Preface ........................................................ xv
Acknowledgements ............................................... xv
About the authors ............................................. xix
Introduction
1 Solids
1.1 Crystal structure ....................................... 8
1.2 Crystal form ........................................... 10
1.2.1 Crystallisation and factors affecting crystal
form ............................................ 11
1.3 Polymorphism ........................................... 13
1.3.1 Pharmaceutical implications of polymorphism ..... 16
1.4 Crystal hydrates ....................................... 19
1.4.1 Pharmaceutical consequences of solvate
formation ....................................... 20
1.5 Dissolution of solid drugs ............................. 22
1.6 Biopharmaceutical importance of particle size .......... 23
1.7 Wetting of powders ..................................... 26
1.7.1 Contact angle and wettability of solid
surfaces ........................................ 27
1.7.2 Wettability of powders .......................... 27
1.8 Solid dispersions ...................................... 28
1.8.1 Eutectics and drug identification ............... 30
Summary ..................................................... 31
References .................................................. 32
2 Gases and volatile agents
2.1 Pressure units ......................................... 36
2.2 Ideal and nonideal gases ............................... 36
2.3 Vapour pressure ........................................ 37
2.3.1 Vapour pressure and solution composition:
Raoult's law .................................... 37
2.3.2 Variation of vapour pressure with temperature:
Clausius-Clapeyron equation ..................... 40
2.3.3 Vapour pressure lowering ........................ 43
2.4 Solubility of gases in liquids ......................... 46
2.4.1 Effect of temperature on solubility ............. 46
2.4.2 Effect of pressure on solubility ................ 46
2.4.3 The solubility of volatile anaesthetics in
oil ............................................. 48
2.5 The solubility of gases in blood and tissues ........... 49
2.5.1 The solubility of oxygen in the blood ........... 49
2.5.2 The solubility of anaesthetic gases in blood
and tissues ..................................... 50
Summary ..................................................... 53
References .................................................. 54
3 Physicochemical properties of drugs in solution
3.1 Concentration units .................................... 56
3.1.1 Weight concentration ............................ 56
3.1.2 Molarity and molality ........................... 56
3.1.3 Milliequivalents ................................ 56
3.1.4 Mole fraction ................................... 57
3.2 Thermodynamics - a brief introduction .................. 57
3.2.1 Energy .......................................... 57
3.2.2 Enthalpy ........................................ 58
3.2.3 Entropy ......................................... 58
3.2.4 Free energy ..................................... 60
3.3 Activity and chemical potential ........................ 62
3.3.1 Activity and standard states .................... 62
3.3.2 Activity of ionised drugs ....................... 63
3.3.3 Solvent activity ................................ 65
3.3.4 Chemical potential .............................. 66
3.4 Osmotic properties of drug solutions ................... 69
3.4.1 Osmotic pressure ................................ 69
3.4.2 Osmolality and osmolarity ....................... 69
3.4.3 Clinical relevance of osmotic effects ........... 70
3.4.4 Preparation of isotonic solution ................ 73
3.5 lonisation of drugs in solution ........................ 75
3.5.1 Dissociation of weakly acidic and basic drugs
and their salts ................................. 75
3.5.2 The effect of pH on the ionisation of weakly
acidic or basic and their salts ................. 77
3.5.3 Ionisation of amphoteric drugs .................. 82
3.5.4 Ionisation of polyprotic drugs .................. 83
3.5.5 Microdissociation constants ..................... 84
3.5.6 pKα values of proteins .......................... 85
3.5.7 Calculation of the pH of drug solutions ......... 85
3.5.8 Preparation of buffer solutions ................. 87
3.6 Diffusion of drugs in solution ......................... 89
Summary ..................................................... 90
References .................................................. 91
4 Drug stability
4.1 The chemical decomposition of drugs .................... 94
4.1.1 Hydrolysis ...................................... 94
4.1.2 Oxidation ....................................... 95
4.1.3 Isomerisation ................................... 98
4.1.4 Photochemical decomposition ..................... 99
4.1.5 Polymerisation ................................. 102
4.2 Kinetics of chemical decomposition in solution ........ 102
4.2.1 Classifying reactions: the order of reaction ... 103
4.2.2 Zero-order reactions ........................... 104
4.2.3 First-order reactions .......................... 104
4.2.4 Second-order reactions ......................... 106
4.2.5 Third-order reactions .......................... 106
4.2.6 Determination of the order of reaction ......... 106
4.2.7 Complex reactions .............................. 107
4.3 Solid dosage forms: kinetics of chemical
decomposition ......................................... 110
4.4 Factors influencing drug stability .................... 113
4.4.1 Liquid dosage forms ............................ 113
4.4.2 Semisolid dosage forms ......................... 123
4.4.3 Solid dosage forms ............................. 123
4.5 Stability testing and prediction of shelf-life ........ 127
4.5.1 Effect of temperature on stability ............. 128
4.5.2 Other environmental factors affecting
stability ...................................... 133
4.5.3 Protocol for stability testing ................. 134
Summary .................................................... 136
References ................................................. 137
5 The solubility of drugs
5.1 Definitions ........................................... 140
5.1.1 Expressions of solubility ...................... 140
5.2 Factors influencing solubility ........................ 141
5.2.1 Structural features and aqueous solubility ..... 142
5.2.2 Hydration and solvation ........................ 146
5.2.3 The effect of simple additives on solubility ... 149
5.2.4 The effect of pH on the solubility of
ionisable drugs ................................ 150
5.3 Measurement of solubility ............................. 155
5.4 The solubility parameter .............................. 156
5.4.1 Solubility parameters and biological
processes ...................................... 157
5.5 Solubility in mixed solvents .......................... 157
5.6 Cyclodextrins as solubilising agents .................. 158
5.7 Solubility problems in formulation .................... 160
5.7.1 Mixtures of acidic and basic compounds ......... 160
5.7.2 Choice of drug salt to optimise solubility ..... 161
5.7.3 Drug solubility and biological activity ........ 162
5.8 Partitioning .......................................... 164
5.8.1 Theoretical background ......................... 164
5.8.2 Free energies of transfer ...................... 166
5.8.3 Octanol as a nonaqueous phase .................. 166
5.9 Biological activity and partition coefficients:
thermodynamic activity and Ferguson's principle ....... 166
5.10 Using log P ........................................... 168
5.10.1 The relationship between lipophilicity and
behaviour of tetracyclines ..................... 168
5.10.2 Sorption ....................................... 171
5.10.3 A chromatographic model for the biophase ....... 174
5.10.4 Calculating log P from molecular structures .... 174
5.10.5 Drug distribution into human milk .............. 174
Summary .................................................... 175
References ................................................. 176
6 Surfactants ................................................ 177
6.1 Amphipathic compounds ................................. 178
6.2 Surface and interfacial properties of surfactants ..... 179
6.2.1 Effects of amphiphiles on surface and
interfacial tension ............................ 179
6.2.2 Change of surface tension with surfactant
concentration - the critical micelle
concentration .................................. 180
6.2.3 Gibbs adsorption equation ...................... 180
6.2.4 The influence of the surfactant structure on
surface activity ............................... 182
6.2.5 Surface activity of drugs ...................... 183
6.2.6 Insoluble monolayers ........................... 185
6.2.7 Pharmaceutical applications of surface film
studies ........................................ 190
6.2.8 Adsorption at the solid/liquid interface ....... 194
6.3 Micellisation ......................................... 201
6.3.1 Water structure and hydrophobic bonding ........ 202
6.3.2 Theories of micelle formation .................. 203
6.3.3 Micellar structure ............................. 204
6.3.4 Factors affecting the critical micelle
concentration and micellar size ................ 207
6.4 Liquid crystals and surfactant vesicles ............... 210
6.4.1 Liquid crystals ................................ 210
6.4.2 Liposomes, niosomes and surfactant vesicles .... 215
6.5 Properties of some commonly used surfactants .......... 216
6.5.1 Anionic surfactants ............................ 216
6.5.2 Cationic surfactants ........................... 216
6.5.3 Nonionic surfactants ........................... 217
6.6 Solubilisation ........................................ 220
6.6.1 Determination of maximum additive
concentration .................................. 220
6.6.2 Location of the solubilisate ................... 221
6.6.3 Factors affecting solubilisation ............... 222
6.6.4 Pharmaceutical applications of
solubilisation ................................. 225
Summary .................................................... 227
References ................................................. 228
7 Emulsions, suspensions and other disperse systems
7.1 Classification of colloids ............................ 230
7.2 Colloid stability ..................................... 231
7.2.1 Forces of interaction between colloidal
particles ...................................... 231
7.2.2 Repulsion between hydrated surfaces ............ 235
7.3 Emulsions ............................................. 237
7.3.1 Stability of o/w and w/o emulsions ............. 237
7.3.2 HLB system ..................................... 239
7.3.3 Multiple emulsions ............................. 242
7.3.4 Microemulsions ................................. 245
7.3.5 Structured (semisolid) emulsions ............... 247
7.3.6 Biopharmaceutical aspects of emulsions ......... 249
7.3.7 Preservative availability in emulsified
systems ........................................ 249
7.3.8 Mass transport in oil-in-water emulsions ....... 250
7.3.9 Intravenous fat emulsions ...................... 251
7.3.10 The rheology of emulsions ...................... 253
7.4 Suspensions ........................................... 254
7.4.1 Stability of suspensions ....................... 255
7.4.2 Aspects of suspension stability ................ 255
7.4.3 Extemporaneous suspensions ..................... 259
7.4.4 Suspension rheology ............................ 260
7.4.5 Nonaqueous suspensions ......................... 261
7.4.6 Adhesion of suspension particles to
containers: immersional, spreading and
adhesional wetting ............................. 262
7.5 Applications of colloid stability theory to other
systems ............................................... 265
7.5.1 Cell-cell interactions ......................... 265
7.5.2 Adsorption of microbial cells to surfaces ...... 266
7.5.3 Blood as a colloidal system .................... 267
7.6 Foams and defoamers ................................... 269
7.6.1 Clinical considerations ........................ 271
Summary .................................................... 271
References ................................................. 272
8 Polymers and macromolecules ................................ 273
8.1 Pharmaceutical polymers ............................... 274
8.1.1 Definitions .................................... 274
8.1.2 Polydispersity ................................. 276
8.1.3 Polymer mixtures or blends ..................... 278
8.1.4 Solubility ..................................... 281
8.2 Water-soluble polymers ................................ 281
8.3 General properties of polymer solutions ............... 282
8.3.1 Viscosity of polymer solutions ................. 282
8.3.2 Gelling water-soluble polymers ................. 284
8.3.3 Syneresis ...................................... 286
8.3.4 Polymer complexes .............................. 286
8.3.5 Binding of ions to macromolecules .............. 288
8.3.6 Interaction of polymers with solvents
including water ................................ 288
8.3.7 Adsorption of macromolecules ................... 291
8.4 Some water-soluble polymers used in pharmacy and
medicine .............................................. 293
8.4.1 Carboxypolymethylene (Carbomer, Carbopol) ...... 293
8.4.2 Cellulose derivatives .......................... 295
8.4.3 Natural gums and mucilages ..................... 296
8.4.4 Chitosan ....................................... 298
8.4.5 Dextran ........................................ 298
8.4.6 Polyvinylpyrrolidone ........................... 300
8.4.7 Polyoxyethylene glycols (Macrogols) ............ 300
8.4.8 Bioadhesivity of water-soluble polymers ........ 302
8.4.9 Polymers as wound dressings .................... 302
8.4.10 Polymer crystallinity .......................... 303
8.5 Water-insoluble polymers and polymer membranes ........ 303
8.5.1 Permeability of polymers ....................... 303
8.5.2 Ion-exchange resins ............................ 307
8.5.3 Silicone oligomers and polymers ................ 310
8.6 Some applications of polymeric systems in drug
delivery .............................................. 311
8.6.1 Film coating ................................... 311
8.6.2 Matrices ....................................... 311
8.6.3 "Microcapsules and microspheres ................ 314
8.6.4 Rate-limiting membranes and devices ............ 320
8.6.5 Eroding systems ................................ 322
8.6.6 Osmotic pump ................................... 322
Summary .................................................... 326
References ................................................. 327
9 Drug absorption and routes of administration
9.1 Biological membranes and drug transport ............... 331
9.1.1 Lipophilicity and absorption ................... 334
9.1.2 Permeability and the pH-partition hypothesis ... 335
9.1.3 Problems in the quantitative application of
the pH-partition hypothesis .................... 337
9.2 The oral route and oral absorption .................... 341
9.2.1 Drug absorption from the gastrointestinal
tract .......................................... 341
9.2.2 Structure of the gastrointestinal tract ........ 343
9.2.3 Bile salts and fat absorption pathways ......... 344
9.2.4 Gastric emptying, motility and volume of
contents ....................................... 345
9.3 Buccal and sublingual absorption ...................... 346
9.3.1 Mechanisms of absorption ....................... 346
9.4 Intramuscular and subcutaneous injection .............. 349
9.4.1 Vehicles ....................................... 351
9.4.2 Blood flow ..................................... 351
9.4.3 Formulation effects ............................ 352
9.4.4 Insulin ........................................ 352
9.5 Transdermal delivery .................................. 335
9.5.1 Routes of skin penetration ..................... 356
9.5.2 Influence of drug .............................. 357
9.5.3 Influence of vehicle ........................... 359
9.5.4 Dilution of topical steroid preparations ....... 362
9.5.5 Transdermal medication: patches and devices .... 363
9.5.6 Ultrasound and transdermal penetration ......... 365
9.5.7 Jet injectors .................................. 365
9.6 Medication of the eye and the eye as a route for
systemic delivery ..................................... 366
9.6.1 The eye ........................................ 366
9.6.2 Absorption of drugs applied to the eye ......... 367
9.6.3 Influence of formulation ....................... 369
9.6.4 Systemic effects from eye-drops ................ 374
9.7 The ear ............................................... 374
9.8 Absorption from the vagina ............................ 375
9.8.1 Delivery systems ............................... 376
9.9 Inhalation therapy .................................... 376
9.9.1 Physical factors affecting deposition of
aerosols ....................................... 377
9.9.2 Experimental observations ...................... 379
9.10 The nasal route ....................................... 383
9.11 Rectal absorption of drugs ............................ 385
9.12 Intrathecal drug administration ....................... 389
9.13 Intracavernosal injection ............................. 390
Summary .................................................... 390
References ................................................. 390
10 Physicochemical drug interactions and incompatibilities .... 393
10.1 pH effects In vitro and in vivo ....................... 395
10.1.1 In vitro pH effects ............................ 395
10.1.2 in vivo pH effects ............................. 395
10.2 Dilution of mixed solvent systems ..................... 401
10.3 Cation-anion interactions ............................. 402
10.4 Polyions and drug solutions ........................... 405
10.5 Chelation and other forms of complexation ............. 405
10.6 Other complexes ....................................... 410
10.6.1 Interaction of drugs with cyclodextrins ....... 412
10.6.2 Ion-exchange interactions ..................... 413
10.7 Adsorption of drugs ................................... 414
10.7.1 Protein and peptide adsorption ................ 416
10.8 Drug interactions with plastics ....................... 417
10.9 Protein binding ....................................... 419
10.9.1 Thermodynamics of protein binding .............. 421
10.9.2 Lipophilicity and protein binding .............. 422
10.9.3 Penetration of specialised sites ............... 424
Summary .................................................... 425
Appendix: Drugs interactions based on physical
mechanisms ....................................... 425
A: Interactions based on absorption of drugs .......... 425
B: Interactions involving protein binding ............. 427
References ................................................. 429
11 Peptides, proteins and other biopharmaceuticals ............ 431
11.1 Structure and solution properties of peptides and
proteins .............................................. 433
11.1.1 Structure of peptides and proteins ............. 433
11.1.2 Hydrophobicity of peptides and proteins ........ 433
11.1.3 Solubility of peptides and proteins ............ 437
11.2 The stability of proteins and peptides ................ 440
11.2.1 Physical instability ........................... 441
11.2.2 Formulation and protein stabilisation .......... 443
11.2.3 Chemical instability ........................... 445
11.2.4 Accelerated stability testing of protein
formulations ................................... 450
11.3 Protein formulation and delivery ...................... 451
11.3.1 Protein and peptide transport .................. 451
11.3.2 Lyophilised proteins ........................... 452
11.3.3 Water adsorption isotherms ..................... 452
11.3.4 Routes of delivery ............................. 455
11.4 A therapeutic protein and a peptide ................... 455
11.4.1 Insulin ........................................ 455
11.4.2 Calcitonin ..................................... 458
11.5 DNA and oligonucleotides .............................. 458
11.5.1 DNA ............................................ 458
11.5.2 Oligonucleotides ............................... 459
11.6 Therapeutic monoclonal antibodies ..................... 460
Summary .................................................... 460
References ................................................. 460
12 In vitro assessment of dosage forms ........................ 463
12.1 Dissolution testing of solid dosage forms ............. 464
12.1.1 Pharmacopoeial and compendial dissolution
tests .......................................... 466
12.1.2 Flow-through systems ........................... 466
12.2 In vitro-in vivo correlations ......................... 467
12.3 In vitro evaluation of nonoral systems ................ 467
12.3.1 Suppository formulations ....................... 467
12.3.2 In vitro release from topical products and
transdermal systems ............................ 467
12.4 Rheological characteristics of products ............... 471
12.5 Adhesivity of dosage forms ............................ 472
12.6 Analysis of particle size distribution in aerosols .... 475
Summary .................................................... 478
References ................................................. 478
Index ......................................................... 479
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