt selection | 395 | ||
| Salt formation | 395 | ||
| Selection of a salt-forming acid or base | 397 | ||
| Salt screening | 399 | ||
| Solubility of salts | 399 | ||
| Solubility of basic salts | 400 | ||
| Solubility of acidic salts | 400 | ||
| The importance of pHmax | 400 | ||
| Dissolution of salts | 400 | ||
| Effect of salts on partitioning | 401 | ||
| Hygroscopicity | 401 | ||
| Physical form | 402 | ||
| Polymorphism | 402 | ||
| Polymorph screening | 402 | ||
| Amorphous materials | 403 | ||
| Powder properties | 404 | ||
| Particle size and shape | 404 | ||
| Powder flow | 404 | ||
| Compaction properties | 404 | ||
| Summary | 405 | ||
| References | 405 | ||
| Bibliography | 406 | ||
| 24 Solutions | 407 | ||
| Chapter contents | 407 | ||
| Key points | 407 | ||
| Introduction | 407 | ||
| The solvent system | 407 | ||
| Aqueous solvents | 407 | ||
| Nonaqueous solvents | 408 | ||
| The drug | 408 | ||
| The excipients | 408 | ||
| Pharmaceutical solutions | 409 | ||
| Advantages of pharmaceutical solutions | 410 | ||
| Disadvantages of solutions | 413 | ||
| Solution stability | 413 | ||
| Enhancement of drug solubility | 413 | ||
| pH adjustment | 414 | ||
| Cosolvents | 414 | ||
| Complexation with cyclodextrins | 414 | ||
| Surfactants and micelles | 416 | ||
| Bibliography | 416 | ||
| 25 Clarification | 417 | ||
| Chapter contents | 417 | ||
| Key points | 417 | ||
| Introduction | 417 | ||
| Filtration | 417 | ||
| Types of filtration | 417 | ||
| Solid–fluid filtration | 417 | ||
| Solid–liquid filtration. | 418 | ||
| Solid–gas filtration. | 418 | ||
| Fluid–fluid filtration | 418 | ||
| Mechanisms of filtration | 418 | ||
| Straining/sieving | 418 | ||
| Impingement | 418 | ||
| Attractive forces | 419 | ||
| Autofiltration | 419 | ||
| Factors affecting the rate of filtration | 419 | ||
| Darcy’s equation | 420 | ||
| Methods used to increase the filtration rate | 420 | ||
| Increase the area available for filtration. | 420 | ||
| Increase the pressure difference across the filter cake. | 420 | ||
| Decrease the filtrate viscosity. | 421 | ||
| Decrease the thickness of the filter cake. | 421 | ||
| Increase the permeability of the cake. | 421 | ||
| Filtration equipment | 421 | ||
| Equipment selection | 421 | ||
| Industrial filtration equipment | 422 | ||
| Gravity filters | 422 | ||
| Vacuum filters | 422 | ||
| The rotary vacuum filter | 422 | ||
| Pressure filters | 423 | ||
| The metafilter. | 423 | ||
| Cartridge filters. | 424 | ||
| Cross-flow microfiltration. | 424 | ||
| Centrifugation | 425 | ||
| Principles of centrifugation | 425 | ||
| Industrial centrifuges | 425 | ||
| Perforated-basket centrifuges (centrifugal filters) | 425 | ||
| Tubular-bowl centrifuges (centrifugal sedimenters) | 426 | ||
| Bibliography | 426 | ||
| 26 Suspensions | 427 | ||
| Chapter contents | 427 | ||
| Key points | 427 | ||
| Introduction | 427 | ||
| Definition of a suspension | 428 | ||
| Solid particle–liquid vehicle interactions | 428 | ||
| The ‘electrical double layer’ theory | 428 | ||
| Factors affecting the electrical double layer | 429 | ||
| The Derjaguin–Landau–Verwey–Overbeek (DLVO) theory | 431 | ||
| The primary minimum | 431 | ||
| The primary maximum | 432 | ||
| The secondary minimum | 432 | ||
| Controlling particulate behaviour in suspensions | 433 | ||
| A, the Hamaker constant (Eqn 5.25). | 433 | ||
| ε, the permittivity of the medium (Eqn 5.24). | 433 | ||
| H, the distance between particles (Eqns 5.24 and 5.25). | 433 | ||
| ψo, the surface potential (Eqn 5.24). | 433 | ||
| κ, the Debye–Hückel reciprocal length parameter (Eqn 5.24). | 434 | ||
| a, the radius of the particle (Eqns 5.24 and 5.25). | 434 | ||
| Effects of additives | 434 | ||
| Particle movement in suspensions | 434 | ||
| Diffusion | 435 | ||
| Sedimentation | 435 | ||
| Controlling particulate movement in suspensions | 435 | ||
| a, the radius of the particle. | 436 | ||
| ρ, the density of the particle. | 436 | ||
| ρo, the density of the medium. | 436 | ||
| η, the viscosity of the medium. | 436 | ||
| T, temperature (in kelvins). | 436 | ||
| Measuring particle movement | 437 | ||
| What is the desired sedimentation pattern? | 437 | ||
| Dispersibility issues – surface wetting | 438 | ||
| Dissolution issues | 439 | ||
| Ostwald ripening | 439 | ||
| General suspension formulation 1considerations | 440 | ||
| Solubility | 440 | ||
| Formulation excipients | 441 | ||
| Flavours, sweeteners and colours | 441 | ||
| Antimicrobial preservatives | 441 | ||
| Buffers | 442 | ||
| Chemical stabilizers | 442 | ||
| Density and viscosity modifiers/suspending agents | 442 | ||
| Wetting agents | 443 | ||
| Flocculation modifiers | 444 | ||
| Colloid stabilizers | 444 | ||
| Stability considerations for suspensions | 444 | ||
| Manufacturing considerations | 445 | ||
| Summary | 445 | ||
| Bibliography | 445 | ||
| 27 Emulsions and creams | 446 | ||
| Chapter contents | 446 | ||
| Key points | 446 | ||
| Introduction | 447 | ||
| Emulsion formation | 447 | ||
| Partially miscible liquids | 448 | ||
| Emulsions in pharmacy | 448 | ||
| Development of pharmaceutical emulsions | 449 | ||
| Nanoemulsions | 450 | ||
| Nomenclature relating to nanoemulsions | 450 | ||
| Conventional emulsions (macroemulsions) and nanoemulsions. | 450 | ||
| Microemulsions and nanoemulsions. | 450 | ||
| Properties of nanoemulsions | 450 | ||
| Emulsion theory related to pharmaceutical emulsions and creams | 450 | ||
| Formulation of emulsions | 450 | ||
| Selection of the oil phase | 451 | ||
| Selection of the emulsifying agent (emulsifier) | 452 | ||
| Other excipients | 452 | ||
| Preservatives | 452 | ||
| Antioxidants and humectants | 452 | ||
| Emulsifying agents (emulsifiers) | 452 | ||
| Function of emulsifying agents | 452 | ||
| Emulsion type | 453 | ||
| Classification of emulsifying agents | 453 | ||
| Surface-active agents and polymers | 453 | ||
| Anionic surfactants | 455 | ||
| Alkyl sulfates. | 455 | ||
| Monovalent salts of fatty acids. | 455 | ||
| Divalent salts of fatty acids. | 455 | ||
| Cationic surfactants | 455 | ||
| Quaternary ammonium compounds. | 455 | ||
| Nonionic surfactants | 455 | ||
| Polyoxyethylene glycol ethers (macrogols). | 456 | ||
| Sorbitan esters. | 456 | ||
| Polyoxyethylene sorbitan esters (polysorbates). | 456 | ||
| Fatty amphiphiles | 456 | ||
| Fatty alcohols and fatty acids. | 456 | ||
| Glycerol monoesters. | 456 | ||
| Polymeric surfactants | 457 | ||
| Natural macromolecular materials | 457 | ||
| Phospholipids | 457 | ||
| Hydrophilic colloids; polysaccharides | 457 | ||
| Steroidal emulsifiers | 457 | ||
| Solid particles | 457 | ||
| Emulsifier selection | 458 | ||
| The hydrophile-lipophile balance (HLB) method | 458 | ||
| Determination of ‘required HLB’ value | 458 | ||
| Calculation of ratio of emulsifier to produce a particular required HLB value | 459 | ||
| Limitations of the HLB method | 459 | ||
| The HLB–phase inversion temperature system | 460 | ||
| Creams | 460 | ||
| Formulation of aqueous creams | 460 | ||
| The gel network theory of emulsion stability | 461 | ||
| Interaction of mixed emulsifiers in water | 461 | ||
| Microstructure of creams | 462 | ||
| Self-bodying action | 463 | ||
| Fatty alcohol mixed emulsifiers | 463 | ||
| Ionic surfactants. | 463 | ||
| Nonionic polyoxyethylene surfactants. | 463 | ||
| Fatty acid mixed emulsifiers | 465 | ||
| Self-emulsifying glyceryl monoesters | 465 | ||
| Molar ratio of fatty amphiphile to surfactant | 465 | ||
| Source and batch variations of components | 465 | ||
| Surfactants. | 465 | ||
| Fatty amphiphiles. | 466 | ||
| Manufacture and processing of emulsions and creams | 466 | ||
| Fluid emulsions | 466 | ||
| Multiple emulsions | 467 | ||
| Creams | 467 | ||
| Emulsion properties | 468 | ||
| Identification of emulsion type | 468 | ||
| Water or oil miscibility. | 468 | ||
| Filter paper test. | 468 | ||
| Conductivity measurements. | 468 | ||
| Dye solubility tests. | 469 | ||
| Droplet size distribution | 469 | ||
| Rheology | 469 | ||
| Emulsion stability | 470 | ||
| Definition of stability | 470 | ||
| Chemical instability | 470 | ||
| Physical instability | 470 | ||
| Creaming | 470 | ||
| Flocculation | 470 | ||
| Coalescence | 471 | ||
| Ostwald ripening | 472 | ||
| Emulsion inversion | 472 | ||
| Stabilization by use of mixed emulsifiers | 473 | ||
| Multiphase emulsions | 473 | ||
| Emulsifier concentration | 473 | ||
| Lamellar liquid crystalline and gel phases | 473 | ||
| α-Crystalline gel network phases. | 473 | ||
| Lamellar liquid crystalline phases. | 473 | ||
| Nanoemulsion stability | 473 | ||
| Stability testing | 474 | ||
| Evaluation of emulsion stability | 474 | ||
| Appearance | 474 | ||
| Droplet size analysis | 474 | ||
| Droplet charge, zeta potential | 474 | ||
| Rheological measurements | 474 | ||
| Thermal techniques | 475 | ||
| X-ray diffraction | 475 | ||
| Bibliography | 475 | ||
| 28 Powders, granules and granulation | 476 | ||
| Chapter contents | 476 | ||
| Key points | 476 | ||
| Introduction to powders and granules | 476 | ||
| What is a powder? | 477 | ||
| What is a granule? | 477 | ||
| Reasons for granulation | 477 | ||
| Prevention of segregation of the constituents of the powder mix | 477 | ||
| Improvement of the flow properties of the mix | 477 | ||
| Improvement of the compaction characteristics of the mix | 477 | ||
| Other reasons | 478 | ||
| Powdered and granulated products as dosage forms | 478 | ||
| Powders and granules for oral administration | 479 | ||
| Oral powders | 479 | ||
| Effervescent powders | 479 | ||
| Granules | 480 | ||
| Effervescent granules. | 480 | ||
| Coated granules. | 480 | ||
| Modified-release granules. | 480 | ||
| Gastro-resistant granules. | 480 | ||
| Powders for other routes of administration | 481 | ||
| Powders for inhalation | 481 | ||
| Nasal powders | 481 | ||
| Powders for external use | 481 | ||
| Powders for cutaneous application (topical powders) | 481 | ||
| Dusting powders | 481 | ||
| Ear powders | 482 | ||
| Preparations requiring further treatment at the time of dispensing | 482 | ||
| Powders and granules for solution or suspension | 482 | ||
| Powders and granules for syrups | 482 | ||
| Antibiotic syrups. | 482 | ||
| Powders for oral drops | 482 | ||
| Powders for injection | 483 | ||
| Pharmacopoeial tests | 483 | ||
| Uniformity of dosage units. | 483 | ||
| Uniformity of mass. | 483 | ||
| Uniformity of content. | 483 | ||
| Uniformity of mass of delivered doses from multidose containers. | 483 | ||
| Drug release. | 483 | ||
| Sterility. | 483 | ||
| Granules used as an intermediate in tablet manufacture | 483 | ||
| Pharmaceutical technology of granule production | 483 | ||
| Pharmaceutical granulation processes | 483 | ||
| Dry granulation | 484 | ||
| Wet granulation (involving wet massing) | 484 | ||
| Effect of the granulation method on granule structure | 484 | ||
| Granulation mechanisms | 484 | ||
| Particle bonding mechanisms | 484 | ||
| Adhesion and cohesion forces in immobile films | 485 | ||
| Interfacial forces in mobile liquid films | 485 | ||
| Solid bridges | 486 | ||
| Partial melting. | 486 | ||
| Hardening binders. | 486 | ||
| Crystallization of dissolved substances. | 486 | ||
| Attractive forces between solid particles | 486 | ||
| Mechanisms of granule formation | 486 | ||
| Nucleation | 486 | ||
| Transition | 487 | ||
| Ball growth | 487 | ||
| Coalescence. | 487 | ||
| Breakage. | 487 | ||
| Abrasion transfer. | 487 | ||
| Layering. | 487 | ||
| Pharmaceutical granulation equipment and processes | 487 | ||
| Wet granulators | 487 | ||
| Shear granulators | 488 | ||
| High-speed mixer/granulators | 488 | ||
| Fluidized-bed granulators | 489 | ||
| Advantages of fluidized-bed granulation. | 490 | ||
| Disadvantages of fluidized-bed granulation. | 490 | ||
| Spray-dryers | 490 | ||
| Spheronizers/pelletizers | 491 | ||
| Extrusion–spheronization | 491 | ||
| Applications of extrusion–spheronization | 491 | ||
| Controlled drug release. | 491 | ||
| Processing. | 492 | ||
| Desirable properties of pellets | 492 | ||
| Process | 492 | ||
| Dry mixing of ingredients. | 492 | ||
| Wet massing. | 492 | ||
| Extrusion. | 492 | ||
| Spheronization. | 493 | ||
| Drying. | 493 | ||
| Screening (optional). | 493 | ||
| Formulation variables | 493 | ||
| Summary | 493 | ||
| Rotorgranulation | 494 | ||
| Melt granulation | 494 | ||
| Introduction | 494 | ||
| Hot-melt binders | 495 | ||
| Hot-melt processes | 495 | ||
| Advantages and limitations | 495 | ||
| Dry granulators | 495 | ||
| Slugging | 496 | ||
| Roller compaction | 496 | ||
| Advantages of the roller compaction process | 496 | ||
| Bibliography | 497 | ||
| 29 Drying | 498 | ||
| Chapter contents | 498 | ||
| Key points | 498 | ||
| Introduction | 498 | ||
| Drying of wet solids | 499 | ||
| Fundamental properties and interrelationships | 499 | ||
| Moisture content of wet solids | 499 | ||
| Total moisture content | 499 | ||
| Unbound water. | 499 | ||
| Equilibrium moisture content | 499 | ||
| Bound water. | 500 | ||
| Moisture content of air | 500 | ||
| Relative humidity of air | 500 | ||
| Relationship between equilibrium moisture content, relative humidity and the nature of the solid | 501 | ||
| Loss of water from wet solids | 501 | ||
| Types of drying method | 502 | ||
| Choice of drying method | 502 | ||
| Dryers in the pharmaceutical industry | 502 | ||
| Convective drying of wet solids | 502 | ||
| Dynamic convective dryers | 502 | ||
| Fluidized-bed dryer | 502 | ||
| Advantages of fluidized-bed drying | 503 | ||
| Disadvantages of fluidized-bed drying | 504 | ||
| Conductive drying of wet solids | 504 | ||
| Vacuum oven | 504 | ||
| Radiation drying of wet solids | 505 | ||
| Radiant heat transmission | 505 | ||
| Use of microwave radiation | 505 | ||
| Generation and action of microwaves | 505 | ||
| Microwave dryers for granulates | 505 | ||
| Advantages of microwave drying | 506 | ||
| Disadvantages of microwave drying | 506 | ||
| Drying of solutions and suspensions | 506 | ||
| Spray-drying | 506 | ||
| Atomization | 506 | ||
| Pressure nozzle atomization. | 507 | ||
| Two-fluid nozzle atomization. | 507 | ||
| Centrifugal atomization. | 507 | ||
| Ultrasonic nozzles. | 508 | ||
| Droplet drying and particle formation | 508 | ||
| Collection of dried product | 508 | ||
| Spray-dried product | 508 | ||
| Nano spray-dryer | 508 | ||
| Advantages of the spray-drying process | 509 | ||
| Disadvantages of the spray-drying process | 509 | ||
| Pharmaceutical applications of spray-drying | 509 | ||
| Direct compressibility. | 509 | ||
| Enhancement of the bioavailability of poorly water-soluble drugs. | 510 | ||
| Modified release and taste masking. | 510 | ||
| Dry powders for inhalation. | 510 | ||
| Aseptic production with spray-drying. | 510 | ||
| Fluidized spray-dryer | 510 | ||
| Freeze-drying (lyophilization) | 510 | ||
| The phase diagram for water | 510 | ||
| Application of the phase diagram for water to freeze-drying | 511 | ||
| Stages of the freeze-drying process | 511 | ||
| Freezing stage | 511 | ||
| Shell freezing. | 512 | ||
| Centrifugal evaporative freezing. | 512 | ||
| Vacuum application stage | 512 | ||
| Sublimation stage | 512 | ||
| Primary drying. | 512 | ||
| Heat transfer. | 512 | ||
| Vapour removal. | 512 | ||
| Rate of drying. | 513 | ||
| Secondary drying | 513 | ||
| Packaging | 513 | ||
| Spray–freeze-drying | 513 | ||
| Advantages of freeze-drying | 513 | ||
| Disadvantages of freeze-drying | 513 | ||
| Pharmaceutical applications of freeze-drying | 514 | ||
| Freeze-dried tablets. | 514 | ||
| Stabilization of novel drug delivery systems. | 514 | ||
| Solute migration during drying | 514 | ||
| Intergranular migration | 514 | ||
| Intragranular migration | 514 | ||
| Consequences of solute migration | 514 | ||
| Loss of active drug | 514 | ||
| Mottling of coloured tablets | 515 | ||
| Migration of soluble binders | 515 | ||
| Influence of formulation factors on solute migration | 515 | ||
| Nature of the substrate | 515 | ||
| Viscosity of granulating fluid | 515 | ||
| Influence of process factors on solute migration | 516 | ||
| Drying method | 516 | ||
| Initial moisture content | 516 | ||
| Some practical means of minimizing solute migration | 516 | ||
| Bibliography | 516 | ||
| 30 Tablets and compaction | 517 | ||
| Chapter contents | 517 | ||
| Key points | 517 | ||
| Introduction | 518 | ||
| Quality attributes of tablets | 519 | ||
| Tablet manufacturing | 519 | ||
| Stages in tablet formation | 519 | ||
| Die filling | 519 | ||
| Tablet formation | 519 | ||
| Tablet ejection | 519 | ||
| Tablet presses | 520 | ||
| Single-punch press (eccentric press) | 520 | ||
| Rotary press | 520 | ||
| Computerized presses | 521 | ||
| Instrumentation of tablet presses | 521 | ||
| Tablet tooling | 523 | ||
| Technical problems during tableting | 523 | ||
| Tablet production via granulation | 524 | ||
| Rationale for granulating powders before tableting | 524 | ||
| Granulation by convective mixing | 524 | ||
| Alternative granulation procedures | 525 | ||
| Tablet production by direct compaction | 525 | ||
| Tablet excipients | 526 | ||
| Filler (or diluent) | 526 | ||
| Matrix former | 527 | ||
| Disintegrant | 527 | ||
| Dissolution enhancer | 529 | ||
| Absorption enhancer | 530 | ||
| Binder | 530 | ||
| Glidant | 530 | ||
| Lubricant | 530 | ||
| Antiadherent | 532 | ||
| Sorbent | 532 | ||
| Flavour | 532 | ||
| Colourant | 532 | ||
| Tablet types | 533 | ||
| Classification of tablets | 533 | ||
| Disintegrating tablets | 533 | ||
| Chewable tablets | 535 | ||
| Effervescent tablets | 535 | ||
| Compressed lozenges | 536 | ||
| Sublingual tablets and buccal tablets | 536 | ||
| Prolonged-release and pulsatile-release tablets | 536 | ||
| Classification | 536 | ||
| Diffusion-controlled release systems | 537 | ||
| Reservoir systems. | 537 | ||
| Matrix systems. | 538 | ||
| Dissolution-controlled release systems | 538 | ||
| Erosion-controlled release systems | 539 | ||
| Osmosis-controlled release systems | 540 | ||
| Tablet testing | 540 | ||
| Test methods | 540 | ||
| Uniformity of content of active ingredient | 540 | ||
| Disintegration | 541 | ||
| Dissolution | 542 | ||
| Stirred-vessel methods | 542 | ||
| Continuous-flow methods | 542 | ||
| Mechanical strength | 543 | ||
| Attrition resistance methods | 544 | ||
| Fracture resistance methods | 545 | ||
| Fundamental aspects of the compression of powders | 546 | ||
| Mechanisms of compression of particles | 546 | ||
| Evaluation of compression behaviour | 547 | ||
| Procedures | 547 | ||
| Inspection of tablets | 548 | ||
| Pore structure and specific surface area of tablets | 548 | ||
| Force–displacement profiles | 549 | ||
| Tablet volume–applied pressure profiles | 550 | ||
| Heckel equation | 550 | ||
| Strain rate sensitivity | 550 | ||
| Kawakita equation | 551 | ||
| Powder and particle scale modelling | 551 | ||
| Evaluation of die wall friction during compression | 552 | ||
| Fundamental aspects of the compaction of powders | 554 | ||
| Bonding in tablets | 554 | ||
| Compactability of powders and the strength of tablets | 555 | ||
| Postcompaction tablet strength changes | 558 | ||
| Relationships between material properties and tablet strength | 558 | ||
| Factors of importance for powder compactability | 558 | ||
| Compaction of solid particles | 558 | ||
| Compaction of granules | 560 | ||
| Compaction of binary mixtures | 561 | ||
| References | 562 | ||
| Bibliography | 563 | ||
| 31 Modified-release oral drug delivery | 564 | ||
| Chapter contents | 564 | ||
| Key points | 564 | ||
| Modified-release oral drug delivery | 564 | ||
| What modified-release drug delivery means for the patient | 565 | ||
| Keeping the drug in the therapeutic range. | 565 | ||
| Maintaining drug levels overnight. | 566 | ||
| Chronotherapy. | 567 | ||
| Reducing side effects. | 567 | ||
| Improving patient adherence. | 567 | ||
| Treatment of local areas in the gastrointestinal tract. | 567 | ||
| What modified-release drug delivery means for health care professionals and the pharmaceutical industry | 567 | ||
| Provides physician, pharmacist and patient choice. | 567 | ||
| Product life extension. | 567 | ||
| Higher development costs. | 567 | ||
| Cost savings for health care providers. | 567 | ||
| Sites of action for modified-release dosage forms and biopharmaceutical considerations | 567 | ||
| The gastrointestinal tract | 567 | ||
| pH | 567 | ||
| Transit time | 568 | ||
| Fluid | 568 | ||
| Designing a modified-release formulation: factors to consider | 569 | ||
| Single-unit dosage form or multiple-unit dosage form | 569 | ||
| Matrix formulation or coated formulation | 569 | ||
| Type of release rate | 570 | ||
| Extended release | 570 | ||
| Hydrophilic matrix systems | 570 | ||
| Insoluble polymer matrix | 575 | ||
| Membrane-controlled systems | 575 | ||
| Osmotic systems | 576 | ||
| Gastroretention | 576 | ||
| Delayed release | 576 | ||
| Gastro-resistant coatings | 576 | ||
| Colonic drug delivery | 578 | ||
| 3D printing | 578 | ||
| Conclusions | 579 | ||
| References | 579 | ||
| Bibliography | 579 | ||
| 32 Coating of tablets and multiparticulates | 580 | ||
| Chapter contents | 580 | ||
| Key Points | 580 | ||
| Introduction | 581 | ||
| Definition of coating | 581 | ||
| Reasons for coating | 581 | ||
| Types of coating processes | 581 | ||
| Film coating | 582 | ||
| Types of film coatings | 582 | ||
| Description of the film-coating process | 582 | ||
| Process equipment | 583 | ||
| Basic process requirements for film coating | 584 | ||
| Film-coating formulations | 584 | ||
| Film-coating polymers | 584 | ||
| Solubility | 584 | ||
| Viscosity | 585 | ||
| Permeability | 585 | ||
| Mechanical properties | 585 | ||
| Types of film-coating polymers: immediate-release coatings | 585 | ||
| Cellulose derivatives | 585 | ||
| Vinyl derivatives | 586 | ||
| Aminoalkyl methacrylate copolymers | 586 | ||
| Types of film-coating polymers: modified-release coatings | 586 | ||
| Cellulose derivatives | 586 | ||
| Methylmethacrylate copolymers | 586 | ||
| Methacrylic acid copolymers | 586 | ||
| Phthalate esters | 587 | ||
| Plasticizers | 587 | ||
| Colourants | 587 | ||
| Solvents | 587 | ||
| Aqueous polymer dispersions | 588 | ||
| Ideal characteristics of film-coated products | 588 | ||
| Film-coating defects | 588 | ||
| Sugar coating | 589 | ||
| Types of sugar coatings | 589 | ||
| Ideal characteristics of sugar-coated tablets | 589 | ||
| Process equipment | 589 | ||
| Description of the sugar-coating process | 590 | ||
| Sealing | 590 | ||
| Subcoating | 590 | ||
| Smoothing | 590 | ||
| Colouring | 591 | ||
| Polishing | 591 | ||
| Printing | 591 | ||
| Sugar-coating defects | 591 | ||
| Compression coating | 591 | ||
| Description of the compression-coating process | 591 | ||
| Types of compression coatings | 592 | ||
| Coating of tablets | 592 | ||
| Overview of coating of tablets | 592 | ||
| Standards for coated tablets | 592 | ||
| Coating of multiparticulates | 592 | ||
| Types of multiparticulates | 593 | ||
| Drug crystals. | 593 | ||
| Irregular granules. | 593 | ||
| Spheronized granules. | 593 | ||
| Drug-loaded nonpareils. | 593 | ||
| Mini tablets. | 593 | ||
| Mechanisms of drug release from multiparticulates | 594 | ||
| Diffusion | 594 | ||
| Osmosis | 594 | ||
| Dialysis | 594 | ||
| Erosion | 594 | ||
| Processes for coating multiparticulates | 595 | ||
| Hot-melt coating | 595 | ||
| References | 595 | ||
| Bibliography | 596 | ||
| 33 Hard capsules | 597 | ||
| Chapter contents | 597 | ||
| Key points | 597 | ||
| Introduction | 597 | ||
| Raw materials | 598 | ||
| Gelatin and hypromellose | 598 | ||
| Colourants | 599 | ||
| Process aids | 599 | ||
| Manufacture | 599 | ||
| Empty capsule properties | 601 | ||
| Capsule filling | 601 | ||
| Capsule sizes | 601 | ||
| Capsule shell filling | 602 | ||
| Capsule-filling machines | 602 | ||
| Filling of capsules with powder formulations | 602 | ||
| Bench-scale filling | 602 | ||
| Industrial-scale filling | 603 | ||
| Dependent dosing systems | 603 | ||
| The auger. | 603 | ||
| Independent dosing systems | 603 | ||
| Dosator. | 603 | ||
| Dosing disc and tamping finger. | 604 | ||
| Instrumented capsule-filling machines and simulators | 604 | ||
| Filling of capsules with pellets | 604 | ||
| Filling of capsules with tablets | 605 | ||
| Filling of capsules with semisolids and liquids | 605 | ||
| Formulation | 605 | ||
| Powder formulation | 605 | ||
| Formulation for filling properties | 606 | ||
| Formulation for release of active ingredients | 606 | ||
| Formulation optimization | 608 | ||
| Formulation for position of release | 609 | ||
| References | 610 | ||
| Bibliography | 611 | ||
| 34 Soft capsules | 612 | ||
| Chapter contents | 612 | ||
| Key points | 612 | ||
| Introduction | 612 | ||
| Description of the soft gelatin capsule dosage form (softgels) | 613 | ||
| Rationale for the selection of softgels as a dosage form | 614 | ||
| Improved drug absorption characteristics | 615 | ||
| Increased rate of absorption | 615 | ||
| Increased bioavailability | 615 | ||
| Decreased plasma variability | 615 | ||
| Patient adherence and consumer preference | 616 | ||
| Safety for potent and cytotoxic drugs | 616 | ||
| Oils and low melting point drugs | 616 | ||
| Dose uniformity of low-dose drugs | 616 | ||
| Product stability | 616 | ||
| Manufacture of softgels | 617 | ||
| Formulation of softgels | 619 | ||
| Gelatin shell formulation | 619 | ||
| Gelatin | 619 | ||
| Plasticizers | 619 | ||
| Water | 619 | ||
| Colourants/opacifiers | 620 | ||
| Properties of soft gelatin shells | 620 | ||
| Oxygen permeability | 620 | ||
| Residual water content | 620 | ||
| Formulation of softgel fill materials | 621 | ||
| Types of softgel fill matrices | 621 | ||
| Lipophilic liquids/oils | 621 | ||
| Hydrophilic liquids | 621 | ||
| Self-emulsifying drug delivery systems (SEDDS) | 621 | ||
| Lipolysis systems | 622 | ||
| Product quality considerations | 624 | ||
| Ingredient specifications | 624 | ||
| In-process testing | 624 | ||
| Finished product testing | 624 | ||
| References | 624 | ||
| 35 Dissolution testing of solid dosage forms | 626 | ||
| Chapter contents | 626 | ||
| Key points | 626 | ||
| The relevance of drug dissolution and dissolution testing | 626 | ||
| General requirements for in vitro dissolution testing | 627 | ||
| pH of the gastrointestinal luminal fluids | 628 | ||
| Composition of the gastrointestinal luminal fluids | 628 | ||
| As a quality control tool | 629 | ||
| Predictive dissolution testing | 629 | ||
| Dissolution testing | 629 | ||
| Type of dissolution apparatus used. | 629 | ||
| Volume and composition of the dissolution medium. | 629 | ||
| Hydrodynamics. | 629 | ||
| Number of units to be tested. | 629 | ||
| The design of suitable dissolution tests; quality control versus predictive dissolution testing | 630 | ||
| Dissolution testing for quality control | 630 | ||
| Compendial dissolution apparatus | 630 | ||
| Basket apparatus (USP Apparatus 1) | 632 | ||
| Paddle apparatus (USP Apparatus 2) | 632 | ||
| Reciprocating cylinder (USP Apparatus 3) | 632 | ||
| Flow-through cell (USP Apparatus 4) | 632 | ||
| Volume and composition of the dissolution medium | 632 | ||
| Dissolution limits | 633 | ||
| Predictive dissolution testing | 633 | ||
| Biorelevant dissolution media | 634 | ||
| Milk and nutritional liquid products | 634 | ||
| Simulated gastric and intestinal fluids | 634 | ||
| Bicarbonate buffers | 634 | ||
| Noncompendial apparatus | 635 | ||
| Stress test apparatus | 635 | ||
| Dynamic Gastric Model | 636 | ||
| Simulator of the gastrointestinal tract (TIM-1) | 636 | ||
| Conclusions | 636 | ||
| References | 637 | ||
| Bibliography | 637 | ||
| 36 Parenteral drug delivery | 638 | ||
| Chapter contents | 638 | ||
| Key Points | 638 | ||
| Introduction | 639 | ||
| Reasons for choosing parenteral administration | 639 | ||
| Routes of parenteral administration | 639 | ||
| Intravenous injections and infusions | 640 | ||
| Intra-arterial and intracardiac injections | 640 | ||
| Intradermal injections | 640 | ||
| Subcutaneous injections | 641 | ||
| Intramuscular injections | 641 | ||
| Intraspinal injections | 641 | ||
| Intra-articular injections | 642 | ||
| Ophthalmic injections | 642 | ||
| Pharmacopoeial requirements | 642 | ||
| General requirements | 642 | ||
| Sterility | 642 | ||
| Excipients | 642 | ||
| Containers | 642 | ||
| Endotoxins and pyrogens | 642 | ||
| Particulates | 643 | ||
| Category-specific requirements | 643 | ||
| Injections | 643 | ||
| Infusions | 643 | ||
| Concentrates for injection or infusions | 644 | ||
| Powders for injection or infusion | 644 | ||
| Absorption from injection sites | 644 | ||
| Factors affecting absorption from the injection site | 644 | ||
| Formulation factors | 644 | ||
| Excipients | 646 | ||
| Vehicles for injections | 646 | ||
| Preservatives | 646 | ||
| Antioxidants | 647 | ||
| pH adjustment and buffers | 647 | ||
| Tonicity-adjusting agents | 648 | ||
| Isotonicity calculation based on freezing point depression | 648 | ||
| Suspending agents | 648 | ||
| Containers | 648 | ||
| Ampoules | 649 | ||
| Vials | 650 | ||
| Infusion bags and bottles | 651 | ||
| Bibliography | 652 | ||
| 37 Pulmonary drug delivery | 653 | ||
| Chapter contents | 653 | ||
| Key points | 653 | ||
| Inhaled drug delivery | 653 | ||
| Lung anatomy | 654 | ||
| Inhalation aerosols and the importance of particle size distribution | 654 | ||
| Influence of environmental humidity on particle size | 655 | ||
| Particle deposition in the airways | 655 | ||
| Inertial impaction | 655 | ||
| Gravitational sedimentation | 656 | ||
| Brownian diffusion | 656 | ||
| Other mechanisms of deposition | 656 | ||
| Effect of particle size on deposition mechanism | 656 | ||
| Breathing patterns | 656 | ||
| Clearance of inhaled particles and drug absorption | 656 | ||
| Formulating and delivering therapeutic inhalation aerosols | 657 | ||
| Pressurized metered-dose inhalers | 657 | ||
| Containers | 657 | ||
| Propellants | 657 | ||
| Metering valve | 658 | ||
| Formulating pMDIs | 659 | ||
| Filling pMDI canisters | 659 | ||
| Advantages and disadvantages of pMDIs | 659 | ||
| Spacers, valved-holding chambers and breath-actuated metered-dose inhalers | 660 | ||
| Dry powder inhalers | 660 | ||
| Formulating DPIs | 660 | ||
| Unit-dose devices with drug in hard gelatin capsules | 661 | ||
| Multidose devices with drug preloaded in the inhaler | 661 | ||
| Breath-assisted devices | 662 | ||
| Nebulizers | 662 | ||
| Jet nebulizers | 662 | ||
| Ultrasonic nebulizers | 664 | ||
| Mesh nebulizers | 664 | ||
| Formulating nebulizer fluids | 664 | ||
| Physicochemical properties of nebulizer fluids | 665 | ||
| Temperature effects during nebulization | 665 | ||
| Duration of nebulization and residual volume | 665 | ||
| Variability between nebulizers | 666 | ||
| Novel delivery devices | 666 | ||
| Methods of aerosol size analysis | 666 | ||
| Cascade impactors and impingers | 667 | ||
| Reference | 670 | ||
| Bibliography | 670 | ||
| 38 Nasal drug delivery | 671 | ||
| Chapter contents | 671 | ||
| Key points | 671 | ||
| Introduction | 671 | ||
| Anatomy and physiology | 674 | ||
| Drug delivery | 674 | ||
| Local delivery | 676 | ||
| Systemic delivery | 676 | ||
| Anatomical and physiological factors affecting intranasal systemic delivery | 676 | ||
| Mucociliary clearance | 676 | ||
| Barrier provided by mucus | 676 | ||
| Enzymatic activity | 678 | ||
| Epithelial barrier – efflux transporters | 678 | ||
| Physicochemical properties of drugs affecting intranasal systemic delivery | 678 | ||
| Solubility | 678 | ||
| Lipophilicity/hydrophilicity and molecular size | 679 | ||
| Degree of ionization | 679 | ||
| Formulation factors affecting intranasal systemic delivery | 679 | ||
| Increasing aqueous solubility | 679 | ||
| pH of the formulation | 680 | ||
| Use of enzyme inhibitors | 680 | ||
| Increasing nasal residence time | 680 | ||
| Enhancing the permeability of the nasal epithelium | 682 | ||
| Patient factors affecting intranasal systemic delivery | 684 | ||
| Patient adherence. | 684 | ||
| Disease. | 684 | ||
| Nasal vaccines | 685 | ||
| CNS delivery | 685 | ||
| Nasal delivery systems | 686 | ||
| Summary | 688 | ||
| Bibliography | 688 | ||
| 39 Ocular drug delivery | 690 | ||
| Chapter contents | 690 | ||
| Key points | 690 | ||
| Introduction | 691 | ||
| Anatomy and physiology of the eye | 691 | ||
| Layers of the eye | 691 | ||
| Chambers of the eye | 693 | ||
| Ocular drug delivery routes and elimination pathways | 693 | ||
| Some common ocular conditions and pharmacological interventions | 694 | ||
| Dry eye syndrome. | 694 | ||
| Cataract. | 694 | ||
| Glaucoma. | 694 | ||
| Age-related macular degeneration. | 694 | ||
| Endophthalmitis. | 694 | ||
| Topical ophthalmic preparations | 695 | ||
| Formulating ophthalmic preparations | 695 | ||
| Osmolality | 695 | ||
| Hydrogen ion concentration (pH) | 696 | ||
| Surface tension | 696 | ||
| Viscosity | 696 | ||
| Topical, liquid ophthalmic preparations | 697 | ||
| Solutions | 697 | ||
| Suspensions | 697 | ||
| Submicron emulsions | 698 | ||
| Topical, semisolid ophthalmic preparations | 698 | ||
| Ointments | 698 | ||
| Gels | 698 | ||
| Mucoadhesive systems | 699 | ||
| Ion-exchange resins | 700 | ||
| Barriers to topical ocular drug absorption | 700 | ||
| The corneal barrier | 700 | ||
| Noncorneal routes of absorption | 701 | ||
| Increasing drug solubility and absorption in topical ophthalmic preparations | 702 | ||
| Drug ionization, salts and esters | 702 | ||
| Cyclodextrins | 702 | ||
| Prodrugs | 702 | ||
| Sterility of ophthalmic preparations | 703 | ||
| Ocular drug pharmacokinetics | 704 | ||
| Drug half-life in the anterior chamber | 704 | ||
| Active transporters of the cornea | 704 | ||
| Blood–retinal barrier | 705 | ||
| Ocular metabolism | 705 | ||
| Targeting the posterior segment of the eye | 706 | ||
| Systemic drug delivery | 706 | ||
| Intraocular injections | 706 | ||
| Intraocular implants | 707 | ||
| Nonbiodegradable intraocular implants | 707 | ||
| Biodegradable intraocular implants | 709 | ||
| Periocular drug delivery routes | 711 | ||
| Intravitreal pharmacokinetics | 712 | ||
| Problems with traditional and new ocular drug delivery systems | 712 | ||
| Patient adherence and instillation of eye drops | 713 | ||
| References | 714 | ||
| Bibliography | 714 | ||
| 40 Topical and transdermal drug delivery | 715 | ||
| Chapter contents | 715 | ||
| Key points | 715 | ||
| Introduction | 715 | ||
| Terminology | 716 | ||
| Topical drug delivery. | 716 | ||
| Transdermal drug delivery. | 716 | ||
| Locally acting. | 716 | ||
| Regionally acting. | 716 | ||
| Permeant. | 716 | ||
| Permeation. | 716 | ||
| Penetration. | 716 | ||
| Diffusion. | 716 | ||
| Diffusivity. | 716 | ||
| Diffusion coefficient (D). | 716 | ||
| Permeability coefficient (kp). | 716 | ||
| Partition coefficient (P). | 716 | ||
| Partitioning. | 716 | ||
| Flux (J). | 716 | ||
| Lag time (L). | 716 | ||
| Vehicle. | 717 | ||
| Thermodynamic activity. | 717 | ||
| Skin structure and function | 717 | ||
| Structure of the skin | 717 | ||
| The subcutaneous layer | 717 | ||
| The dermis | 717 | ||
| The epidermis | 718 | ||
| The stratum corneum | 718 | ||
| The appendages | 718 | ||
| Transport through the skin | 718 | ||
| Permeant properties affecting permeation | 720 | ||
| Mathematics of skin permeation | 720 | ||
| Fick’s laws of diffusion | 721 | ||
| Experimental estimation of skin penetration | 721 | ||
| Experimental methods for studying transdermal drug delivery | 722 | ||
| In vivo experiments | 723 | ||
| In vitro diffusion cells | 723 | ||
| Selection of an appropriate membrane | 723 | ||
| Receptor solution | 725 | ||
| Temperature | 725 | ||
| Other factors | 725 | ||
| Transdermal and topical preparations | 725 | ||
| Formulation principles | 726 | ||
| Principle 1: select a suitable drug molecule. | 726 | ||
| Principle 2: release of the drug. | 726 | ||
| Principle 3: use thermodynamics. | 726 | ||
| Principle 4: alcohol can help. | 726 | ||
| Principle 5: occlusion increases delivery of most drugs. | 727 | ||
| Formulation options | 727 | ||
| Common formulation types | 728 | ||
| Liquid formulations | 728 | ||
| Semisolid formulations | 729 | ||
| Ointments | 729 | ||
| Absorption bases | 730 | ||
| Emulsifying bases | 730 | ||
| Water-soluble bases | 730 | ||
| Gels | 730 | ||
| Creams | 730 | ||
| Multiphase semisolid formulations | 731 | ||
| Solid formulations | 731 | ||
| Powders. | 731 | ||
| Topical sprays. | 731 | ||
| Dusting powders. | 731 | ||
| Patches. | 731 | ||
| Transdermal delivery patches | 731 | ||
| Designs of transdermal patches | 732 | ||
| Removable release liner. | 732 | ||
| Adhesive. | 732 | ||
| Backing layer. | 733 | ||
| Matrix/reservoir. | 733 | ||
| Rate-limiting membrane. | 733 | ||
| Other formulations | 733 | ||
| Liposomes. | 733 | ||
| Foams. | 734 | ||
| Solids or particulates. | 734 | ||
| Enhancement of transdermal and topical drug delivery | 734 | ||
| Formulation manipulation | 734 | ||
| Skin modification | 735 | ||
| External forces | 735 | ||
| Nail delivery | 737 | ||
| Bibliography | 738 | ||
| 41 Rectal and vaginal drug delivery | 739 | ||
| Chapter contents | 739 | ||
| Key points | 739 | ||
| Introduction | 740 | ||
| Rectal drug delivery | 740 | ||
| Anatomy and physiology of the rectum | 740 | ||
| Absorption of drugs from the rectum | 742 | ||
| Rectal dosage forms | 742 | ||
| Local action | 742 | ||
| Systemic action | 743 | ||
| Suppositories | 743 | ||
| Vehicle (suppository base) | 743 | ||
| Fatty vehicles | 744 | ||
| Water-soluble vehicles | 745 | ||
| Formulation considerations for suppositories | 746 | ||
| Properties of the suppository base | 746 | ||
| Drug properties | 746 | ||
| Drug solubility in rectal fluid. | 746 | ||
| Drug permeation ability in the rectal membrane. | 746 | ||
| Drug solubility in the vehicle. | 746 | ||
| Drug particle size. | 747 | ||
| Displacement value. | 747 | ||
| Additives | 747 | ||
| Viscosity-increasing (hardening) agents. | 747 | ||
| Deagglomerators. | 748 | ||
| Drug solubility enhancers. | 748 | ||
| Absorption (permeation) enhancers. | 748 | ||
| Antimicrobial preservatives. | 748 | ||
| Other rectal preparations | 748 | ||
| Rectal capsules and tablets | 748 | ||
| Rectal enemas | 748 | ||
| Powders and tablets for rectal solutions and suspensions | 749 | ||
| Semisolid rectal preparations | 749 | ||
| Rectal tampons | 749 | ||
| Recent advances in rectal dosage forms | 749 | ||
| Vaginal drug delivery | 749 | ||
| Anatomy and physiology of the vagina | 749 | ||
| Absorption of drugs from the vagina | 750 | ||
| Vaginal dosage forms | 750 | ||
| Local action. | 750 | ||
| Systemic action. | 751 | ||
| Pessaries | 751 | ||
| Vaginal suppositories. | 751 | ||
| Vaginal tablets. | 751 | ||
| Vaginal capsules. | 751 | ||
| Semisolid vaginal preparations | 751 | ||
| Vaginal films | 752 | ||
| Vaginal rings | 752 | ||
| Vaginal solutions, emulsions, foams and suspensions | 753 | ||
| Tablets for vaginal solutions and suspensions | 753 | ||
| Medicated vaginal tampons | 753 | ||
| Manufacture of rectal and vaginal dosage forms | 753 | ||
| Rectal and vaginal suppositories | 753 | ||
| Moulding | 753 | ||
| Compression | 753 | ||
| Vaginal films | 754 | ||
| Solvent casting | 754 | ||
| Hot-melt extrusion | 754 | ||
| Vaginal rings | 754 | ||
| Rectal and vaginal tablets | 754 | ||
| Other rectal and vaginal dosage forms | 754 | ||
| Quality control of rectal and vaginal dosage forms | 754 | ||
| Assessment of drug release from suppositories | 755 | ||
| In vitro testing considerations | 755 | ||
| In vivo testing considerations | 756 | ||
| Tests for vaginal irritation | 756 | ||
| References | 756 | ||
| Bibliography | 756 | ||
| 42 The formulation and manufacture of plant medicines | 758 | ||
| Chapter contents | 758 | ||
| Key points | 758 | ||
| Introduction | 758 | ||
| Plant-based products in medicinal use | 759 | ||
| Quality control of crude plant drugs | 759 | ||
| Production methods used to obtain plant-derived active constituents | 761 | ||
| Harvesting | 761 | ||
| Drying | 761 | ||
| Size reduction | 761 | ||
| Extraction of active constituents | 762 | ||
| Types of extracts | 762 | ||
| Extraction procedures | 762 | ||
| Removal of acellular products. | 762 | ||
| Distillation. | 763 | ||
| Maceration. | 763 | ||
| Percolation. | 763 | ||
| Countercurrent extraction. | 763 | ||
| Newer extraction techniques. | 763 | ||
| Choice of extraction technique | 764 | ||
| Concentration, purification and drying of extracts | 764 | ||
| Concentration of extracts | 764 | ||
| Purification of extracts | 764 | ||
| Drying of extracts | 764 | ||
| Formulation and manufacture of plant-based medicines | 765 | ||
| Active-constituent considerations | 765 | ||
| Purity of active constituent(s) | 765 | ||
| Variability of crude drug material | 765 | ||
| Finished-product considerations | 765 | ||
| Preparation of solid dosage forms | 765 | ||
| Preparation of liquid dosage forms | 766 | ||
| Newer delivery systems | 766 | ||
| Excipients | 766 | ||
| Preservatives. | 766 | ||
| Antioxidants. | 766 | ||
| Colouring materials. | 766 | ||
| Flavours. | 766 | ||
| Biotechnological production of plant products | 767 | ||
| Quality of finished products | 767 | ||
| Quality of formulated herbal products | 767 | ||
| Shelf life of formulated products | 767 | ||
| Bioequivalence of different formulations | 767 | ||
| Adverse effects and drug interactions | 767 | ||
| Synergy. | 767 | ||
| Drug interactions. | 768 | ||
| Summary | 768 | ||
| References | 768 | ||
| Bibliography | 768 | ||
| 43 Delivery of biopharmaceuticals | 769 | ||
| Chapter contents | 769 | ||
| Key points | 769 | ||
| Introduction | 769 | ||
| Protein and peptide drugs | 770 | ||
| Introduction | 770 | ||
| Production | 772 | ||
| Delivery issues | 773 | ||
| Delivery systems | 776 | ||
| Protein stabilization | 776 | ||
| Protein delivery | 776 | ||
| Antibody–drug conjugates | 777 | ||
| Peptide delivery | 777 | ||
| Vaccines | 778 | ||
| Introduction | 778 | ||
| Production | 779 | ||
| Delivery issues | 779 | ||
| Delivery systems | 779 | ||
| Nucleic acid drugs | 780 | ||
| Introduction | 780 | ||
| Production | 781 | ||
| Delivery issues | 781 | ||
| Delivery systems | 781 | ||
| Summary | 782 | ||
| References | 782 | ||
| Bibliography | 783 | ||
| 44 Pharmaceutical nanotechnology and nanomedicines | 784 | ||
| Chapter contents | 784 | ||
| Key points | 784 | ||
| Introduction | 784 | ||
| Applications of pharmaceutical nanotechnology | 786 | ||
| Polymer–drug conjugates | 786 | ||
| A water-soluble polymer backbone. | 787 | ||
| A linker group. | 787 | ||
| Drug. | 787 | ||
| Rationale for polymer conjugation | 787 | ||
| Increasing solubility | 787 | ||
| Enhancing bioavailability and plasma half-life | 787 | ||
| Protecting against degradation after administration | 788 | ||
| Reducing aggregation, immunogenicity and antigenicity | 788 | ||
| Promoting targeting to specific organs, tissue or cells | 788 | ||
| Continuous endothelial cells. | 789 | ||
| Fenestrated endothelial cells. | 789 | ||
| Sinusoidal endothelial cells. | 789 | ||
| Polymer–drug conjugates: case studies | 789 | ||
| OPAXIO® – a small-molecule conjugate. | 789 | ||
| Oncaspar® – a protein conjugate. | 789 | ||
| Antibodies and antibody-drug conjugates | 789 | ||
| Antibody therapies | 790 | ||
| Antibody conjugates | 790 | ||
| Dendrimers | 791 | ||
| Applications of dendrimers | 792 | ||
| Dendrimer systems: case studies | 793 | ||
| VivaGel® | 793 | ||
| Micelle systems | 793 | ||
| Polymeric micelles | 793 | ||
| Polymeric micelles: case studies | 794 | ||
| Estrasorb®. | 794 | ||
| Genexol®-PM. | 794 | ||
| Solid nanoparticles | 794 | ||
| Nanosized drug particles and drug nanocrystals | 794 | ||
| Solid polymeric nanoparticles | 794 | ||
| Solid-lipid nanoparticles | 795 | ||
| Protein nanoparticles | 795 | ||
| Targeting mechanisms of Abraxane® | 796 | ||
| Inorganic nanoparticles | 796 | ||
| Liposomes and bilayer vesicles | 796 | ||
| Small unilamellar vesicles. | 797 | ||
| Large unilamellar vesicles. | 797 | ||
| Multilamellar vesicles. | 797 | ||
| Multivesicular vesicles. | 797 | ||
| Clinical application of liposomes | 798 | ||
| The application of liposomes in cancer chemotherapy | 799 | ||
| The application of liposomes in the treatment of systemic fungal infections | 800 | ||
| Liposomal delivery of vaccines | 800 | ||
| Sustained drug release from liposomes | 800 | ||
| Formulation design considerations for liposomes | 800 | ||
| Choice of lipid | 800 | ||
| Cholesterol content | 801 | ||
| Surface characteristics | 801 | ||
| Drug characteristics | 801 | ||
| Microcapsules and microspheres | 802 | ||
| Ongoing developments | 802 | ||
| Bibliography | 803 | ||
| 45 Design and administration of medicines for paediatric and geriatric patients | 804 | ||
| Chapter contents | 804 | ||
| Key points | 804 | ||
| Human development, ageing and drug administration | 804 | ||
| Paediatric and geriatric populations | 805 | ||
| Swallowing oral dosage forms | 805 | ||
| The swallowing process | 805 | ||
| Paediatric populations | 805 | ||
| Geriatric populations | 806 | ||
| Assessment of swallowing ability | 807 | ||
| Helping patients with swallowing difficulties | 807 | ||
| Formulation design for paediatric and geriatric patients | 807 | ||
| Liquid peroral dosage forms | 807 | ||
| Paediatric considerations | 808 | ||
| Selection of appropriate excipients | 808 | ||
| Sweeteners and flavouring agents. | 808 | ||
| Sugar-free sweeteners. | 808 | ||
| Colouring agents. | 809 | ||
| Geriatric considerations | 809 | ||
| Other oral dosage forms | 810 | ||
| Nonperoral dosage forms | 810 | ||
| Parenteral routes | 810 | ||
| Pulmonary route | 811 | ||
| Nasal route | 812 | ||
| Delivery to and through the skin | 812 | ||
| Rectal route | 812 | ||
| Other routes of drug administration | 812 | ||
| Adaptation of existing dosage forms | 813 | ||
| Unlicensed products | 813 | ||
| Dosage form issues | 814 | ||
| Immediate-release film-coated tablets | 814 | ||
| Gastro-resistant (enteric) coated tablets | 814 | ||
| Modified-release products | 814 | ||
| Dosage form administration issues | 815 | ||
| Administering medicines via enteral feed tubes | 815 | ||
| The practice of tablet splitting | 816 | ||
| Mixing medicines with food and beverages | 816 | ||
| Future developments in the formulation of paediatric and geriatric medicines | 816 | ||
| Considerations for a patient-centric approach in formulation development | 816 | ||
| Summary | 817 | ||
| References | 818 | ||
| Bibliography | 819 | ||
| 6 Packaging and stability of pharmaceutical products | 820 | ||
| 46 Packaging | 820 | ||
| Chapter contents | 820 | ||
| Key points | 820 | ||
| Introduction | 820 | ||
| The pharmaceutical pack | 821 | ||
| Primary packs | 821 | ||
| Packaging for product stability | 821 | ||
| Packaging for tamper resistance, tamper evidence, child resistance and access by older people | 823 | ||
| Closures | 823 | ||
| Packaging materials | 824 | ||
| Glass | 824 | ||
| Glass is not totally inert | 824 | ||
| Pharmaceutical types of glass and containers | 826 | ||
| Type I glass and containers. | 826 | ||
| Type II glass and containers. | 826 | ||
| Type III glass and containers. | 826 | ||
| Plastics | 827 | ||
| Advantages and limitations of plastics | 827 | ||
| Plastic chemistry | 827 | ||
| Thermoplastic and thermosetting polymers | 827 | ||
| Process residues and additives in plastics | 830 | ||
| Rubbers and elastomers | 831 | ||
| Metal | 832 | ||
| Paper | 832 | ||
| Advantages and disadvantages of paper as a packaging material | 833 | ||
| Laminates | 833 | ||
| Packaging and regulatory bodies | 833 | ||
| Repackaging | 833 | ||
| Designing packaging for safe medicine use | 834 | ||
| References | 834 | ||
| Bibliography | 835 | ||
| 47 Chemical stability in dosage forms | 836 | ||
| Chapter contents | 836 | ||
| Key points | 836 | ||
| Introduction | 836 | ||
| Chemical degradation reactions | 837 | ||
| Hydrolysis | 837 | ||
| Oxidation | 838 | ||
| Dimerization and polymerization | 840 | ||
| Hofmann elimination | 840 | ||
| Isomeric change | 841 | ||
| Photodegradation | 843 | ||
| Chemical incompatibilities | 844 | ||
| Stability of proteins and peptides | 844 | ||
| Physical stability of proteins | 846 | ||
| Chemical aspects of protein stability | 846 | ||
| Oxidation of amino acid residues | 846 | ||
| Disulfide bond interchange | 847 | ||
| Hydrolysis of proteins | 847 | ||
| Deamidation | 847 | ||
| Racemization of amino acid residues | 847 | ||
| Chemical modification of protein stability | 848 | ||
| Bibliography | 849 | ||
| 48 Microbial contamination, spoilage and preservation of medicines | 850 | ||
| Chapter contents | 850 | ||
| Key points | 850 | ||
| The need to protect medicines against microbial spoilage | 851 | ||
| Products and materials vulnerable to spoilage | 852 | ||
| Sources and control of microbial contamination | 853 | ||
| Sources and types of contaminating organisms | 853 | ||
| Factors influencing the growth of spoilage organisms | 855 | ||
| Control of contamination and spoilage during manufacture | 856 | ||
| Selection and use of preservatives | 857 | ||
| Preservative interactions with formulation components and containers | 858 | ||
| References | 860 | ||
| 49 Product stability and stability testing | 862 | ||
| Chapter contents | 862 | ||
| Key Points | 862 | ||
| Introduction | 862 | ||
| Mechanisms of degradation | 863 | ||
| Chemical stability | 863 | ||
| Oxidation | 863 | ||
| Hydrolysis | 864 | ||
| Photochemical reactions | 865 | ||
| Formation of adducts and complexes | 866 | ||
| Isomerization and polymerization | 866 | ||
| Temperature | 866 | ||
| Corrosion | 867 | ||
| Physical stability | 867 | ||
| Appearance | 868 | ||
| Polymorphic form | 868 | ||
| Precipitation and particle size | 868 | ||
| Rheological properties | 868 | ||
| Water content | 868 | ||
| Acidity and alkalinity | 869 | ||
| Resistance to crushing, friability, disintegration and dissolution | 869 | ||
| Redispersibility and reconstitution | 869 | ||
| Functionality | 869 | ||
| Absorption, adsorption and leaching | 869 | ||
| Microbiological stability | 870 | ||
| Stability testing of pharmaceutical products | 870 | ||
| Types of stability studies | 870 | ||
| Preformulation studies | 870 | ||
| Binary mixes | 871 | ||
| Formulation and container development stability studies | 871 | ||
| Postauthorization stability studies | 872 | ||
| GMP and good distribution practice stability studies | 873 | ||
| Climatic zones | 873 | ||
| Mean kinetic temperature | 873 | ||
| Stability test conditions | 874 | ||
| Testing at accelerated and intermediate conditions | 875 | ||
| Long-term stability testing | 876 | ||
| Stability studies supporting marketing authorization submissions | 876 | ||
| Photostability testing | 878 | ||
| Stability specification | 878 | ||
| Analytical test procedures | 880 | ||
| Evaluation of stability data | 881 | ||
| Stability studies supporting clinical trials | 882 | ||
| Concluding comments | 883 | ||
| References | 883 | ||
| Bibliography | 884 | ||
| Index | 886 | ||
| A | 886 | ||
| B | 887 | ||
| C | 889 | ||
| D | 892 | ||
| E | 894 | ||
| F | 895 | ||
| G | 897 | ||
| H | 898 | ||
| I | 898 | ||
| J | 899 | ||
| K | 899 | ||
| L | 900 | ||
| M | 900 | ||
| N | 903 | ||
| O | 904 | ||
| P | 905 | ||
| Q | 909 | ||
| R | 909 | ||
| S | 910 | ||
| T | 915 | ||
| U | 917 | ||
| V | 917 | ||
| W | 918 | ||
| X | 918 | ||
| Y | 918 | ||
| Z | 918 | ||
| IBC_Clinical Key ad | IBC1 |