title: Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs.
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.
authors: Physical Chemistry, Analytical Research Laboratories, Eisai Product Creation Systems, Eisai Company Ltd., Tsukuba, Ibaraki 300-2635, Japan. s3-ozaki@hhc.eisai.co.jp
authors: Shunsuke
authors: S
authors: Ozaki
authors: Ikuo
authors: I
authors: Kushida
authors: Taro
authors: T
authors: Yamashita
authors: Takashi
authors: T
authors: Hasebe
authors: Osamu
authors: O
authors: Shirai
authors: Kenji
authors: K
authors: Kano
mesh_terms: D003460:Crystallization; D065347:Hypromellose Derivatives; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D011109:Polymethacrylic Acids; D014867:Water; C038300:methylmethacrylate-methacrylic acid copolymer; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D011205:Povidone