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42 May 2016 Tablets & Capsules formulations are pegylated esters, polyethoxylated sorbitan esters, and polyethoxylated glycerides. Pegylated esters are manufactured through the esterification of polyethylene glycol with its respective fatty acids, the rearrangement of oils and alcohols, or the direct in situ ethoxylation of par- tial glycerides. Polyethoxylated castor oil is prepared by reacting ethylene oxide with castor oil, and polyethoxy- lated sorbitan esters are made through the esterification of polyethoxylated sorbitan with its respective fatty acids after cyclization of sorbitol. Pre-concentrate formulation There are four general steps in for- mulating a pre-concentrate for a SEDDS: 1) select the pre-concentrate component candidates, 2) determine the maximum API solubility in the pre-concentrate components, 3) determine the emulsion's characteris- tics upon pre-concentrate dilution, and 4) conduct in vitro evaluation of the pre-concentrate, including disso- lution testing and other physiochemi- cal characterization. Select component candidates. First, determine the aqueous solubil- ity, log P, melting point, and solubil- ity parameter of the API. Typically, a log P greater than four indicates that a fully esterified solubilizer should be included in the pre-concentrate [1]. By matching the required HLB of the solubilized API to the HLB values of the proposed SEDDS components, you can select SEDDS pre-concen- trate candidates for a solubility study. Determine maximum API solubil- ity. Once you identify candidate SEDDS pre-concentrate compo- nents, determine the maximum API solubility in all candidates. This can be done by adding an excess of API to each of the SEDDS pre-concen- trate candidate components individu- ally or in combination, if desired. These combinations are then vor- texed in order to adequately disperse the API in the SEDDS pre-concen- trate candidates. Next, the vortexed combinations are shaken by wrist action for 24 hours at 37°C, and the solutions are then allowed to stand for 24 hours at 25°C. The last step is to filter and analyze the combina- tions for API content in order to determine the maximum API solubil- ity in each pre-concentrate candidate or in selected candidate mixtures. Determine the emulsion's charac- teristics. After you determine the maximum solubility, the SEDDS pre- are plotted on two vertices and water occupies the third vertex. Next, binary mixtures—containing different concentrations of the pre-concentrate base components and of the pre-con- centrate surfactant components—are diluted systematically with water, and the phase characteristics of these combinations are observed (usually by eye). You can then evaluate the droplet size where desired in the phase diagram. The most common phase observations are emulsion for- mation, micro-emulsion formation, or gel formation. Figure 2 shows an example of a phase diagram [2]. The emulsion's characteristics can be very important to bioavailability considerations. This has been shown in the case of cyclosporine A, where the micro-emulsion was much more bioavailable than the emulsion [3]. The optimization of SEDDS pre-con- centrate components focuses on both maximizing the solubility of the API in the SEDDS pre-concentrate and on the emulsion performance of the pre-concentrate upon dilution with water. The emulsion's droplet size and its stability are of specific interest because they will ultimately affect the absorption of the API and, subse- quently, the API's bioavailability. Table 1 provides a classification sys- tem for lipid formulations according to their makeup and droplet size [1]. Conduct in vitro evaluation, including dissolution testing. In vitro dissolution testing is important to demonstrate the API's superior aqueous solubility in the optimized SEDDS system compared to the same API in a non-SEDDS formulation. Additionally, in vitro testing can allow you to analyze the pre-concen- trate behavior under sink conditions. The dissolution parameters you choose can be adjusted based upon each individual formulation project. Researchers at St. John's University have suggested an in vitro dispersion test [4], a method that employs a dis- solution tester outfitted with USP Apparatus 2 (0.01 M HCl, 37°C, 50 rpm). Both API concentration and emulsion droplet size are analyzed over time as a means of determining API release and how the SEDDS per- Figure 1 Time-elapsed photos of simvastatin dissolving in SEDDS pre-concentrate 0 seconds 126 seconds 252 seconds 378 seconds 504 seconds concentrate components that can dis- solve the greatest amount of the API are plotted in various concentrations on a phase diagram. Typically, indi- vidual known combinations of the SEDDS pre-concentrate components