Probing the mechanisms of drug release from amorphous solid dispersions

Oral delivery of poorly water-soluble drugs has presented growing challenges for pharmaceutical scientists looking to maximize drug absorption in the body because poor aqueous solubility often leads to low bioavailability and suboptimal therapeutic effects.

To combat the limitations of these drugs, pharmaceutical scientists often convert low solubility crystalline drugs into amorphous solid dispersions (ASDs) using soluble polymer carriers to stabilize the amorphous drug formulations, which provide accelerated rate of dissolution and elevated kinetic solubility thereby improving oral absorption. However, it is well known that these formulations based on soluble carriers frequently spur a heavily spiked drug supersaturation up front, which tapers off quickly triggered by the drug precipitation under nonsink dissolution conditions in the gastrointestinal track. On the other hand, recent studies from the Lee group have shown that ASDs based on medium-insoluble hydrogels produced a modest buildup of supersaturation and maintained a sustained supersaturation over an extended period. There is no a priori reason why the supersturation produced by ASDs based on medium-insoluble carriers should be sustained and not resulting in the typical surge and decline in supersaturation profiles as that of medium-soluble carriers. As a result, there are still unanswered questions regarding the mechanisms at work that differentiate the dissolution and supersturation behavior of amorphous drugs from solid dispersions based on medium-soluble versus medium-insoluble carriers under nonsink dissolution conditions.

To bridge this knowledge gap, Professor Ping Lee and PhD graduate Dajun Sun recently published a paper, “Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers,” that was featured on the cover of the most recent issue of Journal of Controlled Release.

Using a simple but clever experimental design to control polymer solubility and mode of drug release, this study differentiates the dissolution and supersaturation behaviours of ASDs in medium-soluble and medium-insoluble polymer carriers under nonsink conditions by employing pH-dependent carrier polymers which provide an easy way of controlling the polymer solubility and thus the mechanism of supersaturation buildup by altering the solution pH. In so doing, Professor Lee and Dr. Sun show that the supersaturation profile of the medium-insoluble carriers are distinctively different than those based on conventional medium-soluble carriers, as they lack the initiation surge of supersaturation and provide sustained supersaturation profiles without the use of crystallization inhibitors because the drug release is controlled by a matrix diffusion-regulated mechanism. Such a direct head-to-head comparison provides unequivocal evidence of the transition of supersatuation kinetic profiles from the same ASD induced only by changing the pH of the dissolution medium.

In the commentary that accompanies this study, Journal of Controlled Release editor-in-chief Professor Kinam Park notes that based on “an important discovery” made by the Lee group that a previously unknown parameter, the rate of supersaturation, is actually a critical factor impacting the overall supersaturation kinetic profiles, the present study “demonstrates that the characteristic sustained supersaturation behavior can be obtained in ASDs using medium-insoluble carriers.” It also shows “that the same ASDs can exhibit different supersaturation profiles when the same pH-dependent carrier polymers are rendered soluble or insoluble by changing the pH of the medium.”

Professor Park also observes how “the mechanistic insights gained here should open new avenues for improving the in vivo supersaturation behaviours of poorly water-soluble drugs through selecting appropriate medium-soluble and/or medium-insoluble ASD carriers.” 

Ultimately, this discovery by Professor Lee and Dr. Sun (now working at the US Food and Drug Administration) should enable formulation scientists to “adopt and utilize different release mechanisms from soluble and insoluble solid dispersion matrices when designing appropriate supersaturating systems to achieve desired kinetic solubility profiles for poorly water-soluble drugs potentially leading to enhanced oral availability.”