Michael J. Hageman

Enol esters as potential prodrugs. IV. Enhanced delivery of the quaternary species coralyne to rat brain using 6′-acetylpapaverin and its enol esters as prodrugs☆

Coralyne (I), 6-acetylpapaverin (II) and three 6-acetylpapverin enol esters (acetate, IIIa; isobutyrate, IIIb; and pivalate, IIIc) were compared for their ability to deliver the cytotoxic quaternary coralyne ion to the brains of rats following i.v. administration. Maximum levels of coralyne were achieved in all cases within one hour of dosing and remained essentially constant for up to 90 h, indicating an inability of the quaternary ion to escape from the brain. The brain levels achieved decreased in the following order; II >IIIa, IIIb >IIIc >I, with II and IIIa producing ~ 60- and ~ 30-fold greater brain coralyne levels than achieved when I was administered. n nBased on the results obtained and previous work it appears that the determining factor in the accumulation of coralyne in brain following administration of the enol esters is the rate of production of II in the general circulation and not the rate of hydrolysis in brain tissue. Additionally, this study has demonstrated the utility of selected enol esters as prodrugs.

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.

Preparation of lapatinib ditosylate solid dispersions using solvent rotary evaporation and hot melt extrusion for solubility and dissolution enhancement

ABSTRACT The objective of this study was to enhance solubility and dissolution of lapatinib (LB) ditosylate (DT) using solid dispersions (SD) prepared by solvent rotary evaporation (SRE) and hot melt extrusion (HME). A series of models based on solubility parameter, the solid‐liquid equilibrium equation, and the Flory‐Huggins equation were employed to provide insight to data and evaluate drug/polymer interactions. Experimentally, nine SD formulas were prepared and characterized by various analytical techniques including differential scanning calorimetry (DSC), powder X‐ray diffraction (PXRD), scanning electron microscope (SEM), solubility, and dissolution. It was found that both material attributes (e.g., drug loading and solid state) and process parameters (e.g., extrusion temperature) significantly affected manufacturability and solubility/dissolution behaviors. Among the formulas investigated, Formula #9 containing LB‐DT, Soluplus®, and poloxamer 188 at a weight ratio of 1:3:1 was screened as the first ranked one. While comparing production routes, the SDs prepared by SRE showed more amorphicity as well as higher solubility/dissolution. This study provided the insight of introducing theoretical models to guide SD formulation/process development and illustrating the potential of bioavailability enhancement for LB‐DT.