Tosylate salts of the anticancer drug lapatinib

Abstract

Two tosylate salts of an anticancer drug lapatinib, viz. a monotosylate [systematic name: ({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl)[2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate], C29H27ClFN4O4S(+)·C7H7O3S(-), (I), and a ditosylate [systematic name: 4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)-6-]5-({[2-(methylsulfonyl)ethyl]azaniumyl}methyl)furan-2-yl[quinazolin-1-ium bis(4-methylbenzenesulfonate)], C29H28ClFN4O4S(2+)·2C7H7O3S(-), (II), were obtained during crystallization attempts for polymorphism. In both structures, the lapatinib cation is in a distorted U-like conformation and the tosylate anion is clamped between the aniline N atom and methylamine N atom through N-H···O hydrogen bonds, forming an R2(2)(15) ring motif. The 4-anilinoquinazoline ring system is essentially planar in (I), while it is twisted in (II), controlled by an intramolecular C-H···N interaction. In (I), alternating cations and anions are linked by N-H···O hydrogen bonds into C2(2)(6) chains. These chains are linked by cations in a helical manner. The presence of the additional tosylate anion in (II) results in the formation of one-dimensional tapes of fused hydrogen-bonded rings through N-H···O and C-H···O interactions. These studies augment our understanding of the role of nonbonded interactions in the solid state, which is useful for correlation to the physicochemical properties of drug products.

Effect of Triton X-100 on the Electrochemical Behavior of Hydrophobic Lapatinib Used in the Treatment of Breast Cancer: A First Electroanalytical Study

“…In literature, the pKa 1 and pKa 2 values of LPT were given as 3.80 and 7.20, respectively. 23 Figure S1b confirmed that the anionic form of LPT, at pH > 3.80, is more difficult to oxidize than the uncharged form. The 0.1 M H 2 SO 4 was chosen as the supporting electrolyte for further studies.…”

Protonation of Tyrosine Kinase Inhibitor Lapatinib: A Theoretical and Experimental Study

“…Simulation of protonation constants using iLabs software [4] predicted two calculated pKa macroconstants (5.6 ± 0.4 and 4.7 ± 0.4) emerging from a combination of various protonation microstates, including all three protonable nitrogen atoms. In the known crystal structures of lapatinib tosylate and ditosylate [5] protonation occurred on nitrogen atoms N1 and N1N2 respectively. However, the route of protonation and exact protonation sites in solution, which are important for better understanding of biological activity as well as environmental protection and development of manufacturing technology, still remain unclear.…”

New solvates of the drug naltrexone: protonation, conformation and interplay of synthons

“…The search for novel solid-state forms of marketed drugs by crystal engineers and crystallographers has become widespread in recent years (Childs et al, 2004;Blagden et al, 2007;Sridhar & Ravikumar, 2009;Ravikumar et al, 2013;Nechipadappu et al, 2017;Durá n-Palma et al, 2017). Indeed, many advances have been made from studies dealing with polymorphism, solvatomorphism and the cocrystallization of commercial drugs (Babu & Nangia, 2011;Padrela et al, 2017).…”