Solvent Systems for Crystallization and Polymorph Selection

Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume VI)


Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodríguez-Hornedo and Murphy, 1999; Shekunov and York, 2000; Rodríguez- Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purification during the intermediate and final stages of drug synthesis. Moreover, solution crystallization determines the final solid-state modification of the API namely polymorphs, solvates, and hydrates.


Nucleation Rate Growth Unit Stable Polymorph Intrinsic Dissolution Rate Relative Thermodynamic Stability 
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  1. Abraham MH. Hydrogen Bonding. 31. Construction of A Scale of Solute Effective or Summation Hydrogen-Bond Basicity. J Phys Org Chem 1993, 6: 660–684.CrossRefGoogle Scholar
  2. Abraham MH. Scales of Solute Hydrogen-bonding: Their Construction and Application to Physicochemical and Biochemical Processes. Chem Soc Rev 1993, 73–83.Google Scholar
  3. Abraham MH, Chadha, HS, Whiting GS, and Mitchell RC. Hydrogen Bonding. 32. An Analysis of Water-Octanol and Water-Alkane Partitioning and the Δ Log P Parameter of Seiler. J Pharm Sci 1994, 1085–1100.Google Scholar
  4. Becker R and Döring W. The Kinetic Treatment of Nuclear Formation in Supersaturated Vapors. Ann Phys 1935; 24: 719–752.CrossRefGoogle Scholar
  5. Beckmann W and Winter G. Stability of the Hydrate and Anhydrate of Pyrazzocarnil Hydrochloride in Water-Ethanol Mixtures and in Moist Air. Int Symp Ind Cryst 1999; 14: 236–245.Google Scholar
  6. Behme RJ and Brooke D. Heat of Fusion Measurement of a Low Melting Polymorph of Carbamazepine that Undergoes Multiple-Phase Changes During Differential Scanning Calorimetry Analysis. J Pharm Sci 1991; 80: 986–990.PubMedCrossRefGoogle Scholar
  7. Bernstein J. Polymorphism in Molecular Crystals. Oxford University Press, Oxford, 2002.Google Scholar
  8. Bernstein J, Davey RJ, and Henck JO. Concomitant Polymorphs. Angew Chem Int Ed 1999; 38:3441–3461.CrossRefGoogle Scholar
  9. Beyer T, Day GM, and Price SL. The Prediction, Morphology, and Mechanical Properties of the Polymorphs of Paracetamol. J Am Chem Soc 2001; 123:5086–5094.PubMedCrossRefGoogle Scholar
  10. Bingham AL, Hughes DS, Hursthouse MB, Lancaster RW, Tavener S, and Threlfall TL. Over One Hundred Solvates of Sulfathiazole. Chem. Commun 2001; 7: 603–604.CrossRefGoogle Scholar
  11. Birchall JD and Davey RJ. The Crystallization of Sodium Chloride from Aqueous Solution in the Presence of Polysaccharides. J Cryst Growth 1981; 54: 323–329.CrossRefGoogle Scholar
  12. Blagden N. Crystal Engineering of Polymorph Appearance: The Case of Sulphathiazole Powder Tech 2001; 121:46–52.CrossRefGoogle Scholar
  13. Blagden N, Cross WI, Davey RJ, Broderick M, Pritchard RG, Roberts RJ, and Rowe RC. Can Crystal Structure Prediction be used as Part of an Integrated Strategy for Ensuring Maximum Diversity of Isolated Crystal Forms? The Case of 2-amino-4-nitrophenol. Phys Chem Chem Phys 2001; 3: 3819–3825.CrossRefGoogle Scholar
  14. Blagden N and Davey RJ. Polymorph Selection: Challenges for the Future? Cryst Growth Des 2003; 3:873–885.CrossRefGoogle Scholar
  15. Blagden N, Davey RJ, Lieberman HF, Williams L, Payne R, Roberts R, Rowe R, and Docherty R. Crystal Chemistry and Solvent Effects in Polymorphic Systems- Sulfathiazole J Chem Soc Faraday Trans 1998; 94: 1035–1044.CrossRefGoogle Scholar
  16. Blagden N, Davey RJ, Rowe R, and Roberts R. Disappearing Polymorphs and the Role of Reaction By-Products: The Case of Sulphathiazole. Int J Pharm 1998; 172: 169–177.CrossRefGoogle Scholar
  17. Bourne JR and Davey RJ. The Role of Solvent-Solute Interactions in Determining Crystal Growth Mechanisms from Solution I. The Surface Entropy Factor. J Cryst Growth 1976; 36: 278–286.CrossRefGoogle Scholar
  18. Byrn SR, Pfeiffer RR, and Stowell JG. Solid-State Chemistry of Drugs. SSCI, West Lafayette, IN, 1999.Google Scholar
  19. Cardew PT and Davey RJ. The Kinetics of Solvent-Mediated Phase Transformations. Proc R Soc Lond 1985; A398: 415–428.Google Scholar
  20. Carlson ED, Cong P, Chandler Jr. WH, Chau HK, Crevier T, Desrosiers PJ, Doolen RD, Freitag C, Hall LA, Kudla T, Luo R, Masui C, Rogers J, Song L, Tangkilisan A, Ung KQ, and Wu L. An Integrated High Throughput Workflow for Pre-Formulations: Polymorph and Salt Selection Studies. Pharma Chem 2003; 2:10–15.Google Scholar
  21. Chyall LJ, Tower JM, Coates DA, Houston TL, and Childs SL. Polymorph Generation in Capillary Spaces: The Preparation and Structural Analysis of a Metastable Polymorph of Nabumetone. Cryst Growth Des 2002; 2: 505–510.CrossRefGoogle Scholar
  22. Cross WI, Blagden N, Davey RJ, Pritchard RG, Neumann MA, Roberts RJ, and Rowe RC. A Whole Output Strategy for Polymorph Screening: Combining Crystal Structure Prediction, Graph Set Analysis, and Targeted Crystallization Experiments in the Case of Diflunisal. Cryst Growth Des 2003; 3: 151–158.CrossRefGoogle Scholar
  23. Davey RJ. The Control of Crystal Habit. In: de Jong EJ and Jancic SJ. Industrial Crystallization 78. North-Holland, New York, NY, 1979, pp. 169–183.Google Scholar
  24. Davey RJ. Solvent Effects in Crystallization Processes. In: Kaldis E (ed.). Current Topics in Materials Science. North-Holland, Amsterdam, 1982, pp. 429–479.Google Scholar
  25. Davey RJ, Allen K, Blagden N, Cross WI, Lieberman HF, Quayle MJ, Righini S, Seton L, and Tiddy GJT. Crystal Engineering- Nucleation, the Key Step. Cryst Eng Commun 2002; 4: 257–264.Google Scholar
  26. Davey RJ, Blagden N, Potts GD, and Docherty R. Polymorphism in Molecular Crystals: Stabilization of a Metastable Form by Conformational Mimicry. J Am Chem Soc 1997; 119: 1767–1772.CrossRefGoogle Scholar
  27. Davey RJ, Blagden N, Righini S, Alison H, and Ferrari ES. Nucleation Control in Solution Mediated Polymorphic Phase Transformations: The Case of 2,6-Dihydroxybenzoic Acid. J Phys Chem B 2002; 106: 1954–1959.CrossRefGoogle Scholar
  28. Davey RJ, Blagden N, Righini S, Alison H, Quayle MJ, and Fuller S. Crystal Polymorphism as a Probe for Molecular Self-Assembly during Nucleation from Solutions: The Case of 2,6-Dihydroxybenzoic Acid Cryst Growth Des 2001; 1: 59–65.CrossRefGoogle Scholar
  29. Davey RJ, Cardew PT, Mcewan D, and Sadler DE. Rate Controlling Processes in Solvent-Mediated Phase Transformations. J Cryst Growth 1986; 79: 648–653.CrossRefGoogle Scholar
  30. Day GM, Chisholm J, Shan N, Motherwell WDS, and Jones W. An Assessment of Lattice Energy Minimization for the Prediction of Molecular Organic Crystal Structures. Cryst Growth Des 2004; 4: 1327–1340.CrossRefGoogle Scholar
  31. Day GM, Motherwell WDS, and Jones W. Beyond the Isotropic Atom Model in Crystal Structure Prediction of Rigid Molecules: Atomic Multipoles versus Point Charges. Cryst Growth Des 2005; 5: 1023–1033.CrossRefGoogle Scholar
  32. Desiraju GR. Crystal Gazing: Structure Prediction and Polymorphism. Science 1997; 278: 404–405.CrossRefGoogle Scholar
  33. Dunitz JD and Bernstein J. Disappearing Polymorphs. Acc Chem Res 1995; 28: 193–200.CrossRefGoogle Scholar
  34. Etter MC. Encoding and Decoding Hydrogen-Bond Patterns of Organic Compounds. Acc Chem Res 1990; 23: 120–126.CrossRefGoogle Scholar
  35. Etter MC, MacDonald JC, and Bernstein J. Graph-Set Analysis of Hydrogen-Bond Patterns in Organic Crystals. Acta Cryst B Struct Sci 1990; B46: 256–262.CrossRefGoogle Scholar
  36. Ferrari ES, Davey RJ, Cross WI, Gillon AL, and Towler CS. Crystallization in Polymorphic Systems: The Solution-Mediated Transformation of β to α Glycine. Cryst Growth Des 2003; 3: 53–60.CrossRefGoogle Scholar
  37. Frank TC, Downey JR, and Gupta SK. Quickly Screen Solvents for Organic Solids. Chem Eng Progress 1999; 95: 41–61.Google Scholar
  38. Garetz BA, Aber JE, Goddard NL, Young RG, and Myerson AS. Nonphotochemical, Polarization-Dependent, Laser Induced Nucleation in Supersaturated Aqueous Urea Solutions. Phys Rev Lett 1996; 77: 3475–3476.PubMedCrossRefGoogle Scholar
  39. Garti N, Leci CL, and Sarig S. The Effect of Solvents on Crystal Habit of 1,4-Di-Tert-Butylbenzene (DTBB). J Cryst Growth 1981; 54: 227–231.CrossRefGoogle Scholar
  40. Gavezzotti A. Are Crystal Structures Predictable? Acc Chem. Res 1994; 27: 309–314.CrossRefGoogle Scholar
  41. Getsoian A, Lodaya R, and Blackburn AC. Single-Solvent Polymorph Screening. Int J Pharm 2006; In Preparation.Google Scholar
  42. Gibbs JW. Collected Works. Yale University Press, New Haven, 1948.Google Scholar
  43. Gillon AL, Feeder N, Davey RJ, and Storey R, Hydration in Molecular Crystals- A Cambridge Structural Database Analysis. Cryst Growth Des 2003; 3: 663–673.CrossRefGoogle Scholar
  44. Gölles F. Examination and Calculation of Thermodynamic Data from Experimental Measurements I. The Numerical Integration of the Vapour-Pressure Curves of the System Methanol-Water. Montash Chem 1961; 92: 981–991.CrossRefGoogle Scholar
  45. Görbitz CH and Hersleth HP. On the Inclusion of Solvent Molecules in the Crystal Structures of Organic Compounds. Acta Crys B 2000; B56: 526–534.CrossRefGoogle Scholar
  46. Gosselin PM, Thibert R, Preda M, and McMullen JN. Polymorphic Properties of Micronized Carbamazepine Produced by RESS. Int J Pharm 2003; 252: 225–233.PubMedCrossRefGoogle Scholar
  47. Grant DJW. Theory and Origin of Polymorphism. In: Brittain HG. Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, 1999, pp. 1–33.Google Scholar
  48. Grant DJW and Higuchi T. Solubility Behavior of Organic Compounds. Wiley, New York, 1990.Google Scholar
  49. Greene LR, Miller JM, and Blackburn AC. Rapid, Small-Scale Determination of Organic Solvent Solubility Using a Thermogravimetric Analyzer. J Pharm Biomed Anal 2005; 35: 344–347.CrossRefGoogle Scholar
  50. Gu C, Chatterjee K, Young Jr. V, Grant DJW. Stabilization of a Metastable Polymorph of Sulfamerazine by Structurally Related Additives. J Cryst Grow 2002; 235: 471–481.CrossRefGoogle Scholar
  51. Gu CH, Li H, Gandhi RB, and Raghavan K. Grouping Solvents by Statistical Analysis of Solvent Property Parameters: Implication to Polymorph Screening. Int J Pharm 2004; 283: 117–125.PubMedCrossRefGoogle Scholar
  52. Gu CH, Young Jr. V, and Grant DJW. Polymorph Screening: Influence of Solvents on the Rate of Solvent-mediated Polymorphic Transformation. J Pharm Sci 2001; 90: 1878–1890.PubMedCrossRefGoogle Scholar
  53. Hilfiker R, Berghausen J, Blatter F, Burkhard A, De Paul SM, Freiermuth B, Geoffroy A, Hofmeier U, Marcolli C, Siebenhaar B, Szelagiewicz M, Vit A, and von Raumer M. Polymorphism - Integrated Approach from High-Throughput Screening to Crystallization Optimization. J Them Anal Calor 2003; 73: 429–440.CrossRefGoogle Scholar
  54. Infantes L and Motherwell S. Water Clusters in Organic Molecular Crystals. Cryst Eng Commun 2002; 4: 454–461.Google Scholar
  55. Katritzky AR, Tamm T, Wang Y, and Karelson M. A Unified Treatment of Solvent Properties. J Chem Inf Comp Sci 1999; 39: 692–698.CrossRefGoogle Scholar
  56. Kelly RC. A Molecular Approach to Understanding the Directed Nucleation and Phase Transformation of Carbamazepine and Nitrofurantoin in Aqueous and Organic Solutions. PhD Thesis University of Michigan 2003.Google Scholar
  57. Khankari RK and Grant DJW. Prediction of Nedocromil Sodium Hydrate Phases in Isopropanol-Water Mixtures from the Relative Humidity Phase Diagram. Pharm Res 1993; 10:S-153 (PT 6106).Google Scholar
  58. Khankari RK and Grant DJW, Pharmaceutical Hydrates. Thermochim Acta 1995; 248: 61–79.CrossRefGoogle Scholar
  59. Kolář P, Shen J, Tsuboi A, and Ishikawa T. Solvent Selection for Pharmaceuticals. Fluid Phase Equil 2002; 194–197: 771–782.Google Scholar
  60. Koshkhoo S and Anwar J. Crystallization of Polymorphs: The Effect of Solvent J Phys D: Appl Phys 1993; 26: B90–B93.CrossRefGoogle Scholar
  61. Lang MD, Grzesiak AL, and Matzger AJ. The Use of Polymer Heteronuclei for Crystalline Polymorph Selection. J Am Chem Soc 2002; 124: 14834–14835.PubMedCrossRefGoogle Scholar
  62. Lide DR. Handbook of Organic Solvents. CRC Press, Boca Raton, FL, 1995.Google Scholar
  63. Lide DR, Database. CRC Handbook of Chemistry and Physics, 85th Edition, 2004–2005. (accessed October 2005).Google Scholar
  64. McKay B, Hoogenraad M, Damen EWP, and Smith AA. Advances in Multivariate Analysis in Pharmaceutical Process Development.Curr Opin Drug Disc Dev 2003; 6: 966–977.Google Scholar
  65. Mersmann A. Calculation of Interfacial Tensions. J Cryst Growth 1990; 102: 841–847.CrossRefGoogle Scholar
  66. Mersmann A. Crystallization Technology Handbook. Marcel Dekker, Inc., New York, 1995.Google Scholar
  67. Miller JM, Collman BM, Greene LR, Grant DJW, and Blackburn AC. Identifying the Stable Polymorph Early in the Drug Discovery-Development Process. Pharm Dev Tech 2005; 10: 275–281.CrossRefGoogle Scholar
  68. Mitchell CA, Yu L, and Ward MD. Selective Nucleation and Discovery of Organic Polymorphs Through Epitaxy with Single Crystal Substrates. J Am Chem Soc 2001; 123: 10830–10839.PubMedCrossRefGoogle Scholar
  69. Morris KR. Structural Aspects of Hydrates and Solvates. In: Brittain HG. Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, 1999, pp. 125–181.Google Scholar
  70. Morris KR and Rodríguez-Hornedo N. Hydrates. In: Encyclopedia of Pharmaceutical Technology. Marcel Dekker, New York, 1993, pp. 393–440.Google Scholar
  71. Motherwell WDS, Ammon HL, Dunitz JD, Dzyabchenko A, Erk P, Gavezzotti A, Hofmann DWM, Leusen FJJ, Lommerse JPM, Mooij WTM, Price SL, Scheraga H, Schweizer B, Schmidt MU, van Eijck BP, Verwern P, and Williams DE. Crystal Structure Prediction of Small Organic Molecules: A Second Blind Test. Acta Cryst B 2002; B58: 647–661.CrossRefGoogle Scholar
  72. Mukuta T, Lee AY, Kawakami T, and Myerson AS. Influence of Impurities on the Solution-Mediated Phase Transformation of an Active Pharmaceutical Ingredient. Cryst Growth Des 2005; 5: 1429–1436.CrossRefGoogle Scholar
  73. Mullin JW. Crystallization. Butterworth-Heinemann Ltd, Oxford, 2001.Google Scholar
  74. Murphy D, Rodríguez-Cintrón F, Langevin B, Kelly RC, and Rodríguez Hornedo N. Solution-Mediated Phase Transformation of Anhydrous to Dihydrate Carbamazepine and the Effect of Lattice Disorder. Int J Pharm 2002; 246: 121–134.PubMedCrossRefGoogle Scholar
  75. Myerson AS. Handbook of Industrial Crystallization. Butterworth-Heinemann Ltd, Oxford, 2002.Google Scholar
  76. Nakai T, Aoyama Y, and Miyake K. Application of the Thermal History of Copper Sulfate Solution to Industrial Crystallization I. Crystallization with Pilot Plant. Krist. u. Technik 1973; 8: 1313–1324.CrossRefGoogle Scholar
  77. Nangia A and Desiraju GR. Pseudopolymorphism: Occurrences of Hydrogen Bonding Organic Solvents in Molecular Crystals. Chem Commun 1999; 7: 605–606.CrossRefGoogle Scholar
  78. Nass KK. Process Implications of Polymorphism in Organic Compounds. AIChE 1991; 284: 72–81.Google Scholar
  79. Nyvlt J, Söhnel O, Matuchova M, and Broul M. The Kinetics of Industrial Crystallization. Elsevier, New York, 1985.Google Scholar
  80. Okamoto M, Hamano M, Igarashi K, and Ooshima H. The Effects of Impurities on Crystallization of Polymorphs of a Drug Substance AE1-923. J Chem. Eng Jap 2004; 37: 1224–1231.CrossRefGoogle Scholar
  81. Okamoto M, Hamano M, and Ooshima H. Active Utilization of Solvent-Mediated Transformation for Exclusive Production of Metastable Polymorph Crystals of AE1-923. J Chem Eng Jap 2004; 37: 95–101.CrossRefGoogle Scholar
  82. Ostwald W. Studien Uber Die Bildung und Umwandlung Fester Korper. Z Physik Chem 1897; 22: 289–302.Google Scholar
  83. Otsuka M, Kaneniwa N, Kawakami K, Umezawa O, Udovenko VV, and Mazanko TF. Liquid-Vapour Equilibrium in the 2-Propanol-Water and 2-Propanol-Benzene System. Rus J Phys Chem 1967; 41: 863–866.Google Scholar
  84. Price CP, Grzesiak AL, and Matzger AJ. Crystalline Polymorph Selection and Discovery with Polymer Heteronuclei. J Am Chem Soc 2005; 127: 5512–5517.PubMedCrossRefGoogle Scholar
  85. Pudipeddi M and Serajuddin ATM. Trends in Solubility of Polymorphs. J Pharm Sci 2005; 94: 929–939.PubMedCrossRefGoogle Scholar
  86. Riddick JA, Bunger WB, and Sakano TK. Organic Solvents. Wiley, New York, NY, 1986.Google Scholar
  87. Rodríguez-Hornedo N, Lechuga-Ballesteros D, and Wu HJ. Phase Transition and Heterogeneous/epitaxial Nucleation of Hydrated and Anhydrous Theophylline Crystals. Int J Pharm 1992; 85: 149–162.CrossRefGoogle Scholar
  88. Rodríguez-Hornedo N and Murphy D. Significance of Controlling Crystallization Mechanisms and Kinetics in Pharmaceutical Systems. J Pharm Sci 1999; 88: 651–660.PubMedCrossRefGoogle Scholar
  89. Rodríguez-Hornedo N and Murphy D. Surfactant-Facilitated Crystallization of Dihydrate Carbamazepine During Dissolution of Anhydrous Polymorph. J Pharm Sci 2004; 93: 449–460.PubMedCrossRefGoogle Scholar
  90. Rodríguez-Hornedo N and Sinclair BD. Crystallization: Significance in Product Development, Processing, and Performance. In: Boylan JC, and Swarbrick J (eds.), Encyclopedia of Pharmaceutical Technology. Marcel Dekker, New York, NY, 2002, pp. 671–690.Google Scholar
  91. Rodríguez-Hornedo N. Crystallization and the Properties of Crystals. In: Boylan JC, and Swarbrick J (eds.), Encyclopedia of Pharmaceutical Technology. Marcel Dekker, New York, NY, 1991, pp. 399–434.Google Scholar
  92. Rodríguez-Spong B, Price CP, Jayasankar A, Matzger AJ, and Rodríguez-Hornedo N. General Principles of Pharmaceutical Solid Polymorphism. A Supramolecular Perspective. Adv Drug Deliv Rev 2004; 56: 241–274.PubMedCrossRefGoogle Scholar
  93. Sacchetti M. Determining the Relative Physical Stability of Anhydrous and Hydrous Crystal Forms of GW2016. Int J Pharm 2004; 273: 195–202.PubMedCrossRefGoogle Scholar
  94. Shalaev E and Zografi G. The Concept Of ‘Structure’ in Amorphous Solids From the Perspective of the Pharmaceutical Sciences. In: Amorphous Food and Pharmaceutical Systems. Cambridge: The Royal Society of Chemistry; 2002. 11–30.CrossRefGoogle Scholar
  95. Shekunov BY and York P. Crystallization Processes in Pharmaceutical Technology and Drug Delivery Design. J Cryst Growth 2000; 211: 122–136.CrossRefGoogle Scholar
  96. Söhnel O and Garside J. Precipitation: Basic Principles and Industrial Applications. Butterworth-Heinemann Ltd, Oxford, 1992.Google Scholar
  97. Sokolova EP and Morachevskii AG. Thermodynamic Properties of the Acetone-Water System. Vestn Leningr Univ Fiz Khim 1967; 3: 110–115.Google Scholar
  98. Threlfall T. Crystallization of Polymorphs: Thermodynamic Insight into the Role of Solvent. Org Process Res Dev 2000; 4: 384–390.CrossRefGoogle Scholar
  99. Ticehurst MD, Storey RA, and Watt C. Application of Slurry Bridging Experiments at Controlled Water Activities to Predict the Solid-State Conversion Between Anhydrous and Hydrated Forms Using Theophylline as a Model Drug. Int J Pharm 2002; 247: 1–10.PubMedCrossRefGoogle Scholar
  100. Turnbull D and Fisher J.C. Rate of Nucleation in Condensed Systems. J Chem Phys 1949; 17: 71–73.CrossRefGoogle Scholar
  101. van Langevelde A and Blomsma E. High-Throughput Screening in Solid Form Section. Acta Cryst 2002; A58: C9.Google Scholar
  102. Velaga SP, Berger R, and Carlfors J. Supercritical Fluids Crystallization of Budesonide and Flunisolide. Pharm Res 2002; 19: 1564–1571.PubMedCrossRefGoogle Scholar
  103. Vippagunta SR, Brittain HG, and Grant DJW. Crystalline Solids. Adv Drug Deliv Rev 2001; 48: 3–26.PubMedCrossRefGoogle Scholar
  104. Volmer M. Kinetic der Phasenbildung. Steinkopff, Leipzig, 1939.Google Scholar
  105. Washburn, EW. International Critical Tables of Numerical Data, Physics, Chemistry, and Technology. McGraw Hill, New York, 1928. p. 290.Google Scholar
  106. Zaccaro J, Matic J, Myerson AS, and Garetz BA. Nonphotochemical, Laser-Induced Nucleation of Supersaturated Aqueous Glycine Produces Unexpected Gamma-Polymorph. Cryst Growth Des 2001; 1: 5–8.CrossRefGoogle Scholar
  107. Zettlemoyer AC. Nucleation. Marcel Dekker, New York, 1969.Google Scholar
  108. Zhu HJ and Grant DJW. Influence of Water Activity in Organic Solvent Plus Water Mixtures on the Nature of the Crystallizing Drug Phase 2. Ampicillin. Int J Pharm 1996; 139: 33–43.CrossRefGoogle Scholar
  109. Zhu HJ, Yuen CM, and Grant DJW. Influence of Water Activity in Organic Solvent Plus Water Mixtures on the Nature of the Crystallizing Drug Phase 1. Theophylline. Int J Pharm 1996; 135: 151–160.CrossRefGoogle Scholar

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Authors and Affiliations

    • 1
    • 1
    • 2
    • 2
    • 2
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of MichiganAnn ArborUSA
  2. 2.Materials Science, Research Formulations, Pfizer Global Research and Development, Ann Arbor LaboratoriesAnn ArborUSA

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