Dissolution testing profile assessment

The plasma concentration-time data of a test formulation can be predicted from a dissolution-time profile, obtained from the in vitro model, and measured plasma concentrations for a reference formulation in the IVIVC bioavailability study (e.g., an oral solution), by use of convolution (see previous section). The difference in Cmax and AUC based on predicted and measured plasma concentrations can be numerically assessed for each formulation by a simple estimation of the relative difference, denoted prediction error (PE), as follows ... 

The accuracy of a method should be assessed using a minimum of nine determinations conducted over a minimum range of three concentration levels (80%, 100%, and 120% of the target concentration) [37]. Experience from our laboratory has showed that by using at least five levels of concentrations in duplicate (i.e., 80%, 90%i, 100%i, 110%, and 120% of the target concentration), a better result can be achieved. For dissolution studies, the accuracy of the required profile should be tested at 40%, 75%, and 110% of the theoretical release) [20],... 

For 12-hour controlled-release tablets, the accuracy of the 12-hour dissolution profile obtained from in situ measurements was assessed by comparison with measurements obtained by manual withdrawal and analysis by HPLC. The results (Fig. 22) obtained by two analysts on different days show that the 12-hour dissolution profile obtained from in situ fiber-optic-probe-based measurements is as accurate as that obtained by the automated withdrawal of the sample and analysis by HPLC. In addition, in situ measurements were obtained with fiber-optic probes placed in the medium at the USP sampling position throughout the test, whereas the cannulas used to manually withdraw medium were inserted and removed at each measurement interval. The fiber-optic dissolution system displays excellent stability and validation char-... 

In addition to the online analyses described, offline tests are also required. Specifically, standard release tests such as a product s dissolution profile and any degradation products must be assessed. If not obtained online via PAT, the assay and content uniformity of extrudate must be measured via off-line lab tests. Any residual solvents (including water) should be measured as they can have a plasticizing effect potentially influencing both extrudate physical and chemical stability. Finally, tests such as differential scaling calorimetry (DSC), X-ray diffraction (XRD), or others must be conducted before and after holding the product at controlled environmental conditions, to ensure that the phase state of the extrudate is understood and controlled over time. 

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