Impact of Surfactants on Polymer Maintained Nifedipine Supersaturation in Aqueous Solution.

PURPOSE: To study the impact of different surfactants on the supersaturation of nifedipine stabilized with HPMC and PVP-VA. METHODS: Different kinds of surfactants, including one cationic surfactant, two anionic surfactants, and three nonionic surfactants, were used to evaluate their impacts on the supersaturation of nifedipine stabilized with HPMC and PVP-VA. Polymer-surfactant interaction was studied by nuclear magnetic resonance (NMR) and fluorescent method. Solubility of nifedipine in solutions containing different amounts of polymers and surfactants was measured. Drug-polymer affinity was evaluated by measuring the percentage of polymer coprecipitated together with the drug from supersaturated solutions. RESULTS: Different polymer-surfactant combinations had different impacts on the supersaturation of nifedipine. Some combinations, such as PVP-VA/SLS and PVP-VA/NaTC under higher surfactant concentrations, showed improved drug supersaturation, due to increased drug solubility or polymer-surfactant synergy; while other combinations, such as HPMC/SLS and HPMC/Tween 20 under lower surfactant concentrations, showed reduced drug supersaturation, which could result from competitive surfactant-polymer or drug-surfactant interaction that disrupted pre-existent drug-polymer interaction. CONCLUSIONS: The ultimate impacts of various surfactants on polymer stabilized nifedipine supersaturation could be attributed to the interplay between different factors, including solubility enhancement of the drug, drug-polymer-surfactant interactions, and polymer-surfactant synergy.

Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers.

We aim to understand the potential impact of a modest chemical modification of a drug molecule on the downstream design of its amorphous solid dispersion (ASD) formulation. To this end, we used sorafenib (SOR) and its fluorinated form, regorafenib (REG), as model drugs, to assess the impact of a single hydrogen substitution by fluorine on the molecular interaction and miscibility between drug and PVP or PVP-VA, two commonly used polymers for ASDs. In this study, we observed that the Tg values of PVP or PVP-VA based ASDs of SOR deviated positively from the Gordon-Taylor prediction, which assumes ideal mixing, yet the Tg of REG ASDs deviated negatively from or matched well with the ideal mixing model, suggesting much stronger drug-polymer interactions in SOR ASDs compared with the REG ASDs. Using solution NMR and computational methods, we proved that a six-member-ring formed between the carbonyl groups on the polymers and the uramido hydrogen of SOR or REG, through intermolecular hydrogen bonding. However, steric hindrance resulting from fluorination in REG caused weaker interaction between REG-polymer than SOR-polymer. To further confirm this mechanism, we investigated the molecular interactions of other two uramido-containing model compounds, triclocarban (TCC) and gliclazide (GCZ), with PVP. We found that TCC but not GCZ formed a hexatomic ring with PVP. We concluded that PVP based polymers can easily interact with N, N'-disubstituted urea compounds with a trans-trans structure in the form of hexatomic rings, and the interaction strength of the hexatomic ring largely depended on the chemistry of drug molecules. This study illustrated that even a slight chemical modification on drug molecules could result in substantial difference in drug-polymer interactions, thus significantly impacting polymer selection and pharmaceutical performance of their ASD formulations.

Aggregation of Hydroxypropyl Methylcellulose Acetate Succinate under Its Dissolving pH and the Impact on Drug Supersaturation.

Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the commonly selected polymers used in amorphous solid dispersions (ASD) with excellent capabilities to maintain aqueous supersaturation of poorly water-soluble drugs and inhibit their crystallization, but the underlying mechanisms remain elusive. In this study, posaconazole was chosen as the model drug to study the supersaturation maintaining and crystallization inhibition capabilities of different types of HPMC-AS under pH 5.5-7.5. We analyzed the HPMC-AS aggregation status in solution using combination of static and dynamic light scattering and observed higher polymer aggregation number when higher grade HPMC-AS or lower pH was used, which correlates well with prolonged drug supersaturation or crystallization inhibition. The amount of HPMC-AS coprecipitated with PSZ, a direct indicator of drug/HPMC-AS affinity, also showed positive correlation with the drug supersaturation and crystallization inhibition in the dissolution process. Therefore, we conclude that the aggregation behavior of HPMC-AS and the drug/HPMC-AS affinity are the key mechanisms that lead to posaconazole supersaturation and crystallization inhibition when HPMC-AS was applied.

Predictive Modeling of Micellar Solubilization by Single and Mixed Nonionic Surfactants.

Micellar solubilization is an important concept in the delivery of poorly water-soluble drugs. The rational selection of the type and the amount of surfactant to be incorporated in a formulation require comprehensive solubility studies. These studies are time and material demanding, both of which are scarce, especially during late discovery and early development stages. We hypothesized that, if the solubilization mechanism or molecular interaction is similar, the solubilization capacity ratio (a newly defined parameter) is dictated by micellar structures, independent of drugs. We tested this hypothesis by performing solubility studies using 8 commonly used nonionic surfactants and 17 insoluble compounds with diverse characteristics. The results show a striking constant solubilization capacity ratio among the 8 nonionic surfactants, which allow us to develop predictive solubility models for both single and mixed surfactant systems. The vast majority of the predicted solubility values, using our developed models, fall within 2-fold of the experimentally determined values with high correlation coefficients. As expected, systems involving ionic surfactant sodium dodecyl sulfate, used as a negative control, do not follow this trend. Deviations from the model, observed in this study or envisioned, were discussed. In conclusion, we have established predictive models that are capable of predicting solubility in a wide range of nonionic micellar solutions with only 1 experimental measurement. The application of such a model will significantly reduce resource and greatly enhance drug product development efficiency.