Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study

showed that the original formulation for the tablets led to a significant increase of unknown degradants in

the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS

layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

Key words bilayer tablet; interface; mass spectroscopy; maltose; compatibility

Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets
Naoya Matsuzaki,a,b Yousuke Yamamoto,a Daisuke Murayama,a Yoshifumi Katakawa,a
Hisashi Mimura,a Shin-ichiro Kimura,b Yasunori Iwao,b and Shigeru Itai*,b
a Analytical Research Laboratories, Technology, Astellas Pharma Inc.; 180 Ozumi, Yaizu, Shizuoka 425–0072,
Japan: and b Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, University of Shizuoka;
52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.
Received November 29, 2016; accepted February 13, 2017
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