Improving the Dissolution Rate of the Anticancer Drug Dabrafenib

Dabrafenib ( DBF ) is an anticancer drug with selective B-Raf (BRAF) inhibition activity. In 2013, DBF was approved by the U.S. Food and Drug Administration (US-FDA) as a dabrafenib mesylate salt ( DBF·MS ). Because of insolubility in aqueous medium, specifically at the pH 4–8 biorelevant range, DBF is a Biopharmaceutics Classification System (BCS) Class II drug (i.e., low solubility and high permeability). Therefore, screening of novel salts and cocrystals was carried out using Generally Recognized as Safe (GRAS) coformers. A total of 10 salts/cocrystals including the mesylate salt were found to be stable under the crystallization conditions. Among acidic coformers, methane sulfonic acid ( MS ) and saccharin ( SACH ) formed salts, while fumaric acid ( FA ), succinic acid ( SA ), and adipic acid ( ADA ) gave cocrystals. However, monoamines formed a monohydrate salt where the water molecule is hydrogen bonded with the aminopyrimidine moiety of DBF . The replacement of monoamines with ethylenediamine ( EN ) dislocated the water molecule near the free amine of EN in the crystal structure with a change in space group from triclinic ( P 1̅) to monoclinic ( P 2 1 / n ). Dissolution measurements at pH 1.2 (0.1 N HCl) showed that DBF·EN⊃H 2 O dissolved rapidly compared to the DBF·MS salt (the dissolution rate of DBF·EN⊃H 2 O and DBF·MS is 11 and 2 times faster than that of DBF ). Structure–activity relationship analysis showed that bonding of the aminopyrimidine moiety with strong hydrogen bond synthons inhibited dissolution, whereas a loosely bound or free site at the aminopyrimidine moiety enhanced the dissolution rate. Finally, a cytotoxicity study was performed for DBF, DBF·MS, and DBF·EN⊃H 2 O, which showed that DBF·EN⊃H 2 O is safe for normal cells and yet equally potent against cancer cells. Crystal engineering of an improved formulation of dabrafenib·ethylenediamine hydrate is presented as a new anticancer drug.