Hostname: page-component-848d4c4894-4hhp2 Total loading time: 0 Render date: 2024-05-21T10:55:24.248Z Has data issue: false hasContentIssue false

Particle Engineering: Fundamentals of Particle Formation and Crystal Growth

Published online by Cambridge University Press:  31 January 2011

Get access


The engineering of particles with customized properties optimized for dosage form manufacture (tablet, capsule, ointment, etc.) has long been a goal of the pharmaceutical industry. Particles can be designed through modification in the size, morphology, and packing arrangement of the solids. The most common approach in achieving this is through crystallization. In this bottom-up process, the two main steps, nucleation and crystal growth, both play a decisive role in shaping the quality of the final crystalline product. In this review, the role of nucleation and crystal growth in controlling particle properties is discussed, and examples are provided that demonstrate the variation in solid-state properties as a function of size, habit (morphology), and internal structure of the particles. In addition, the role of particle properties in product performance and dosage form development of pharmaceuticals is also discussed.

Research Article
Copyright © Materials Research Society 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


1. Paul, E.L.Tung, H.H. and Midler, M.Powd. Technol. 150 (2005) p. 133.CrossRefGoogle Scholar
2. Shekunov, B.Y. and York, P.J. Cryst. Growth 21 1 (2000) p. 122.CrossRefGoogle Scholar
3. Desiraju, G.Crystal Engineering: The Design of Organic Solids (Elsevier, Amsterdam, 1989).Google Scholar
4. Erk, P.Hengelsberg, H.Haddow, M.F. and Gelder, R. Van, Cryst. Eng. Comm. 6 (2004) p. 474.CrossRefGoogle Scholar
5. Volmer, M.Kinetik der Phasenbildung (Steinkopff, Germany, 1939).Google Scholar
6. Oxtoby, D.W.Acc. Chem. Res. 31 (1998) p. 91.CrossRefGoogle Scholar
7. Vekilov, P.G.Cryst. Growth Des. 4 (2004) p.671.CrossRefGoogle Scholar
8. Schuth, F.Curr. Opin. Solid State Mater. Sci. 5 (2001) p.389.CrossRefGoogle Scholar
9. Oxtoby, D.W.Philos. Trans. R. Soc. London Ser. A. 361 (2003) p.419.CrossRefGoogle Scholar
10. ten Wolde, P.R. and Frenkel, D.Science 277 (1997) p.1975.CrossRefGoogle Scholar
11. Shore, J.D.Perchak, D. and Shnidman, Y.J.Chem. Phys. 113 (2000) p.6276.CrossRefGoogle Scholar
12. Galkin, O. and Vekilov, P.G.J.Am. Chem. Soc. 122 (2000) p.156.CrossRefGoogle Scholar
13. Chattopadhyay, S.Erdemir, D.Evans, J.M.B.Ilavsky, J.Amenitsch, H.Segre, C.U. and Myerson, A.S.Cryst. Growth. Des. 5 (2005) p.523.CrossRefGoogle Scholar
14. Kimura, M.Cryst. Growth Des. 6 (2006) p.854.CrossRefGoogle Scholar
15. Garetz, B.A.Matic, J. and Myerson, A.S.Phys. Rev. Lett. 89 175501 (2002).CrossRefGoogle Scholar
16. Davey, R.J.Allen, K.Blagden, N.Cross, W.I.Lieberman, H.F.Quayle, M.J.Righini, S.Seton, L. and Tiddy, G.J.T.Cryst. Eng. Comm. 4 (2002) p.257.CrossRefGoogle Scholar
17. Hilfiker, R. Ed., Polymorphism in the Pharmaceutical Industry (John Wiley & Sons, Chichester, 2006); G. Winter in Reactivity of Molecular Solids, edited by E.V. Boldyreva and V.V. Boldyrev (John Wiley &; Sons, Chichester, 1999) p.241.CrossRefGoogle Scholar
18. Bernstein, J., Polymorphism in Molecular Crystals (Oxford University Press, New York, 2002).Google Scholar
19. Henck, J.O.Griesser, U.J. and Burger, A.Pharm. Ind. 59 (1997) p.165.Google Scholar
20. Caira, M.R. in Topics in Current Chemistry, Vol. 198, edited by Weber, E. (Springer, New York, 1998) p.163.Google Scholar
21. Briancon, S. and Fessi, H.STP Pharma. Prat. 13 (2003) p.215; E. Doelker STP Pharma. Prat. 9 (1999) p.399.Google Scholar
22. Sun, C. and Grant, D.J.W.Pharm. Res. 18 (2001) p. 274; C. Sun and D.J.W. Grant Pharm. Res. 21 (2004) p.382.CrossRefGoogle Scholar
23. Chen, X.Morris, K.R.Griesser, U.J.Byrn, S.R. and Stowell, J.G.J. Am. Chem. Soc. 124 (2002) p.15012.CrossRefGoogle Scholar
24. Dunitz, J.D. and Bernstein, J., Acc. Chem. Res. 28 (1995) p. 193.CrossRefGoogle Scholar
25. Gavezzotti, A. and Filippini, G.J.Am. Chem. Soc. 117 (1995) p.12299.CrossRefGoogle Scholar
26. Bauer, J.Spanton, S.Henry, R.Quick, J.Dziki, W.Porter, W. and Morris, J.Pharm. Res. 18 (2001) p.859.CrossRefGoogle Scholar
27. Guillory, J.K. in Polymorphism in Pharmaceutical Solids, edited by Brittain, H.G. (Marcel Dekker, New York, 1999) p. 183; M. Maiwald Am. Pharm. Rev. 9 (2006) p.95.Google Scholar
28. Janik, M.Malarski, Z.Mrozinski, J.Wajcht, J. and Zborucki, Z., J. Crystallogr. Spectrosc. Res. 21 (1991) p.519.CrossRefGoogle Scholar
29. Morissette, S.L.Almarsson, O.Peterson, M.L.Remenar, J.F.Read, M.J.Lemmo, A.V.Ellis, S.Cima, M.J. and Gardner, C.R.Adv. Drug Delivery Rev. 56 (2004) p.275.CrossRefGoogle Scholar
30. Furedi-Milhofer, H., Garti, N. and Kamyshny, A.J. Cryst. Growth 198–199 (1999) p.1365.CrossRefGoogle Scholar
31. Ha, J.M.Wolf, J.H.Hillmyer, M.A. and Ward, M.D.J.Am. Chem. Soc. 126 (2004) p.3382.CrossRefGoogle Scholar
32. Lee, A.Y.Lee, I.S.Dette, S.S.Boerner, J. and Myerson, A.S.J. Am. Chem. Soc. 127 (2005) p.14982.CrossRefGoogle Scholar
33. Price, C.P.Grzesiak, A.L. and Matzger, A.J.J.Am. Chem. Soc. 127 (2005) p.5512.CrossRefGoogle Scholar
34. Hiremath, R.Basile, J.A.Varney, S.W. and Swift, J.A.J.Am. Chem. Soc. 127 (2005) p.18321.CrossRefGoogle Scholar
35. Chen, S.Xi, H. and Yu, L.J. Am. Chem. Soc. 127 (2005) p.17439.CrossRefGoogle Scholar
36. Meyer, M.C.Straughn, A.B.Jaryi, E.J.Wood, G.C.Pelsor, F.R. and Shah, V.P.Pharm. Res. 9 (1992) p.1612.CrossRefGoogle Scholar
37. Price, S.L.Adv. Drug. Delivery Rev. 56 (2004) p.301.CrossRefGoogle Scholar
38. Docherty, R. and Meenan, P. in Molecular Modeling Applications in Crystallization, edited by Myerson, A.S. (Cambridge University Press, Cambridge, 1999) p.106.CrossRefGoogle Scholar
39. Verwer, P. and Leusen, F.J.J. in Reviews in Computational Chemistry, Vol. 12, edited by Lipkowitz, K.B. and Boyd, D.B. (John Wiley & Sons, New York, 1998) p.327; R.J. Gdanitz Curr. Opin. Solid State Mater. Sci. 3 (1998) p.414.CrossRefGoogle Scholar
40. Lommerse, J.P.M.Motherwell, W.D.S.Ammon, H.L.Dunitz, J.D.Gavezzotti, A.Hofmann, D.W.M.Leusen, F.J.J.Mooij, W.T.M.Price, S.L.Schweizer, B.Schmidt, M.U.van Eijck, B.P., Verwer, P. and Williams, D.E.Acta Crys-tallogr., Sect. B: Struct. Sci. 56 (2000) p. 697; W.D.S. Motherwell, H.L. Ammon, J.D. Dunitz, A. Dzyabchenko, P. Erk, A. Gavezzotti, D.W.M. Hofmann, F.J.J. Leusen, J.P.M. Lommerse, W.T.M. Mooij, P. Verwer, and D.E. Williams, Acta Crystallogr., Sect. B: Struct. Sci. 58 (2002) p. 647; G.M. Day, W.D.S. Motherwell, H.L. Ammon, S.X.M. Boerrigter, R.G. Della Valle, E. Venuti, A. Dzvabchenko, J.D. Dunitz, B. Schweizer, B.P. van Eijck, P. Erk, J.C. Facelli, V.E. Bazterra, M.B. Ferraro, D.W.M. Hofmann, F.J.J. Leusen, C. Liang, C.C. Pantelides, P.G. Karamertzanis, S.L. Price, T.C. Lewis, H. Nowell, A. Torrisi, H.A. Scheraga, Y.A. Arnautova, M.U. Schmidt, and P. Verwer, Acta Crystallogr., Sect. B: Struct. Sci. 61 (2005) p.511.CrossRefGoogle Scholar
41. Price, S.L. in Reviews in Computational Chemistry, Vol.14, edited by Lipkowitz, K.B. and Boyd, D.B. (John Wiley & Sons, New York, 2000) p.225.CrossRefGoogle Scholar
42. Beyer, T.Lewis, T. and Price, S.L.Cryst. Eng. Comm. 44 (2001) p.1.Google Scholar
43. Dunitz, J.D.Chem. Commun. (2003) p. 545.Google Scholar
44. Haleblian, J.K.J. Pharm. Sci. 64 (1975) p.1269.CrossRefGoogle Scholar
45. Walker, E.M.Roberts, K.J. and Maginn, S.J.Langmuir 14 (1998) p.5620.CrossRefGoogle Scholar
46. Weissbuch, I.Popovitz-Biro, R., Lahav, M. and Leiserowitz, L.Acta Crystallogr., Sect. B: Struct. Sci. 51 (1995) p.115.CrossRefGoogle Scholar
47. Addadi, L.Weinstein, S.Gati, E.Weiss-buch, I., and Lahav, M.J. Am. Chem. Soc. 104 (1982) p.4610.CrossRefGoogle Scholar
48. Addadi, L.Berkovitch-Yellin, Z., Weiss-buch, I., Lahav, M. and Leiserowitz, L.Mol. Cryst. Liq. Cryst. 96 (1982) p.1.CrossRefGoogle Scholar
49. Davey, R.J.Blagden, N.Potts, G.D. and Docherty, R.J.Am. Chem. Soc. 119 (1997) p.1767; T. Mukuta A.Y. Lee T. Kawakami and A.S Myer-son, Cryst. Growth Des. 5 (2005) p.1429.CrossRefGoogle Scholar
50. Addadi, L.Berkovitch-Yellin, Z., Domb, N.Gati, E.Lahav, M. and Leiserowitz, L.Nature 296 (1982) p.21.CrossRefGoogle Scholar
51. Kahr, B. and Gurney, R.W.Chem. Rev. 101 (2001) p.893.CrossRefGoogle Scholar
52. Colfen, H. and Qi, L.Chem. Eur. J. 7 (2001) p.106.3.0.CO;2-D>CrossRefGoogle Scholar
53. Kuldipkumar, A. Y.Tan, T.F.Goldstein, M.Nagasaki, Y.Zhang, G.G.Z. and Kwon, G.S.Cryst. Growth Des. 5 (2005) p.1781.CrossRefGoogle Scholar
54. Rasenack, N. and Muller, B.W.Int. J. Pharm. 244 (2002) p.45.CrossRefGoogle Scholar
55. Khan, G.M. and Jiabi, Z.Drug Dev. Ind. Pharm. 24 (1998) p.463.CrossRefGoogle Scholar
56. Wood, W.M.L.Powd. Technol. 121 (2001) p.53.CrossRefGoogle Scholar
57. Chikhalia, V.Forbes, R.T.Storey, R.A. and Ticehurst, M.Eur. J. Pharm. Sci. 27 (2006) p. 19.CrossRefGoogle Scholar
58. Zeng, X.M.Martin, G.P.Marriott, C. and Pritchard, J., Int. J.Pharm. 200 (2000) p.93.CrossRefGoogle Scholar
59. Brunsteiner, M. and Price, S.L., Cryst. Growth Des. 1 (2001) p.447.CrossRefGoogle Scholar
60. Liu, X.Y.Boek, E.S.Briels, W.J. and Ben-nema, P., Nature 374 (1995) p. 342; D. Winn and M.F. Doherty AIChe J. 44 (1998) p.2501.CrossRefGoogle Scholar
61. Boerrigter, S.X.M.Cuppen, H.M.Ristic, R.I.Sherwood, J.N.Bennema, P. and Meekes, H.Cryst. Growth. Des. 2 (2002) p.357.CrossRefGoogle Scholar
62. Berkovitch-Yellin, Z., J. Am. Chem. Soc. 107 (1985) p.8239.CrossRefGoogle Scholar
63. Mougin, P.Clydesdale, G.Hammond, R.B. and Roberts, K.J.J. Phys. Chem. B107 (2003) p.13262.CrossRefGoogle Scholar
64. Hickey, A.J. ed., Pharmaceutical Inhalation Aerosol Technology (Marcel Dekker, New York, 1992).Google Scholar
65. Lipinski, C.A.Am. Pharm. Rev. 5 (2002) p.82.Google Scholar
66. Horn, D. and Rieger, J., Angew. Chem. Int. Ed. 40 (2001) p.4330.3.0.CO;2-W>CrossRefGoogle Scholar
67. Liversidge, G.G. and Cundy, K.C.Int. J.Pharm. 125 (1995) p.91.CrossRefGoogle Scholar
68. Shakhtshneider, T.P. and Boldyrev, V.V. in Reactivity of Molecular Solids, edited by Boldyreva, E.V. and Boldyrev, V.V. (John Wiley & Sons, Chichester, 1999) p.271.Google Scholar
69. Kipp, J.E.Int. J. Pharm. 284 (2004) p. 109; B.E. Rabinow Nat. Rev. Drug Disc. 3 (2004) p.785.CrossRefGoogle Scholar
70. Midler, M. Jr, Paul, E.P.Whittington, E.F.Futran, M.Liu, P.D.>Hsu, J., and Pan, S.H. “Crystallization method to improve crystal structure and size,” U.S. Patent No. 5,314,506 (May 24, 1994).Hsu,+J.,+and+Pan,+S.H.+“Crystallization+method+to+improve+crystal+structure+and+size,”+U.S.+Patent+No.+5,314,506+(May+24,+1994).>Google Scholar
71. York, P.Kompella, U.B. and Shekunov, B.Y. eds., Supercritical Fluid Technology for Drug Product Development (Marcel Dekker, New York, 2004).CrossRefGoogle Scholar
72. Sacchetti, M. and Van Oort, M.M., in Inhalation Aerosols, edited by Hickey, A.J. (Marcel Dekker, New York, 1996) p.337.Google Scholar
73. Yano, J., Furedi-Milhofer, H., Wachtel, E. and Garti, N.Langmuir 16 (2000) p.10005.CrossRefGoogle Scholar
74. Kitaigorodsky, A.I.Molecular Crystals and Molecules (Academic Press, New York, 1973).Google Scholar
75. Mullin, J.W.Crystallization (Butterworth-Heinemann, Boston, 2001).Google Scholar
76. Lee, A.Y.Lee, I.S. and Myerson, A.S.Chem. Eng. Technol. 29 (2006) p.281.CrossRefGoogle Scholar