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there is too little plasticizer, the capsules could become too brittle, while too much plasticizer could cause soften- ing and clumping. Migration of the plasticizer from the fill to the shell often leads to shell softening, even under stable conditions, or crystallization of the fill. With the proper ratio, you can optimize the shell's mechanical properties and ensure the fill's physicochemical stability. After finding the gelatin-to-plasticizer ratio that will give the product its critical quality attributes—such as dis- solution performance—it is important to identify poten- tial sources of reactive impurities in the excipients, such as peroxides or aldehydes, that could lead to crosslinking when the product undergoes stability testing. The following case study illustrates how these consid- erations can be put into practice during formulation of and analytical development for an oil-filled softgel. Case study For product formulation, we studied the effect of the gelatin type and the plasticizer use level on disintegration time using a factorial design of two variables at two levels (2 2 ). The results show that the gelatin type had a signifi- cant effect on disintegration time at the 95 percent confi- dence level. Figure 1 shows that the type B gelatin in combination with the highest use level of plasticizer pro- duced the fastest disintegration results. For analytical development, we first had to establish the dissolution conditions because the product is not compendial. We began by defining the dissolution media. The fill material is oil, and therefore poorly solu- ble, so the use of a surfactant was critical during in vitro dissolution testing. To select the type and use level of surfactant, we determined the dissolution profiles by test- ing USP recommended surfactants [3]. They included Tween (Croda, Edison, NJ), Triton X-100 (Dow, Midland, MI), sodium lauryl sulfate (Spectrum, Gardena, CA) Labrasol (Gattefossé, Paramus, NJ), and Cremophor 40 (BASF, Florham Park, NJ) at different use levels using USP apparatus 3 (reciprocating cylinder) for 60 minutes. Figure 2 shows the results. An aqueous solution of Triton X-100 at 5 percent was selected because it showed the highest percentage of API dissolved from 5 to 60 minutes and is selective. The results obtained using this apparatus were accurate and precise, reaching values close to 100 percent, with low relative standard deviation (RSD), as the error bars in Figure 2 show. Next, the dissolution profile was determined using USP apparatuses 2 (paddle) and 3, using a sinker in both cases, as well as in open and closed systems of USP appa- ratus 4, which used a modified flow-through cell designed for softgels. See Figure 3. Tablets & Capsules May 2017 35 Figure 1 Contour plot of disintegration time of oil-filled softgels based on gelatin type (A and B) and use level of plasticizer Figure 2 Dissolution profiles of oil-filled softgels using different surfactants at recommended levels in apparatus 3 Figure 3 Dissolution profiles of oil-filled softgels using different USP dissolution apparatuses 20.0 18.75 17.5 16.25 15.0 19.0 16.0 13.0 10.0 7.0 Gelatin type B A Plasticizer 120 100 80 60 40 20 0 0 10 20 30 40 50 60 ∞ % dissolved Time (min) 140 120 100 80 60 40 20 0 0 10 20 30 40 50 60 % dissolved Time (min) 5% Tween a 5% Triton X-100 b 3% SLS c 5% Labrasol d 10% Labrasol e 3% Cremophor 40 f Notes: Softgels and surfacants were tested using a 250-milliliter reciprocating cylinder at 30 dips per minute with 40 mesh screens. a. Polyoxyethylene 20 sorbitan monolaurate b. Octylphenol ethoxylate c. Sodium lauryl sulfate d. Caprylocaproyl polyoxylglycerides e. Polyoxyl 40 hydrogenated castor oil Note: 5 percent Triton X-100 in water at 37˚C USP 2 USP 3 USP 4 (closed) USP 4 (open) The fill material is oil, and therefore poorly soluble, so the use of a surfactant was critical during in vitro dissolution testing.