Rapid determination of drug solubilization versus supersaturation in natural and digested lipids

Abstract

Lipid-​based formulations (LBFs) represent one of the successful formulation approaches that enable oral delivery of poorly water-​sol. drugs. This work presents a simple equil. approach based on soly. in lipids and their corresponding digestion media to est. a max. drug supersatn. ratio (SRmax)​. This value of drug concn. normalized by the soly. in the aq. digestion phase indicates the propensity for drug pptn. A set of 16 structurally diverse drugs was first measured for their soly. in tricaprin and tricaprylin and results were compared to an empirical model based on mol. predictors. In the next step, digestion media were either prepd. by in vitro lipolysis or by assembling a compn. to mimic the endpoint of digestion. It was found that drug soly. in the pure lipids mainly was related to the m.p. in that increased values resulted in reduced soly. The soly. values measured in the lipolysis media correlated well with those obtained from assembled digestion media. Interestingly, the solubilization upon digestion was typically higher when using tricaprin than tricaprylin in spite of that the latter oil (as pure excipient) generally was a more potent solvent. This work suggests that a simplified digestion screen can be used to facilitate evaluation of formulations during early development. Estn. of SRmax provides an early risk assessment of drug pptn. for LBFs. The method is easily scaled down to the microtiter plate format and can be used for selecting candidate formulations that merit further evaluation in more complex and dynamic in vitro tests.