Issue link: https://www.e-digitaleditions.com/i/1233462
38 April 2020 Tablets & Capsules are ultimately converted into smaller micelles, which significantly increase the API's solubilization capacity in the gastrointestinal milieu. For these reasons, any in vitro dis- persion testing in the absence of gas- tric and lipolytic media is not repre- sentative of a lipid formulation's in vivo API solubilization capacity and should be used as a characterization tool only. Instead, monitor API sol- ubility under in vitro lipolysis condi- tions, where the SEDDS formulation is dispersed into a buffer with bile salts, and the API in the water phase is monitored with addition of pancre- atic lipase using a pH-stat. DON'T expect enhanced bio- availability if the API isn't solu- bilized in any of the SEDDS components. If a poorly soluble API is dispersed but not solubilized in any lipid vehi- cle in a SEDDS, the API can precip- itate out upon dilution. As a result, it won't be able to participate in the lipolysis process with the lipid vehi- cle as described previously. Optimizing screening for stability and manufacturability DO perform API-excipient com- patibility studies and also consider capsule-shell compatibility. As with any other formulation development, API-excipient com- patibility studies should be part of a SEDDS formulation screening. These studies can be performed by assaying the API in the mixture under forced conditions. Capsule-shell compatibil- ity can be assessed by consulting both the excipient and capsule suppliers. DO consider processing the formulations under vacuum. Manufacturing a SEDDS formu- lation includes a mixing process that occurs either at ambient conditions for liquid formulations or at an ele- vated temperature for solid formula- tions. Processing under vacuum pre- vents air from incorporating into the liquid during mixing. DON'T select two-piece cap- sules for liquid for mulations ubility results and enhanced bioavail- ability. For solid vehicles that become molten at or above their melting points (40°-65°C) before adding the API, DO consider the effect of the short heating and cooling rate on the API-formulation stability. DO select an API dose below 80 percent of the saturation con- centration to avoid nearing the saturation point. A supersaturated solution might be beneficial for bioavailability enhancement. However, supersatu- ration can also jeopardize the formu- lation's physical stability and lead to potential API crystallization during the product's shelf life. D O N ' T e x p e c t l y m p hat i c uptake if the API isn't highly lipo- philic or if your formulation con- sists of short-chain fatty acids. E x c i p i e n t s c o n t a i n i n g l o n g - chain fatty acids such as oleate and linoleate help boost the lymphatic absorption of highly lipophilic APIs that have logP values of 5 or higher. This strategy can be used to avoid the first-pass effect. However, the API needs to have enough lipophilicity and affinity to the oily vehicle (sol- ubility 50 mg/g) to be absorbed and circulated in the lymphatic system. DO evaluate the dispersion size in an aqueous medium or conven- tional dissolution test as a char- acterization tool only, not as an in vitro screening tool. DO test the formulation under lipolysis conditions. Lipid digestion in the gut is the main physiological event that enhances the bioavailability of poorly soluble compounds. Lipoly- sis begins in the stomach with gas- tric lipase and continues in the duo- denum with pancreatic lipase and colipase. A SEDDS formulation con- taining an oily vehicle in a capsule first disperses then emulsifies in the gastrointestinal fluids spontaneously. Lipolysis in the presence of lipases and bile salts creates colloidal struc- tures such as unilamellar and multi- lamellar vesicles and mixed micelles. The initial larger colloidal structures tions requires in vitro lipolysis testing, which assesses the formulation's per- formance upon dilution in the pres- ence of lipolytic enzymes. While performing these screening steps, it's important to strike a bal- ance between bioavailability, stabil- ity, and manufacturability. The fol- lowing are some DOs and DON'Ts to help you optimize the screen- ing and development process for a SEDDS formulation. Optimizing screening for solubility and bioavailability DO deter mine equilibr ium solubility at ambient conditions, even in solid vehicles. DON'T use kinetic solubility to determine the API concentration or dosage in the lipid vehicle(s). Saturation solubility in liquid vehicles can be determined by equil- ibrating the API at room tempera- ture and assaying using high-per- formance liquid chromatography (HPLC). In solid lipids, equilibration can be first achieved at elevated tem- perature. Then, the solidified mix- ture (after 24 hours of repose) can be examined by differential scanning calorimetry (DSC) and/or hot-stage microscopy (HSM) to determine its saturation concentration at room temperature. The melting enthalpy depression of the solid lipid at var- ious concentrations is observed by the DSC method. When the concentration is at the saturation point, a break will be observed in the slope of melt- ing enthalpy versus concentration. HSM provides visual observation of any undissolved API crystals under cross-polarized light upon rapid heating (30°C/min) of the solid excipient. For effective results using HSM, the API's melting point should be 10°C higher than the excipient's melting point. DO screen API solubility in a wide range of excipients, and DON'T limit selections to liquid vehicles only. Depending on the API, some solid excipients can provide sufficient sol-