On the usefulness of sink index in characterizing the degree of nonsinkness in dissolution studies.

To accurately quantify the nonsinkness in dissolution testing of supersaturating formulations, our group previously introduced a dimensionless Sink Index (SI): SI = Cs/(Dose/V), where Cs is the solubility of crystalline drug, V the volume of dissolution medium, and Dose the total amount of drug in the test sample. The objective of this study is to test whether one can consistently generate similar (or superimposable) kinetic solubility profiles (KSP) from a given amorphous solid dispersion (ASD) with different volume, type of dissolution medium, and/or total dose as long as the SI value is kept constant. Dissolution results based on ASDs of model drugs fenofibrate, indomethacin, and posaconazole in polyvinylpyrrolidone and poly(2-hydroxyethyl methacrylate) show that similar (or superimposable) kinetic solubility profiles (relative difference f1 < 15) for ASDs can be achieved when conducting dissolution studies in the same dissolution medium (i.e., same composition and pH), irrespective of variations in medium volume, scale of USP dissolution apparatus, or total dose, as long as the SI value is kept constant. However, maintaining a constant SI did not generate similar kinetic solubility profiles when two different buffer media were compared (f1 ≫ 15) due to changes in API solubility and the final concentration in different media.

Evolution of supersaturation from amorphous solid dispersions in water-insoluble polymer carriers: Effects of swelling capacity and interplay between partition and diffusion.

The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.

Combined Effects of Supersaturation Rates and Doses on the Kinetic-Solubility Profiles of Amorphous Solid Dispersions Based on Water-Insoluble Poly(2-hydroxyethyl methacrylate) Hydrogels.

Under nonsink dissolution conditions, the kinetic-solubility profiles of amorphous solid dispersions (ASDs) based on soluble carriers typically exhibit so-called "spring-and-parachute" concentration-time behaviors. However, the kinetic-solubility profiles of ASDs based on insoluble carriers (including hydrogels) are known to show sustained supersaturation during nonsink dissolution through a matrix-regulated diffusion mechanism by which the supersaturation of the drug is built up gradually and sustained over an extended period without any dissolved polymers acting as crystallization inhibitors. Despite previous findings demonstrating the interplay between supersaturation rates and total doses on the kinetic-solubility profiles of soluble amorphous systems (including ASDs based on dissolution-regulated releases from soluble polymer carriers), the combined effects of supersaturation rates and doses on the kinetic-solubility profiles of ASDs based on diffusion-regulated releases from water-insoluble carriers have not been investigated previously. Thus, the objective of this study is to examine the impacts of total doses and supersaturation-generation rates on the resulting kinetic-solubility profiles of ASDs based on insoluble hydrogel carriers. We employed a previously established ASD-carrier system based on water-insoluble-cross-linked-poly(2-hydroxyethyl methacrylate) (PHEMA)-hydrogel beads and two poorly water soluble model drugs: the weakly acidic indomethacin (IND) and the weakly basic posaconazole (PCZ). Our results show clearly for the first time that by using the smallest-particle-size fraction and a high dose (i.e., above the critical dose), it is indeed possible to significantly shorten the duration of sustained supersaturation in the kinetic-solubility profile of an ASD based on a water-insoluble hydrogel carrier, such that it resembles the spring-and-parachute dissolution profiles normally associated with ASDs based on soluble carriers. This generates sufficiently rapid initial supersaturation buildup above the critical supersaturation, resulting in more rapid precipitation. Above this smallest-particle-size range, the matrix-diffusion-regulated nonlinear rate of drug release gets slower, which results in a more modest rate of supersaturation buildup, leading to a maximum supersaturation below the critical-supersaturation level without appreciable precipitation. The area-under-the-curve (AUC) values of the in vitro kinetic-solubility concentration-time profiles were used to correlate the corresponding trends in dissolution enhancement. There are observed monotonic increases in AUC values with increasing particle sizes for high-dose ASDs based on water-insoluble hydrogel matrixes, as opposed to the previously reported AUC maxima at some intermediate supersaturation rates or doses in soluble amorphous systems, whereas in the case of low-dose ASDs (i.e., below the critical dose levels), crystallization would be negligible, leading to sustained supersaturation with all particle sizes (i.e., eventually reaching the same maximum supersaturation) and the smallest particle size reaching the maximum supersaturation the fastest. As a result, the smallest particle sizes yield the largest AUC values in the case of low-dose ASDs based on water-insoluble hydrogel matrixes. In addition to probing the interplay between the supersaturation-generation rates and total doses in ASDs based on insoluble hydrogel carriers, our results further support the fact that through either increasing the hydrogel-particle size or lowering the total dose to achieve maximum supersaturation still below the critical-supersaturation level, it is possible to avoid drug precipitation so as to maintain sustained supersaturation.

Solid dispersions to enhance the delivery of a potential drug candidate LPSF/FZ4 for the treatment of schistosomiasis.

Drug candidate LPSF/FZ4 with promising schistosomicidal properties in vitro was previously synthesized. However, LPSF/FZ4 has limited aqueous solubility (<1 µg/mL), leading to ineffective dissolution and, therefore, no meaningful in vivo comparative studies could be pursued. This study was aimed to develop a proper amorphous solid dispersion (SD) to enhance the solubility and dissolution rate of LPSF/FZ4 such that its biological activity could be investigated. To better understand its physiological behavior, the pKa of LPSF/FZ4, a monoprotic weak acid with NH group at the imidazolidine ring, was first determined to be 8.13 using an automated SiriusT3. The development of SD systems for LPSF/FZ4 involved the evaluation of various water-soluble polymer carriers such as PVP K-29/32, PVP K-90, HPMC K4M, PVPVA 64 and SOLUPLUS®. The most promising SD systems were selected through in vitro dissolution studies under nonsink conditions, together with physicochemical characterization as well as accelerated stability study. It was shown that SD of 10% LPSF/FZ4 in SOLUPLUS® and PVP K-90 could significantly increase the area-under-the-curve value of the nonsink dissolution profile (AUC values of the SD in SOLUPLUS® and PVP K-90 were 1381.03 and 1342.34 µL/mL·min, respectively, and that of the pure crystalline drug was 0.02 µL/mL·min), a useful surrogate for the in vivo bioavailability. Cmax values for the SD in SOLUPLUS® (12.50 µL/mL) and PVP K-90 (25.86 µL/mL) were also higher than the one of the crystalline drug (0.02 µL/mL). The SD system of LPSF/FZ4 in SOLUPLUS® showed a significant increase in schistosomicidal activity in an animal model as compared with the conventional treatment using crystalline drug, consistent with the AUC trend from the nonsink dissolution. Thus this SD system of LPSF/FZ4 could be useful as a potential formulation for treating schistosomiasis.