Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers.
Hydrogen bonds (HBs) in amorphous solid dispersions may influence physical stability through effects on both drug miscibility and mobility. Amorphous solid dispersions containing the HB-donor ibuprofen (IBP) alone or with one of four model polymers (poly(vinyl pyrrolidone) [PVP], poly(vinyl pyrrolidone/vinyl acetate) [PVP/VA], poly(vinyl acetate) [PVA], or polystyrene [PST]) were monitored by molecular dynamics simulation. HB distributions and contributions of electrostatic, van der Waals, and internal interactions to miscibility and mobility were analyzed versus drug concentration. The probability of IBP-IBP HBs decreases markedly (0.6→0.0) with dilution (100→10% drug) in PVP due to IBP-PVP HBs while dilution in the nonpolar PST has a more modest effect on IBP-IBP HB probability (0.6→0.3). Concentration-dependent Flory-Huggins interaction parameters (χ) were determined to assess drug-polymer miscibility. χIBP-PVP values were -0.9 to -1.8 with a plateau near 50% w/w PVP, whereas χIBP-PST fluctuated near zero (-0.1 to 0.3), suggesting that IBP is more soluble in PVP than in PST. χIBP-polymer values in polymers varying in pyrrolidone/acetate composition were in the order PVP (most favorable) > PVP/VA > PVA (least favorable). Decreased local mobility of IBP measured by the atomic fluctuation correlates with more IBP-PVP HBs with increasing PVP content. The opposite trend in IBP-PST may arise from IBP-IBP HB disruption on dilution.
['Xiang|Tian-Xiang|TX|', 'Anderson|Bradley D|BD|']
D003460:Crystallization D004339:Drug Compounding D005079:Excipients D006860:Hydrogen Bonding D007052:Ibuprofen D056004:Molecular Dynamics Simulation D011137:Polystyrenes D011759:Pyrrolidines D012995:Solubility D014753:Vinyl Compounds
mobility physical stability molecular dynamics amorphous solid dispersion(s) (ASD) drug-excipient interaction(s) excipient(s) formulation self-association solid dispersion(s)