Physicochemical Mechanisms era
Higuchi, in 1963, formulated a diffusion-controlled release model for matrix systems, quantifying dissolution and matrix diffusion as determinants of onset and duration. Lachman, Liberman, and Kanig, in their influential 1960s work and the Theory and Practice of Industrial Pharmacy, codified solubility, dissolution, and diffusion concepts into dosage-form science. Paul Hansch, in the 1960s, introduced lipophilicity metrics such as logP that linked tissue partitioning and permeability to drug distribution and clearance. Together these physicochemical investigations laid the mechanistic scaffolding for later pharmacokinetic modeling and rational dosage-form design, incorporating unbound fractions, protein binding, and tracer-based measurements of tissue penetration.
Model-Based Pharmacokinetics era
In Model-Based Pharmacokinetics from 1970 to 2002, Lewis B. Sheiner and David J. Beal stood at the forefront, advancing nonlinear mixed-effects modeling and the NONMEM platform that made parameter estimation and model comparison routine. Their efforts established population PK and model-based dosing as standard practices within research and regulatory frameworks. Rowland and Tozer provided foundational textbooks and clinical guidance that translated compartmental theory into practical dosing and interpretation for clinicians. Karlsson KE and other Scandinavian contributors helped expand population modeling techniques and translational PK, strengthening cross-study comparability and regulatory relevance.