Mechanistic Insights into Propylparaben Sorption on Polyvinyl Chloride.

The mechanism of loss of propylparaben potency from formulations when in contact with polyvinyl chloride has been determined. It is caused by the adsorption of propylparaben onto polyvinyl chloride surfaces. The adsorption kinetics is best described using a pseudo-second order model based on non-linear fit. The rate of adsorption increases with increasing bulk concentration of propylparaben. Adsorption equilibrium isotherm was fitted to three isotherm models: Langmuir, Freundlich, and Temkin, using non-linear fit. The Freundlich and Temkin models show the best fit, indicating a multi-layer adsorption. Using this case study, we present a methodology to provide mechanistic insights into the compatibility data between pharmaceutical ingredients and product contact materials when sorption is involved.

Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs.

PURPOSE: Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED). METHODS: ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples. RESULTS: The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation. CONCLUSIONS: The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden.

Role of surfactants in improving release from higher drug loading amorphous solid dispersions.

Amorphous solid dispersion formulations (ASD) are increasingly being used as a formulation strategy to improve bioavailability of poorly soluble drugs. One of the limitations of ASDs, in particular for high glass transition temperature (Tg) compounds, is the drug loading threshold (termed the limit of congruency, LoC) below which rapid, complete and congruent release of drug and polymer is achieved. In this study, several ionic and non-ionic surfactants were added to atazanavir-copovidone ASDs with the main goal of increasing the limit of congruency. Atazanavir (ATZ) is a relatively high Tg compound with a LoC of 5 % drug loading (DL). Surface normalized dissolution studies revealed that addition of 5 % w/w of surfactant, sodium dodecyl sulfate (SDS) or cetrimonium bromide (CTAB), to the binary copovidone-based ASD doubled the LoC (from 5 to 10 % DL), resulting in a more than 30-fold increase in total release compared to the corresponding binary ASD. Moreover, addition of 5 % of Span®80 increased the LoC to 15 % DL. ASD Tg was found to decrease upon addition of surfactants and water sorption extent was found to increase. We speculate that surfactants act as plasticizers, which may facilitate polymer release from ASDs containing a high Tg drug, providing a possible explanation for the observed enhancement in drug release from ternary ASDs and the increase in LoC.

Impact of Surfactants on the Performance of Clopidogrel-Copovidone Amorphous Solid Dispersions: Increased Drug Loading and Stabilization of Nanodroplets.

PURPOSE: Surfactants are increasingly being added to amorphous solid dispersion (ASDs) formulations to enhance processability and release performance. The goal of the current work was to investigate the impact of cationic, anionic and non-ionic surfactants on the rate and extent of clopidogrel (CPD) release from copovidone-based ASDs. METHODS: CPD release was evaluated for ASDs with different drug loadings using a surface normalized intrinsic dissolution apparatus. Studies were also carried out using dynamic light scattering, zeta potential measurements, and nuclear magnetic resonance spectroscopy to probe the impact of surfactants on drug-rich nanodroplet physical stability and clopidogrel-surfactant interactions. RESULTS: CPD ASDs showed good release for drug loadings as high as 40%, before the release fell off a cliff at higher drug loadings. Only sodium dodecyl sulfate, added at a 5% level, was able to improve the release at 50% drug loading, with other surfactants proving to be ineffective. However, some of the surfactants evaluated did show some benefits in improving nanodroplet stability against size enlargement. Ionic and non-ionic surfactants were observed to interact differently with CPD-rich nanodroplets, and variations in the kinetics and morphology of water-induced phase separation were noted in the presence and absence of surfactants in ASD films. CONCLUSIONS: In summary, addition of surfactants to ASD formulations may lead to some improvements in formulation performance, but predictive capabilities and mechanisms of surfactant effect still require further studies.