Donepezilium oxalate trihydrate, a therapeutic agent for Alzheimer's disease

Abstract

Donepezil, a cholinesterase inhibitor with good central nervous system penetration, has been crystallized as a tertiary amine salt with a disordered oxalate anion to give the title compound, (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium hydrogen oxalate trihydrate, C24H30NO3+.C2HO4-.3H2O. The indanone and piperidine ring planes are inclined at an angle of 33.4 (1) degrees. A comparison is made with the piperidinium cation bound in acetylcholinesterase in the solid state. The methylene units bridging the indanone-piperidine-benzyl groups determine the molecular shape and conformational features. The structure is stabilized mainly by O-H...O and N-H...O hydrogen bonds, with water molecules mediating interactions between oxalate anions and donepezilium cations.

Electron Density Study Of The Anti-Alzheimer’s Disease Drug Donepezil From Conventional X-Ray Data And Invariom Database Application

“…The molecular conformation is different to the one present in the TcAChE complex with respect to a rotation about the C10-C11 bond. As already mentioned in [12], C8 is trans to C12 in the present case, but gauche in the TcAChE complex.…”

“…The numbering scheme is the same as used in [12]. The molecule is composed of a dimethoxyindanone moiety, a protonated piperidine ring and a benzyl fragment.…”

“…The crystal structure of donepezil is reported in the literature [12]. It co-crystallizes with an oxalate anion and three water molecules, the oxalate anion being partially disordered.…”

“…Although Figure 4 displays a mixture of information (Hirshfeld surface of the actually considered small molecule from [12] on the one hand, and schematic representation of the intermolecular contacts in the complex [10] on the other hand), some interesting conclusions can be drawn. The Hirshfeld surface is practically featureless with two exceptions: the strongest ED concentration is at the site of the piperidine N-H HB donor, followed by a concentration at the carbonyl oxygen atom O(1), which acts as HB acceptor from a water OH group.…”

Characterization of donepezil prepared by cogrinding with salicylic acid and p-aminobenzoic acid

“…In addition, DH has an extremely bitter taste when taken orally; thus, improved physicochemical properties of DH may aid in patient compliance. Salt formation from donepezil with oxalic acid 28 , with various carboxylic acids (e.g., maleic acid, fumaric acid, citric acid, salicylic acid, tartaric acid, and succinic acid) 29 , salicylic acid and derivatives 30 , and sulfonic acids 31 have been reported. Patients claimed that the new donepezil salts, which were mixed with carboxylic acids (including salicylic acid), prevented the bitter taste of DH 29 .…”