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Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs

Authors

  • Shunsuke Ozaki,

    Corresponding author
    1. Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan
    2. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan
    • Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan. Telephone: +81-29-847-5626; Fax: +81-29-847-5771
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  • Ikuo Kushida,

    1. Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan
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  • Taro Yamashita,

    1. Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan
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  • Takashi Hasebe,

    1. Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan
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  • Osamu Shirai,

    1. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan
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  • Kenji Kano

    1. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan
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Abstract

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2273–2281, 2013

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