Effects of Crystal Form on Solubility and Pharmacokinetics: A Crystal Engineering Case Study of Lamotrigine

Abstract

In this contribution, we describe how the supramolecular synthon approach can be used for discovery of novel crystal forms and for enhancing the relevant preclinical properties of a low solubility antiepileptic drug, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine). Ten novel crystal forms are reported: lamotrigine methylparaben cocrystal form I (1:1) (1), lamotrigine methylparaben cocrystal form II (1:1) (2), lamotrigine nicotinamide cocrystal (1:1) (3), lamotrigine nicotinamide cocrystal monohydrate (1:1:1) (4), lamotrigine saccharin salt (1:1) (5), lamotrigine adipate salt (2:1) (6), lamotrigine malate salt (2:1) (7), lamotrigine nicotinate dimethanol solvate (1:1:2) (8), lamotrigine dimethanol solvate (1:2) (9), and lamotrigine ethanol monohydrate (1:1:1) (10). A selected set of the reported crystal forms were studied to determine their dissolution rate, solubility, and pharmacokinetic behavior. The solubilities were measured in aqueous media and in acidified aqueous media (pH = 1). It was observed that 5 and 2 exhibited the highest concentration in the aqueous media and acidified aqueous media, respectively. In the pharmacokinetic study, the serum concentration of lamotrigine, measured in Sprague−Dawley rats, reached the highest level after a single-dose oral administration of 5.