TY - JOUR
T1 - Unravelling the Origin of Solvate Formation in the Anticancer Drug Trametinib
T2 - Insights from Crystal Structure Analysis and Computational Modeling
AU - Shruti, Ipsha
AU - Almehairbi, Mubarak
AU - Saeed, Zeinab M.
AU - Alkhidir, Tamador
AU - Ali, Wesam A.
AU - Vishwakarma, Rampal
AU - Mohamed, Sharmarke
AU - Chopra, Deepak
N1 - Funding Information:
I.S. and R.V. thank SERB for research fellowships from SERB (EMR/2016/006835). D.C., I.S., and R.V. thank the Science and Engineering Research Board (SERB)-India for research funding (Project Grant: EMR/2016/006835). We thank IISER Bhopal for all research facilities and infrastructure. S.M. would like to acknowledge the Advanced Technology Research Council (ATRC) for an ASPIRE Award for Research Excellence 2020 (AARE-2020). The authors would like to acknowledge the support of Dr. Louise Price (UCL) for providing the I···I potential parameters and for useful discussions. The theoretical calculations were performed using the high-performance computing clusters of Khalifa University, and the authors would like to acknowledge the support of the research computing department of Khalifa University.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/10/5
Y1 - 2022/10/5
N2 - The discovery of new crystalline forms of large, flexible drug molecules is of significant interest to the pharmaceutical industry as a means of improving one or more physicochemical properties of the active pharmaceutical ingredient (API). Trametinib (TRMB) is an anticancer drug, for which no solid-state forms are yet reported. Here, we report the results of an extensive screen for cocrystals of TRMB in an effort to improve the poor aqueous solubility of this API. Contrary to expectations, this effort led to the discovery of only six isostructural solvates of TRMB, where the solvent molecules fill the voids of the crystal structure and are stabilized by various intermolecular interactions. Computational crystal structure prediction methods were used to rationalize the high propensity for solvent inclusion in TRMB as arising from the poor crystal packing in TRMB. All predicted polymorphs of TRMB within a relative lattice energy of 44 kJ mol-1 of the global minimum display solvent accessible voids ranging from 1.4 to 16.5% of the unit cell volume. The serendipitous discovery of solvates in experiments targeting cocrystals,strongly suggests that the well-established synthon approach for the discovery of cocrystals works relatively well for documented literature examples that use rigid coformers with minimal conformational flexibility. However, for large APIs such as TRMB, in-silico screening methods should be adopted to reduce the need for extensive experimental cocrystal screens as the ability to form a cocrystal for drug candidates relies on more than synthon complementarity.
AB - The discovery of new crystalline forms of large, flexible drug molecules is of significant interest to the pharmaceutical industry as a means of improving one or more physicochemical properties of the active pharmaceutical ingredient (API). Trametinib (TRMB) is an anticancer drug, for which no solid-state forms are yet reported. Here, we report the results of an extensive screen for cocrystals of TRMB in an effort to improve the poor aqueous solubility of this API. Contrary to expectations, this effort led to the discovery of only six isostructural solvates of TRMB, where the solvent molecules fill the voids of the crystal structure and are stabilized by various intermolecular interactions. Computational crystal structure prediction methods were used to rationalize the high propensity for solvent inclusion in TRMB as arising from the poor crystal packing in TRMB. All predicted polymorphs of TRMB within a relative lattice energy of 44 kJ mol-1 of the global minimum display solvent accessible voids ranging from 1.4 to 16.5% of the unit cell volume. The serendipitous discovery of solvates in experiments targeting cocrystals,strongly suggests that the well-established synthon approach for the discovery of cocrystals works relatively well for documented literature examples that use rigid coformers with minimal conformational flexibility. However, for large APIs such as TRMB, in-silico screening methods should be adopted to reduce the need for extensive experimental cocrystal screens as the ability to form a cocrystal for drug candidates relies on more than synthon complementarity.
UR - http://www.scopus.com/inward/record.url?scp=85138120189&partnerID=8YFLogxK
U2 - 10.1021/acs.cgd.2c00344
DO - 10.1021/acs.cgd.2c00344
M3 - Article
AN - SCOPUS:85138120189
SN - 1528-7483
VL - 22
SP - 5861
EP - 5871
JO - Crystal Growth and Design
JF - Crystal Growth and Design
IS - 10
ER -