pKa, LogP, LogD and Ionisation
The ionisation constant, or pKa, describes the pH at which a molecule exists in equal proportions of its ionised and un-ionised forms, and it is determined...
The ionisation constant, or pKa, describes the pH at which a molecule exists in equal proportions of its ionised and un-ionised forms, and it is determined experimentally by potentiometric titration or, for poorly soluble compounds, by ultraviolet spectrophotometric titration. Because the ionisation state of a molecule at physiological pH governs its membrane permeability — un-ionised species generally permeate lipid membranes more readily than their ionised counterparts — pKa is a foundational parameter for predicting gastrointestinal absorption and for anticipating how a molecule will behave across the differing pH environments of the stomach, small intestine, and systemic circulation.
The octanol–water partition coefficient, or LogP, quantifies the intrinsic lipophilicity of the un-ionised molecule, measured classically by the shake-flask method or, more efficiently for large compound sets, by reversed-phase high-performance liquid chromatography calibrated against reference standards. LogP correlates broadly with passive membrane permeability and is a key input to biopharmaceutical classification, but because it describes only the un-ionised species, it does not by itself capture how a compound will actually partition at physiological pH.
The distribution coefficient, LogD, addresses this limitation by describing the partitioning behaviour of the molecule at a specified pH, most commonly pH 7.4, accounting explicitly for the fraction of drug present in ionised form. LogD is related to LogP through the compound's pKa and the prevailing pH via a logarithmic correction term, and because it reflects the effective lipophilicity under physiologically relevant conditions, LogD is generally regarded as the more clinically meaningful parameter for predicting absorption, distribution, and membrane permeability.
Together, pKa, LogP, and LogD constitute an interlocking set of parameters that preformulation scientists use to anticipate a molecule's ionisation state and lipophilicity across the physiological pH range, informing decisions on salt selection, the feasibility of enhancement technologies such as lipid-based systems, and the likely rate-limiting step in oral absorption — considerations that feed directly into the Biopharmaceutics Classification System discussed later in this chapter.