TY - JOUR
T1 - Effects of crystal form on solubility and pharmacokinetics
T2 - A crystal engineering case study of lamotrigine
AU - Cheney, Miranda L.
AU - Shan, Ning
AU - Healey, Elisabeth R.
AU - Hanna, Mazen
AU - Wojtas, Lukasz
AU - Zaworotko, Michael J.
AU - Sava, Vasyl
AU - Song, Shijie
AU - Sanchez-Ramos, Juan R.
PY - 2010/1/6
Y1 - 2010/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=74049153760&partnerID=8YFLogxK
U2 - 10.1021/cg901010v
DO - 10.1021/cg901010v
M3 - Article
AN - SCOPUS:74049153760
SN - 1528-7483
VL - 10
SP - 394
EP - 405
JO - Crystal Growth and Design
JF - Crystal Growth and Design
IS - 1
ER -