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Particle Engineering: Fundamentals of Particle Formation and Crystal Growth

  • Alfred Y. Lee and Allan S. Myerson


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.



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1. Paul, E.L.Tung, H.H. and Midler, M.Powd. Technol. 150 (2005) p. 133.
2. Shekunov, B.Y. and York, P.J. Cryst. Growth 21 1 (2000) p. 122.
3. Desiraju, G.Crystal Engineering: The Design of Organic Solids (Elsevier, Amsterdam, 1989).
4. Erk, P.Hengelsberg, H.Haddow, M.F. and Gelder, R. Van, Cryst. Eng. Comm. 6 (2004) p. 474.
5. Volmer, M.Kinetik der Phasenbildung (Steinkopff, Germany, 1939).
6. Oxtoby, D.W.Acc. Chem. Res. 31 (1998) p. 91.
7. Vekilov, P.G.Cryst. Growth Des. 4 (2004) p.671.
8. Schuth, F.Curr. Opin. Solid State Mater. Sci. 5 (2001) p.389.
9. Oxtoby, D.W.Philos. Trans. R. Soc. London Ser. A. 361 (2003) p.419.
10. ten Wolde, P.R. and Frenkel, D.Science 277 (1997) p.1975.
11. Shore, J.D.Perchak, D. and Shnidman, Y.J.Chem. Phys. 113 (2000) p.6276.
12. Galkin, O. and Vekilov, P.G.J.Am. Chem. Soc. 122 (2000) p.156.
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.
14. Kimura, M.Cryst. Growth Des. 6 (2006) p.854.
15. Garetz, B.A.Matic, J. and Myerson, A.S.Phys. Rev. Lett. 89 175501 (2002).
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.
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.
18. Bernstein, J., Polymorphism in Molecular Crystals (Oxford University Press, New York, 2002).
19. Henck, J.O.Griesser, U.J. and Burger, A.Pharm. Ind. 59 (1997) p.165.
20. Caira, M.R. in Topics in Current Chemistry, Vol. 198, edited by Weber, E. (Springer, New York, 1998) p.163.
21. Briancon, S. and Fessi, H.STP Pharma. Prat. 13 (2003) p.215; E. Doelker STP Pharma. Prat. 9 (1999) p.399.
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.
23. Chen, X.Morris, K.R.Griesser, U.J.Byrn, S.R. and Stowell, J.G.J. Am. Chem. Soc. 124 (2002) p.15012.
24. Dunitz, J.D. and Bernstein, J., Acc. Chem. Res. 28 (1995) p. 193.
25. Gavezzotti, A. and Filippini, G.J.Am. Chem. Soc. 117 (1995) p.12299.
26. Bauer, J.Spanton, S.Henry, R.Quick, J.Dziki, W.Porter, W. and Morris, J.Pharm. Res. 18 (2001) p.859.
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.
28. Janik, M.Malarski, Z.Mrozinski, J.Wajcht, J. and Zborucki, Z., J. Crystallogr. Spectrosc. Res. 21 (1991) p.519.
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.
30. Furedi-Milhofer, H., Garti, N. and Kamyshny, A.J. Cryst. Growth 198–199 (1999) p.1365.
31. Ha, J.M.Wolf, J.H.Hillmyer, M.A. and Ward, M.D.J.Am. Chem. Soc. 126 (2004) p.3382.
32. Lee, A.Y.Lee, I.S.Dette, S.S.Boerner, J. and Myerson, A.S.J. Am. Chem. Soc. 127 (2005) p.14982.
33. Price, C.P.Grzesiak, A.L. and Matzger, A.J.J.Am. Chem. Soc. 127 (2005) p.5512.
34. Hiremath, R.Basile, J.A.Varney, S.W. and Swift, J.A.J.Am. Chem. Soc. 127 (2005) p.18321.
35. Chen, S.Xi, H. and Yu, L.J. Am. Chem. Soc. 127 (2005) p.17439.
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.
37. Price, S.L.Adv. Drug. Delivery Rev. 56 (2004) p.301.
38. Docherty, R. and Meenan, P. in Molecular Modeling Applications in Crystallization, edited by Myerson, A.S. (Cambridge University Press, Cambridge, 1999) p.106.
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.
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.
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.
42. Beyer, T.Lewis, T. and Price, S.L.Cryst. Eng. Comm. 44 (2001) p.1.
43. Dunitz, J.D.Chem. Commun. (2003) p. 545.
44. Haleblian, J.K.J. Pharm. Sci. 64 (1975) p.1269.
45. Walker, E.M.Roberts, K.J. and Maginn, S.J.Langmuir 14 (1998) p.5620.
46. Weissbuch, I.Popovitz-Biro, R., Lahav, M. and Leiserowitz, L.Acta Crystallogr., Sect. B: Struct. Sci. 51 (1995) p.115.
47. Addadi, L.Weinstein, S.Gati, E.Weiss-buch, I., and Lahav, M.J. Am. Chem. Soc. 104 (1982) p.4610.
48. Addadi, L.Berkovitch-Yellin, Z., Weiss-buch, I., Lahav, M. and Leiserowitz, L.Mol. Cryst. Liq. Cryst. 96 (1982) p.1.
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.
50. Addadi, L.Berkovitch-Yellin, Z., Domb, N.Gati, E.Lahav, M. and Leiserowitz, L.Nature 296 (1982) p.21.
51. Kahr, B. and Gurney, R.W.Chem. Rev. 101 (2001) p.893.
52. Colfen, H. and Qi, L.Chem. Eur. J. 7 (2001) p.106.
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.
54. Rasenack, N. and Muller, B.W.Int. J. Pharm. 244 (2002) p.45.
55. Khan, G.M. and Jiabi, Z.Drug Dev. Ind. Pharm. 24 (1998) p.463.
56. Wood, W.M.L.Powd. Technol. 121 (2001) p.53.
57. Chikhalia, V.Forbes, R.T.Storey, R.A. and Ticehurst, M.Eur. J. Pharm. Sci. 27 (2006) p. 19.
58. Zeng, X.M.Martin, G.P.Marriott, C. and Pritchard, J., Int. J.Pharm. 200 (2000) p.93.
59. Brunsteiner, M. and Price, S.L., Cryst. Growth Des. 1 (2001) p.447.
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.
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.
62. Berkovitch-Yellin, Z., J. Am. Chem. Soc. 107 (1985) p.8239.
63. Mougin, P.Clydesdale, G.Hammond, R.B. and Roberts, K.J.J. Phys. Chem. B107 (2003) p.13262.
64. Hickey, A.J. ed., Pharmaceutical Inhalation Aerosol Technology (Marcel Dekker, New York, 1992).
65. Lipinski, C.A.Am. Pharm. Rev. 5 (2002) p.82.
66. Horn, D. and Rieger, J., Angew. Chem. Int. Ed. 40 (2001) p.4330.
67. Liversidge, G.G. and Cundy, K.C.Int. J.Pharm. 125 (1995) p.91.
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.
69. Kipp, J.E.Int. J. Pharm. 284 (2004) p. 109; B.E. Rabinow Nat. Rev. Drug Disc. 3 (2004) p.785.
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).
71. York, P.Kompella, U.B. and Shekunov, B.Y. eds., Supercritical Fluid Technology for Drug Product Development (Marcel Dekker, New York, 2004).
72. Sacchetti, M. and Van Oort, M.M., in Inhalation Aerosols, edited by Hickey, A.J. (Marcel Dekker, New York, 1996) p.337.
73. Yano, J., Furedi-Milhofer, H., Wachtel, E. and Garti, N.Langmuir 16 (2000) p.10005.
74. Kitaigorodsky, A.I.Molecular Crystals and Molecules (Academic Press, New York, 1973).
75. Mullin, J.W.Crystallization (Butterworth-Heinemann, Boston, 2001).
76. Lee, A.Y.Lee, I.S. and Myerson, A.S.Chem. Eng. Technol. 29 (2006) p.281.



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