Biomolecular Chemistry of Isopropyl Fibrates

Abstract

Isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and isopropyl 2-(4-chlorophenoxy)-2-methylpropanoate, also known as fenofibrate and isopropyl clofibrate, are hypolipidemic agents of the fibrate family. In a previously reported triclinic structure of fenofibrate (polymorph I) the methyl groups of the isopropyl moiety (iPr) are located symmetrically about the carboxylate group. We report a new monoclinic form (polymorph II) of fenofibrate and a first structural description of isopropyl clofibrate, and in these the methyl groups are placed asymmetrically about the carboxylate group. In particular the dihedral (torsion) angle between the hydrogen atom on the secondary C and the C atom of the carboxyl group makes a 2.74° angle about the ester O-C bond in the symmetric fenofibrate structure of polymorph I, whereas the same dihedral angle is 45.94° in polymorph II and -30.9° in the crystal structure of isopropyl clofibrate. Gas phase DFT geometry minimizations of fenofibrate and isopropyl clofibrate result in lowest energy conformations for both molecules with a value of about ± 30° for this same angle between the O=C-O-C plane and the C-H bond of the iPr group. A survey of crystal structures containing an iPr ester group reveals that the asymmetric conformation is predominant. Although the hydrogen atom on the secondary C atom of the isopropyl group is located at a comparable distance from the carbonyl oxygen in the symmetric and asymmetric fenofibrate (2.52 and 2.28 Å) and the isopropyl clofibrate (2.36 Å) structures, this hydrogen atom participates in a puckered five membered ring arrangement in the latter two that is unlike the planar arrangement found in symmetric fenofibrate (polymorph I). Polar molecular surface area (PSA) values indicate fenofibrate and isopropyl clofibrate are less able to act as acceptors of hydrogen bonds than their corresponding acid derivatives. Surface area calculations show dynamic polar molecular surface area (PSAd) values of the iPr esters of the fibrates are lower than those of their acids, implying that the fibrates have better membrane permeability and a higher absorbability and hence are better prodrugs when these agents need to be orally administered.

Thermodynamics of fenofibrate and solubility in pure organic solvents

“…The vast majority of literature dealing with this compound concerns its clinical action, bioavailability, and formulation [1][2][3][4][5]. In addition there is some limited literature concerning its physico-chemical properties [6][7][8][9][10][11], including spectroscopic and analytical data [12][13][14][15], and the crystal structures of its two known polymorphs [16][17][18]. Some rough solubility data for a number of solvents are reported, with no mention of temperature [7].…”

Formation of organic molecular nanocrystals under rigid confinement with analysis by solid state NMR

“…42 FEN possesses two different polymorphs (I/II, stability: form I > form II). 43 IMC was reported to have eight different polymorphs: the most stable form is γ-form and the metastable form often produced is α-form. 44 …”

Characterization of WY 14,643 and its Complex with Aldose Reductase

“…The non-hydrogen atoms were refined anisotropically to convergence with final residual values: R1 = 3.2% and wR(F 2 ) = 8.0%. All OH and NH hydrogen atoms were located from difference Fourier maps and were refined freely using isotropic thermal parameters like in the structure determination of fenofibric acid and fenofibrate following established procedure 47 48 49 . All other H atoms were treated using appropriate riding models (AFIX m3).…”