How chemical structure and composition impact on the release of salt-like drugs from hydrophobic matrices: Variation of mechanism upon adding hydrophilic features to PMMA

The adaptation of polymeric matrices to tailor their drug release characteristics requires the complete understanding of the mechanism involved. We thus explored how chemical and structural modifications of film forming polymethyl methacrylate (PMMA), a polymer often used for its biocompatibility, impact on its release features. Comparing Diclofenac Sodium (NaD) salt release from pure PMMA, mPEG–b–(PMMA)n, and mPEG–b–(PMMA–ran–DMAEMA)n polymeric films (n = 1, 2), we evidenced the impact of successive polymer modifications on the release rate and equilibrium. Thus, PEGylation increased both the release rate and the amount of NaD desorbed (up to 53%) introducing, however, a “burst phase” not present with pure PMMA; the latter released only 3% of NaD. The presence of DMAEMA in mPEG–b–(PMMA–ran–DMAEMA)n, instead, decreased the release rates and led to the complete NaD desorption at physiological conditions. We rationalized our observations with electronic structure calculations and lattice stochastic simulations. The former suggested a tendency for NaD to accumulate in the hydrophilic mPEG portion via the coordination of the sodium cation in low polarity casting solvents. Stochastic simulations, instead, suggested that mPEG ought to form small domains on the film surface favouring fast NaD desorption in the release medium. Importantly, DMAEMA reduced the NaD tendency to accumulate in the mPEG portion due to the coordination on MMA–DMAEMA motifs. In physiological conditions (i.e., pH ≃ 6.4), the basic monomer also dampens the burst phase and reduces the release rate compared to the other matrices thanks to salt bridges between the drug and amino group.