title: Inhibition of a solid phase reaction among excipients that accelerates drug release from a solid dispersion with aging.
abstract: Hydrophobic drug substances can be formulated as a solid dispersion or solution using macromolecular matrices with high glass transition temperatures to attain satisfactory dissolution. However, very few marketed products have previously relied on solid dispersion technology due to physical and chemical instability problems, and processing difficulties. In the present study, a modified release product of a therapeutic drug for hypertension, Barnidipine hydrochloride, was developed. The drug product consisted of solid dispersion based on a matrix of carboxymethylethylcellulose (CMEC), which was produced using the spray-coating method. An enteric coat layer was sprayed on the surface of the solid dispersion to control drug release. Interestingly, the release rate accelerated as the drug product aged, while there were no indications of deceleration of the release rate which was due to crystallization of the drug substance. To prevent changes in the dissolution kinetics during storage periods, a variety of processing conditions were tried. It was found that not only use of non-aqueous solvents but also a reduction in coating temperatures consistently resulted in stable solid dispersions. The molecular bases of dissolution of the drug substance from those matrices were investigated. The molecular weight of CMEC was found to be a dominant factor that determined dissolution kinetics, which followed zero-order release, suggesting an involvement of an osmotic pumping mechanism. While dissolution was faster using a higher molecular weight CMEC, the molecular weight of CMEC in the drug product slowly increased with aging (solid phase reaction) depending on the processing conditions, causing the time-induced elevation of dissolution. While no crystalline components were found in the solid dispersion, the amorphous structure maintained a degree of non-equilibrium by nature. Plasticization by water in the coating solution relaxed the amorphous system and facilitated phase separation of the drug substance and CMEC upon production. The solid phase reaction advanced differentially in the solid dispersion depending on the degree of phase separation set initially. The use of non-aqueous solvents and/or a decrease in the coating temperatures inhibited the occurrence of phase separation upon production, thereby preventing the formation of CMEC-rich phases where the solid phase reaction occurred during storage.
authors.affiliation: Pharmaceutical Research and Development Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Mizuno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirakura
authors.forename: Ikuro
authors.initials: I
authors.lastname: Yamane
authors.forename: Hideo
authors.initials: H
authors.lastname: Miyanishi
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokota
authors.forename: Munetaka
authors.initials: M
authors.lastname: Hattori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kajiyama
mesh_terms: D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008970:Molecular Weight; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical; D013696:Temperature; D013997:Time Factors
chemical_list: D005079:Excipients; D012997:Solvents; C050699:mepirodipine; D009543:Nifedipine; D002266:Carboxymethylcellulose Sodium