Effects of crystal form on solubility and pharmacokinetics: A crystal engineering case study of lamotrigine

Miranda L. Cheney, Ning Shan, Elisabeth R. Healey, Mazen Hanna, Lukasz Wojtas, Michael J. Zaworotko, Vasyl Sava, Shijie Song, Juan R. Sanchez-Ramos

Research output: Contribution to journalArticlepeer-review

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-(2,3dichlorophenyl)-l,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.

Original languageEnglish
Pages (from-to)394-405
Number of pages12
JournalCrystal Growth and Design
Volume10
Issue number1
DOIs
Publication statusPublished - 6 Jan 2010
Externally publishedYes

Fingerprint

Dive into the research topics of 'Effects of crystal form on solubility and pharmacokinetics: A crystal engineering case study of lamotrigine'. Together they form a unique fingerprint.

Cite this