Development of a two-step tier-2 dissolution method for blinded overencapsulated erlotinib tablets using UV fiber optic detection.

摘要

Measuring dissolution of a comparator drug overencapsulated in a hard gelatin shell is necessary when determining performance of the native and blinded formulations. However, the gelatin in the shell may form cross-links upon storage at stressed conditions, resulting in slow dissolution of the encapsulated drug. The aim of this study was to develop a dissolution approach for a hard-gelatin overencapsulated formulation of a comparator drug, erlotinib, which can overcome cross linking of the capsule shell. In this case, following the USP two-tier dissolution test by simply adding an enzyme did not dissolve the cross-linked capsules because the medium used in the method for erlotinib described in the FDA Dissolution Database contains sodium dodecyl sulfate that inhibits the activity of the enzyme. Changing the method by using different surfactants was not considered acceptable because it is preferable to closely follow the compendial method for the comparator. A two-step tier-2 method was developed as a solution, without significant change to the compendial method conditions. It uses 0.1N HCl + pepsin as the initial medium to help capsule break-up. SDS is added at 15 min after the testing starts to ensure dissolution of the drug. This may be a useful general approach for dealing with cross-linking in over-encapsulated comparators. A UV fiber optic spectrophotometer was used for in situ, real-time detection of the dissolution profile during method development studies. The fast sampling rate available with this type of detection was important in elucidating the events occurring during dissolution and determining the optimal time of the SDS addition.