Molecular packing and intermolecular interactions in two structural polymorphs of N-palmitoylethanolamine, a type 2 cannabinoid receptor agonist

Abstract

The molecular structure, packing properties, and intermolecular interactions of two structural polymorphs of N-palmitoylethanolamine (NPEA) have been determined by single-crystal X-ray diffraction. Polymorphs a and b crystallized in monoclinic space group P 2 1 /c and orthorhombic space group P bca, respectively. In both polymorphs, NPEA molecules are organized in a tail-to-tail manner, resembling a bilayer membrane. Although the molecular packing in polymorph a is similar to that in N-myristoylethanolamine and N-stearoylethanolamine, polymorph b is a new form. The acyl chains in both polymorphs are tilted by z35°with respect to the bilayer normal, with their hydrocarbon moieties packed in an orthorhombic subcell. In both structures, the hydroxy group of NPEA forms two hydrogen bonds with the hydroxy groups of molecules in the opposite leaflet, resulting in extended, zig-zag type H-bonded networks along the b-axis in polymorph a and along the a-axis in polymorph b. Additionally, the amide N-H and carbonyl groups of adjacent molecules are involved in N-HÁÁÁO hydrogen bonds that connect adjacent molecules along the baxis and a-axis, respectively, in a and b. Whereas in polymorph a the L-shaped NPEA molecules in opposite layers are arranged to yield a Z-like organization, in polymorph b one of the two NPEA molecules is rotated 180°, leading to a W-like arrangement. Lattice energy calculations indicate that polymorph a is more stable than polymorph b by z2.65 kcal/ mol.-Kamlekar, R. K. and M. J. Swamy. Molecular packing and intermolecular interactions in two structural polymorphs of N-palmitoylethanolamine, a type 2 cannabinoid receptor agonist.

Synthesis, calorimetric studies, and crystal structures of N, O-diacylethanolamines with matched chains

“…All these H-bonds are identical, with an N Ϫ O distance of 2.835(5) Å, and H···O distance of 1.84 Å and an N Ϫ H···O angle of 168°. This is essentially similar to the value of 167° observed for the corresponding N Ϫ H···O angle in the crystal structure of NPEA ( ␣ polymorph) ( 33 ) and the value of 166.7° seen in NMEA ( 34 ).…”

“…The layer thickness (C1 Ϫ C26 distance) in the crystal structure of DLEA is 27.82 Å and the all-trans N -and O -acyl chains of the molecule are tilted by 36.5° and 34.5°, respectively, with respect to the normal to the respective methyl end planes. These values are in the same range as the tilt angles with respect to the bilayer normal found in NMEA, N -palmitoylethanolamine (NPEA), and N -stearoylethanolamine (NSEA) (35-37°) (33)(34)(35). Other long chain molecules such as long chain carboxylic acids and n-alcohols also pack in a bilayer form with tail-to-tail hydrocarbon alignment with tilted chains ( 29 ).…”

“…The carbonyl group and the amide N Ϫ H are also in trans geometry. The conformation of the N -acyl chain and the central ethanolamine moiety in DLEA are essentially identical to that observed in the crystal structures of Npalmitoylethanolamine, N -myristoylethanolamine, and Nstearoylethanolamine (33)(34)(35). Thus, esterifi cation of the hydroxyl group of NAE to produce N-, O -diacylethanolamine does not seem to affect the conformation of the N -acyl region.…”

“…Analysis of the crystal structure of DLEA and comparison of the subcell structures of the N -and O -acyl chains in it with those of NMEA and NPEA, discussed above, have shown that the acyl chains in DLEA are more tightly packed than those in NMEA and NPEA, with DLEA having a smaller area per chain (17.40 and 17.61 Å 2 , respectively, for the N -acyl chain and O -acyl chain) than that in NPEA (18.16 and 18.25 Å 2 , respectively, for the ␣ and ␤ polymorphs) ( 33 ). For NMEA, the corresponding value is 19.14 Å 2 ( 34 ), which is considerably higher than that observed with DLEA.…”

Phases and phase transition in insoluble and adsorbed monolayers of amide amphiphiles: Specific Characteristics of the condensed phases

“…[21][22][23][24][25][26]. Specific information has been obtained about the effects of hydrogen bonding systems, dipole interactions, and sterical hindrance on packing in 3D crystals of selected N-acylethanolamines and N-acylpropanolamines [27][28][29]. The interaction of several N-acylethanolamines with dipalmitoylphosphatidylcholine (DPPC) multilamellar vesicles was studied [30] to develop liposomal drug delivery systems and potential applications as therapeutic agents [30][31][32].…”