Index

Anti-solventaddition, 179–180, 193, 241, 277metastable zone, 180srtategy, 182

Agglomerationaggregation, 5, 102, 106–107,

109–110, 139growth, 105–106, 210, 215impuities, 216, 132, 223nucleation, 132, 193oiling out, 3, 5, 25, 106–109, 132, 168,

175, 180, 181, 217–218reactive crystallization, 215supersaturationreverse addition, 193, 196

Aggregation, 139, 215Amorphous state, 25, 28, 108, 197, 199, 207,

210–211, 217, 223Anti-solvent

normal mode, 179–180reverse addition, 180–181seeding, 110–115, 182–183, 215, 220–221,

224, 228–229impinging jets, 103, 198, 202

Actice pharmaceutical ingredientAPI, 1, 150, 188, 197, 218, 225,

228, 273

Baffles, 127, 129Bimodal distribution, 101, 105, 112, 184,

192, 208, 214Biobatch

regulatory, 10, 117

Computational fluid dynamicsCFD, 10, 238

Continuous operationadvantages, 114, 143, 177–178cooling, 6, 133, 137, 144in-line, 6reactive crystallization, 221

stirred tank-CSTR, 91–92, 260–261, 265stereo isomer separation, 161–166, 259–272

Clusters, 81, 82, 85Cooling

batch operation, 5, 137and evaporation, 175continuous operation, 6–9, 133, 143–147,

221–222, 259–272fluidized bed, 6, 146–147, 260–272mixing, 141, 275, 272rate, 5, 138–140, 274, 276scale-up, 5, 141, 148, 269, 277seeding, 5, 6, 141, 241, 275, 276

Damkoehler Numbercrystallization, 4, 91, 120–124, 134reactions, 132–133, 212

Deliquescence, 39Development of processes, 1, 117, 147, 149,

153, 155, 198, 218–219, 222, 223, 236,238–239, 272–277

Differential scanning calorimetryDSC, 28, 50, 51, 55, 256, 273

Enantiotropymeasurement, 50–53

Encrustation, 118, 126Equipment

alloys, 127for crystallization, 127, 198for evaporative crystallization, 171–174glass-lined, 127–129

Evaporationequipment, 171–174examples, 175–177, 177–178growth, 168, 170–171, 177–178hazard of over concentration, 174issues, 113, 168, 170, 171, 172metastable zone, 167, 168, 170nucleation, 168, 170–171, 172, 177scale-up, 171

Crystallization of Organic Compounds: An Industrial Perspective. By H.-H. Tung, E. L. Paul, M. Midler, andJ. A. McCauleyCopyright # 2009 John Wiley & Sons, Inc.

285

Example crystallizationanti-solvent, Ex 9-1, 184–185anti-solvent, Ex 9-2, 185–188anti-solvent, Ex 9-3, 188–192creation of fine particles, Ex 10-5,

231–133crixivan intermediate, Ex 7-1, 147–150crixivan sulfate salt, Ex 10-1, 218–223dimethyl sulfoxide, 251–254enhanced selectivity, Ex 11-2, 243–246enhanced selectivity, Ex 11-3, 246–251evaporative, Ex 8-1, 175–177evaporative, Ex 8-2, 177–178heel recycle, Ex 7-3, 154–155ibuprofen lysinate, Ex 7-4, 155–159imipenem, acetoxy, Ex 10-2, 223–225imipenem, freeze, Ex 11-5, 255–259imipenem, sterile, Ex 11-1, 238–242impinging jet, Ex 9-4, 192–196impinging jet, Ex 9-5, 197–204impinging jet, recycle, Ex 9-6, 204–205polymorphs, Ex 7-5, 160–161reactive of an API, Ex 10-4, 228–235slow approach to equilibrium, 135–136slow cooling, Ex 7-2, 141, 150sodium salt, Ex 10-3, 225–228stereoisomer resolution, Ex 7-6,

161–166stereoisomer separation, 259–272

Feed pipediameter, 132–133location, 125, 132–133, 188, 212

Feed rate, 216–224Fluidized bed

advantages, 133–134growth rate, 91, 94–96, 105, 146, 163–166scale-up, 259–272sonication, 154, 164–165, 237, 264–270

Focused beam reflective measurementFBRM, 10, 24, 46, 216, 227, 229, 273

FTIR, 10, 19, 23, 273Freeze crystallization

lyophilization, 235, 255–259

Growthcontrol, 210importance, 104, 196–197, 198, 215–218,

242, 259impurities, 89, 90, 91, 137–142, 168–169,

179–180mass transfer, 91, 123mechanisms, 78, 87

mixing effects, 91, 213numbers, 123, 139optical isomers, 161–166, 259–272potential, 108, 182, 188–192,

216–217, 223rate, 91–94, 105–106, 208, 210screw dislocation, 88–89, 92seeding, 83, 113–114, 141, 148–151, 161,

220–221, 241,259–272size dependent, 93, 94, 218wall, 139

Growth ratedispersion, 93, 218effect of impurities, 89–90, 216–217factors, 89–90, 104–106, 125, 177–178, 208,

215–216, 228measurement, 46, 94, 264–265, 272–273needles, 44, 275supersaturation, 77, 105

Habitmorphology, 42

Heat transferrate, 118, 127–128 140, 172–174, 252

Hydrates, 34Hygroscopicity, 29, 39

Impellers, 128–130Impinging jet

examples, 8–9, 192–205, 231–233mixing elbow, 150PSD, 134–135, 196, 197, 205scale-up, 197utilization, 123, 134–135, 193–205, 212with recycle, 203–205

Impurities, 3, 17–18, 20–21, 107, 138, 168–169, 171, 173, 185, 211, 272–277

importance, 90, 142, 179, 216–217nucleation, 91occlusion, 39, 102, 108, 181, 187, 208measurement, 41rejection, 185–188, 197–202

Inclusionmeasurement, 38mechanism, 37,89significance, 39

Induction timegeneral, 21, 23, 25, 78, 209–210measurement, 23mixing, 23, 119, 135, 212–213supersaturation, 24, 214

Inhibitors, 223Instrumentation, 4, 5–6, 10

286 Index

Kineticsgrowth, 77, 93, 163, 235, 264nucleation, 77, 79order, 92–93,163supersaturation, 77, 209

Lyophilization, 255–259

Macromixing, 119–120, 212Mas transfer

growth, 91–92, 123Mesomixing, 118–119, 212–213Melt crystallization, 235, 251Metastable zone

description, 21, 23effect of mixing, 125measurement, 23significance, 24, 79, 137–138, 140, 148,

214, 216supersaturation, 25width, 5, 23, 24, 103, 108, 239–240,

242, 273Microscopes, 43Micromixing, 118, 120, 122, 212Mixing

agglomeration, 110, 193–194, 218effects on crystallization, 4, 117–119, 121,

212, 252equipment, 127–135experimentation, 86, 125–126, 197, 207–213,

275growth, 123–124, 149, 213impellers, 127–133, 174induction time, 23, 119, 135, 212–213macromixing, 119–120, 212mesomixing, 8, 118–119, 212–213metastable zone width, 8micromixing, 8, 197, 212nucleation, 8, 119, 121, 125particle size distribution, 126, 217power, 126and reaction, 211–213, 243scale-up, 8, 122–123, 126, 171, 208, 213,

218–223, 224shear, 118, 134, 222, 224variable speed, 129–130

Morphologyhabit, 42measurement, 43prediction, 44significance, 42, 44, 240, 268, 274size distribution, 99

MSMPR, 97, 144

Needles, 113, 175Nuclear magnetic reasonance

NMR, 50, 52Nucleation

contact, 3, 86,122control, 2, 11, 77–79, 101–102, 168, 197,

211, 272–275Damkoehler number, 120–122heterogeneous, 79, 83homogeneous, 79, 80impurities, 91mixing effects, 8, 119, 212–213and growth, 2–3, 101–102, 116, 137–138,

140, 170–171, 179, 188–192, 204,210–211, 213, 217–218, 223, 227

models, 77, 88–89polymorphs, 82–83primary, 81–82, 119rate, 81, 103–104, 139, 204, 209, 210, 240,

259–260scale-up, 122–123, 161, 171secondary, 79, 85, 171seeding, 4, 82–83, 95, 114, 170–171,

175–177, 215supersaturation, 78, 101, 110, 134, 167–168,

170–171, 177, 179, 182, 190, 207,209–210, 214

and ultrasound, 237

Occlusion, 37–38, 181, 187Oiling out

agglomeration, 25–27, 110, 181, 217–218effect of impurities, 106–108minimization, 110, 188significance, 3, 25, 109, 190

Optical isomersresolution, 29–30, 155–166, 259–272

Ostwald ripening, 82, 98, 111Ostwald

rule of stages, 26, 50, 83, 108, 200, 217

Particle size distributionbimodal, 184–185, 192control, 112, 137, 151, 179, 196–197, 205,

217, 222,238, 241, 274definition, 44–45evaporation, 167, 170–171growth, 104–106, 111impinging jet, 134–135measurement, 46–47, 150–153, 229mixing, 126, 130, 213nucleation, 5prediction, 99

Index 287

Particle size distribution (Continued )regulatory, 1scale-up, 6, 141, 153, 197significance, 47, 117, 208

Phase diagrams, 13–14, 26, 29, 35, 39free energy, 21

Phase rule, 49Pharmaceuticals, 1–2, 77–78, 143, 160,

207, 255Polymorph examples

finasteride, 58HCl salt, 62, 66ibuprofen lysinate, 61indomethacin, 53losartan, 57phthalysulfathiazole, 74prednisolone t-butly acetate, 70sulindac, 55

Polymorphscontrol, 111desdription, 29measurement, 30, 51phase diagram, 29prediction, 30–31nucleation, 82significance, 31transformation, 32, 108

Polymorphismenantiotropy, 30, 49–50examples, 160measurement, 50metastable equilibrium, 50monotropy, 29–30, 50phase rule, 49suspended transformation, 50

Population balance, 96–97, 145,163, 264

Powerscale-up, 126, 172, 213

Precipitation, 78, 84, 121, 207–208,210–211, 218

Process analytical technologyPAT, 19, 225

Process development, 3, 101, 104–106,117, 147, 149, 153, 155, 198

Reactionschemical, 243–246

Regulatorybiobatch, 10, 117pharmaceuticals, 1, 10optical isomers, 155–166,

259–272

Scale-upfluidized bed, 94, 164–166, 262, 269,

271–272issues, 4, 11, 101, 117, 150, 153, 167, 181,

218, 276mixing, 4, 8, 103–104, 125–126nucleation, 102–104, 122–123particle size distribution, 7, 125, 141, 151, 153,

170–171power, 126reactive crystallizationsupersaturation, 2, 5

Seedingage, 98, 114amount, 4, 5–6, 111, 149, 154, 221,

242, 276anti-solvent, 8, 182–183continuous operation, 6–7, 114effectiveness, 85, 110, 113, 115, 141, 148guidelines, 111–112heel recycle, 154instrumentation, 5–6, 114, 152–153method of addition, 4, 6, 183, 190point, 5–6, 113, 148, 175–177,

228–229, 276preparation, 98, 220–221, 241, 276procedures, 112reactive crystallization, 215, 220–223size, 99, 111, 241slurry addition, 6, 115, 276supersaturation, 161

Sheardamage, 4, 118, 211, 213, 214nucleation, 86, 118

Slurrydischarge, 133seeding, 6, 112, 115, 276

Solidcompound, 34measurement, 30, 36mixture, 34significance, 36, 83, 208, 211, 217solution, 34

Solubilityequations, 14general, 13, 137equilibrium, 6, 13, 135–137, 169, 180impurities, 5, 168, 211measurement, 19–20phase diagram, 13–14, 167, 258prediction, 19salts, 18in resolution, 155, 158–159, 260

288 Index

solvent effects, 16temperature, 5, 15

Solvatesmeasurement, 32, 34, 50phase diagram, 32significance, 34

Solvent, 3adsorption, 39anti-, 179–180change in evaporation, 169–170salting out, 169selection, 16, 19, 141–142

Sonicationcrystal cleavage, 9, 44, 113, 134, 154,

164–165, 167, 264–270scale-up, 270

Spinodal points, 22, 79Stereo isomer separation, 156–159, 161–166,

259–272Sterile crystallization

imipenem, 235, 238–242, 255Stirred vessels

baffles, 118, 129general, 117, 127–133impellers, 128–130power, 126scale-up, 117, 122–123, 126

Sub-surface addition, 130–133

Supercritical crystallizationSupersaturation

agglomeration, 37, 110control, 2, 5, 8, 171, 209, 214, 216generation, 24, 26, 78, 101, 113, 115,

138–139, 167, 208, 214impinging jet, 231–233induction time, 214metastable zone width, 23–24, 137, 142,

167–168nucleation rate, 98–99, 103, 134,

209–210oiling out, 107–109, 139, 217–218rate processes, 5, 77, 105–106, 115–116reactive crystallization, 207–210, 214,

216–218, 220, 228scale-up, 102, 105

ThermogravimetryTG, 50

Ultrasound in crystallization, 9, 44, 113, 134,140, 154, 164–165, 167, 237, 264–270

Variable speed, 129–130

X-ray powder diffractionXRPD, 28, 30, 50, 52, 53, 55

Index 289