A

PARTICLE SIZE ANALYSIS

IN PHARMACEUTICS AND
OTHER INDUSTRIES
Theory and Practice

CLIVE WASHINGTON, PH D
Department of Pharmaceutical Sciences,
School of Pharmacy
University of Nottingham

ELLIS HORWOOD
NEW YORK LONDON TORONTO SYDNEY TOKYO SINGAPORE
Table of contents

Preface 7

1. Basic principles 9
RANGE OF PARTICLE SIZES AND UNITS 10
MEASURES OF PARTICLE SIZE 10
DISTRIBUTIONS OF PARTICLE SIZES 12
INCREMENTAL AND CUMULATIVE DISTRIBUTIONS 17
NUMBER, AREA AND MASS DISTRIBUTIONS 18
CHARACTERIZATION OF DISTRIBUTIONS 21
Measures of central tendency 21
Moments of a distribution and moment notation 23
Measures of dispersion 25
Measures of distribution shape 26
MODEL DISTRIBUTIONS 26
The normal distribution 27
Thelognormal distribution 29
The Rosin-Rammler distribution 30
IDENTIFICATION OF SPECIFIC DISTRIBUTIONS 31
PARTICLE SHAPE 33
Descriptive 34
Descriptors based on direct measurement of dimensions 34
Shape factors 35
Fourier transform methods 36
FRACTAL CHARACTERIZATION OF PARTICLES 37
REFERENCES 39

2. Sample selection and preparation 41

SAMPLE SELECTION 41
SELECTION OF PRIMARY SAMPLE 43
Sampling from flowing powders 44
Sampling from stored powders 45
Sampling from liquids 47
SPLITTING THE PRIMARY SAMPLE 47
Manual methods of sample splitting 47
Mechanical methods of sample splitting 48
DISPERSION OF MATERIALS 50
Wetting 51
Disintegration 54
Stabilization and flocculation 55
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PRACTICAL TECHNIQUES FOR SAMPLE DISPERSION 56

CALIBRATION AND REFERENCE STANDARDS 58
REFERENCES 59

3. Sieving 61
SIEVE SIZES AND RANGES 61
What does sieving measure? 62
METHODS OF SIEVE CONSTRUCTION 63
Woven sieves 63
Etched sieves 64
Punched sieves 65
TECHNIQUES FOR USING SIEVES 65
Wet sieving 65
Hand sieving 67
Machine sieving 68
Sonic and ultrasonic sieving 69
Airjet sieving 70
Cleaning of sieves 72
Calibration and testing of sieves 73
ERRORS AND PROBLEMS IN SIEVING 75
Errors in the sieve 75
Sieve load 75
Sieving time 75
Properties of the feedstock 76
WHEN TO USE SIEVING 77
REFERENCES 78

4. Electrical zone sensing 79

PRINCIPLE OF OPERATION 79
Sampling head operation 81
APERTURE CONSTRUCTION AND MAINTENANCE 83
CALIBRATION 84
TECHNIQUES FOR THE USE OF THE COULTER COUNTER 86
Overlapping ranges 89
Mass balance checks 90
Electrolyte selection and preparation 91
ERRORS IN ELECTRICAL ZONE SENSING 93
Interference and vibration 93
Coincidence correction 95
Particle path and shape 96
Flocculation in the electrolyte 98
Particle sedimentation 99
APPLICATIONS 99
Particle counting in parenterals 100
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Parenteral fat emulsions 101

REFERENCES 102

5. Introduction to light scattering 105

LIGHT DIFFRACTION 106
SINGLE PARTICLE SCATTERING 107
PHOTON CORRELATION 107

6. The angular distribution of scattered light 109

INTRODUCTION 109
THEORY OF LIGHT DIFFRACTION 110
Optical properties of materials 110
Mie Theory Ill
Scattering of polarized light 113
Rayleigh scattering 114
Rayleigh-Gans-Debye (RGD) scattering 116
Fraunhofer scattering 116
Anomalous scattering 116
LASER DIFFRACTION PARTICLE SIZERS 117
Data processing 120
Sample preparation 122
Dry powder feeders 123
Aerosol sizing accessories 123
CALIBRATION 125
ERRORS AND DISADVANTAGES OF DIFFRACTION SIZE
ANALYSIS 126
Submicrometre resolution 127
Multiple scattering 128
Flow and refractive index fluctuations 129
Computing artefacts 129
Particle shape 130
LASER SAFETY 131
OPTICS CLEANING 132
REFERENCES 133

7. Photon correlation spectroscopy 135

PRINCIPLE OF PHOTON CORRELATION 136
PARTICLE SIZE DISTRIBUTIONS FROM PCS 140
Cumulant analysis 143
Histogram method 145
Exponential sampling method 146
Constrained regularization 147
Multiple angle measurement 147
EQUIPMENT FOR PHOTON CORRELATION 147
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The laser 148

The sample optics 149
The detector 150
The correlator 151
SAMPLE PREPARATION 153
ERRORS IN PCS SIZE MEASUREMENT 154
ZETA POTENTIAL MEASUREMENT 155
Overview of zeta potential 155
Zeta potential measurement 156
Experimental aspects 158
Electroacoustic analysis 163
Applications 164
REFERENCES 165

8. Particle size analysis of aerosols 169

INERTIALIMPACTION 170
SAMPLING AEROSOL GASES 173
GENERATION OF CALIBRATION AEROSOLS 175
Impaction particle sizers 176
The two-stage impinger 176
The Andersen sampler 178
Setting up and calibration 181
Errors of Andersen sampler analysis 182
OPTICAL COUNTING METHODS 184
Light scattering intensity measurements 184
AERODYNAMIC PARTICLE SIZERS 186
The Malvern Aerosizer 186
Phase Doppler Anemometry 188
MISCELLANEOUS TECHNIQUES 190
Filtration 190
Nucleation counters 191
REFERENCES 192

9. Sedimentation 193
THEORY 194
Limitations of Stokes' law 195
THE ANDREASEN PIPETTE 198
Data analysis 200
SEDIMENTATION BALANCES '.!..'...'.L."'.2O1
Data analysis 202
PHOTOSEDIMENTATION '."."..'.!...!".2O4
X-RAY SEDIMENTATION !.".".".'!"."."!"."!."!!.'207
CENTRIFUGAL SEDIMENTATION 209
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Determination of density 212

REFERENCES 214

10. Microscopy and image analysis 215

RESOLUTION 216
STATISTICAL CONSIDERATIONS 216
SAMPLE SELECTION AND PREPARATION 217
INSTRUMENTATION 219
ELECTRON MICROSCOPY 220
MANUAL METHODS 220
SEMIAUTOMATIC METHODS 222
AUTOMATIC IMAGE ANALYSIS 224
Image processing instrumentation 224
Image display 228
Image enhancement 229
Image measurement 231
FRACTAL MEASUREMENT 231
REFERENCES 234

Index 237