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.

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

“…The possibility of alteration of the physicochemical properties after successful cocrystallization is especially welcomed in the case of active pharmaceutical ingredients (API). There are many examples of significant improvements of API behaviors both in vivo and in vitro [14,15] due to enhancement of pharmacokinetic properties as solubility [4,16,17] and bioavailability [18][19][20]. Also many other physicochemical properties can be modulated by cocrystallization including stability [21][22][23][24], hygroscopicity [25] and prolonged shelf life [26].…”

Improvement of Physicochemical Properties of an Antiepileptic Drug by Salt Engineering

“…Various formulation strategies were reported to improve its solubility and dissolution rate such as prodrug approach (5), nanosuspension (6), solid dispersion with polyethylene glycol and polyvinyl pyrollidone (7,8), complexation with cyclodextrins (8,9) and multicomponent molecular crystals such as solvates, salt, and cocrystals (10,11). Salts are usually formed between ionic drugs and the counter ions, and this approach has been used extensively to improve the solubility of BCS class II drugs.…”

“…Ionized species have higher solubility than unionized species because of dipolar interaction of ions with water (12). Salt formation of LMT with saccharine, adipic acid, and malic acid has been reported (11). However, these approaches achieved limited success in improving solubility and dissolution rate of LMT.…”

“…LMT has the capability to form both salts and cocrystals depending upon the acidities of counter ion or coformer because of its relative basic nature (pKa, 5.5-5.7) (11,23). ΔpKa (ΔpKa= pKa base−pKa acid) is widely used to predict the outcome of adduct products of acids and basic molecules.…”

Cocristais: uma estratégia promissora na área farmacêutica

“…Apesar das óbvias falhas de medir a solubilidade do cocristal desta forma, muitos estudos ainda utilizam o "plateau" ou "C max " da 41,100,109,110 No entanto, esse método normalmente não consegue captar o verdadeiro perfil de concentração do cocristal, em vez disso, um perfil de concentração do fármaco é revelado como resultado da conversão cinética do cocristal. Como consequência, o poder dos cocristais de aumentar a solubilidade pode ser subestimado através do uso de medições cinéticas.…”