The in vitro and ex vivo bioadhesivity of polyacrylic acid (PAA)-based intravaginal caplets was explored from a physicomechanical and chemometrical structural modeling viewpoint. An Extreme Vertices Mixture Design was constructed for analyzing the bioadhesivity of 11 matrices that were optimized. Two sets of crosslinked PAA-based matrices comprising either allyl-sucrose (AS-PAA) or allyl-penta-erythritol (APE-PAA) were explored. Powders were compressed into caplet-shaped matrices and rotational rheological analysis was performed on hydrated polymeric blends. Caplets were evaluated for bioadhesiveness using a simulated vaginal membrane (SVM) with optimized caplets further tested using freshly excised rabbit vaginal tissue. The SVM and caplets were hydrated in simulated vaginal fluid before bioadhesivity testing using a texture analyzer to determine the rupture force between the membranous substrates and hydrated caplets. Computational and molecular structural modeling deduced transient sol-gel mechanisms, chemical interactions and inter-polymeric interfacing during caplet-substrate bioadhesion. Peak adhesive force (PAF) and work of adhesion (AUC(FD)) values for the APE-PAA caplets (1.671+/-0.232N; 0.0010+/-0.0002J) were higher than the AS-PAA caplets (1.168+/-0.093N; 0.00030+/-0.0001J) revealing superior bioadhesiveness. Similarly, rheological analysis revealed APE-PAA blends with higher viscosity and shear stress values (9x10(5)mPa/180Pa). The optimized APE-PAA matrices adhered appreciably to rabbit vaginal tissue (PAF=0.883+/-0.083N; AUC(FD)=(0.0003+/-3.5355)x10(-5)J). Results strongly suggest that the approach may be useful for assessing the bioadhesivity of intravaginal matrices on ex vivo rabbit vaginal tissue with data further supported by molecular structural analysis and energy-dependant bioadhesivity modeling.