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1.
J Pharm Biomed Anal ; 151: 200-208, 2018 Mar 20.
Article in English | MEDLINE | ID: mdl-29353808

ABSTRACT

This paper describes the development of a simple reversed-phase HPLC method that can quantitate trace amounts of a polymeric degradants (BMT-041910) in asunaprevir drug substance and formulated drug product with quantitation limits of ∼0.05% w/w. The method has overcome several challenges of polymer quantitation such as band broadening, peak coeluting and low sensitivity. The hydrophobic function group (BOC) of BMT-041910 is removed to increase its aqueous solubility by a simple sample treatment procedure (des-BOC). The des-BOC polymer (BMT-052076) is excluded from stationary phase pores and eluted as a single peak before solvent front, and then its peak area response can be used to determine BMT-041910 amount. The HPLC conditions were optimized using a 250 × 4.6 mm Waters XSelect CSH column maintained at 30 °C with a mobile phase of water-acetonitrile-trifluoroacetic acid (20:80:0.1 v/v/v). The feasibility of other HPLC approaches including size exclusion chromatography and normal phase chromatography were also investigated and found to be less suitable for this particular application. Validation data for this method in terms of precision, linearity, accuracy and sensitivity are also presented.


Subject(s)
Drug Contamination/prevention & control , Isoquinolines/analysis , Protease Inhibitors/analysis , Sulfonamides/analysis , Technology, Pharmaceutical/methods , Acetonitriles/chemistry , Chemistry, Pharmaceutical/methods , Chromatography, Gel/methods , Chromatography, High Pressure Liquid/methods , Hydrophobic and Hydrophilic Interactions , Polymers/analysis , Reproducibility of Results , Sensitivity and Specificity , Solvents/chemistry , Trifluoroacetic Acid/chemistry
2.
AAPS PharmSciTech ; 15(2): 407-16, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24442773

ABSTRACT

This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.


Subject(s)
Chemistry, Pharmaceutical , Food-Drug Interactions , Animals , Dogs , Humans , Solubility
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