Molecular insights into the formation of drug-​monoacyl phosphatidylcholine solid dispersions for oral delivery

Abstract

Phospholipid-​based formulations provide a key technol. to formulate poorly water-​sol. drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-​acylphospholipids upon aq. dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility. It was tested whether or not a mol. rule of thumb can predict the desirable absence of drug crystallinity in the products. Subsequently, mol. simulations were performed to gain a better understanding of mol. assocn. between drugs and monoacyl PC. Finally, the glass-​forming ability (GFA) of pure drugs was considered with respect to solid dispersion formation. All products were obtained from a solvent-​evapn. process and subsequent anal. of potential drug crystallinity was measured with X-​ray powder diffraction and differential scanning calorimetry. Mol. simulations were making use of a Monte Carlo algorithm and mol. properties relevant for GFA were calcd. As a result, the dataset of 28 drugs confirmed an earlier proposed empirical rule that enthalpy of fusion and logP were important for solid dispersion formation, while some relevance was also evidenced for drug energies of frontal orbitals. Interestingly, the Monte Carlo simulations revealed several likely assocns. between drug and phospholipid rather than a well-​defined single complex formation. However, drug-​excipient interactions were still pivotal, since GFA of pure drug could not predict solid dispersion formation. These findings led to important mol. insights into binary solid dispersions of drug and monoacyl PC, which can guide formulators in early drug product development.