Eyes on Lipinski's Rule of Five: A New “Rule of Thumb” for Physicochemical Design Space of Ophthalmic Drugs

The study objective was to investigate molecular thermodynamic properties of approved ophthalmic drugs and derive a framework outlining physicochemical design space for product development. Unlike the methodology used to obtain molecular descriptors for assessment of drug-like properties by Lipinski's Rule of 5 (Ro5), this work presents a retrospective approach based on in silico analysis of molecular thermodynamic properties beyond Ro5 parameters (ie, free energy of distribution/partitioning in octanol/water, dynamic polar surface area, distribution coefficient, and solubility at physiological pH) by using 145 marketed ophthalmic drugs. The study's focus was to delineate inherent molecular parameters explicitly important for ocular permeability and absorption from topical eye drops. A comprehensive parameter distribution analysis on ophthalmic drugs’ molecular properties was performed. Frequencies in distribution analyses provided groundwork for physicochemical parameter limits of molecular thermodynamic properties having impact on corneal permeability and topical ophthalmic drug delivery. These parameters included free energy of partitioning (ΔG(o/w)) calculated based on thermodynamic free energy equation, distribution coefficient at physiological pH (clog D(pH7.4)), topological polar surface area (TPSA), and aqueous solubility (S(int), S(pH7.4)) with boundaries of clog D(pH7.4) ≤4.0, TPSA ≤250 Å(2), ΔG(o/w) ≤20 kJ/mol (4.8 kcal/mol), and solubility (S(int) and S(pH7.4)) ≥1 μM, respectively. The theoretical free energy of partitioning model streamlined calculation of changes in the free energy of partitioning, Δ(ΔG(o/w)), as a measure of incremental improvements in corneal permeability for congeneric series. The above parameter limits are proposed as “rules of thumb” for topical ophthalmic drugs to assess risks in developability.