Donepezil hydrochloride

Discovery and development of A-benzyl-4-(5,6-dimethoxy-l-oxo-indan-2-ylmethyOpiperidine hydrochloride (donepezil hydrochloride) for treatment of Alzheimer s disease 98YGK320, 99YZ101. 

Figure 3 shows a typical example of the pH-mobility curve for a monobasic drug, donepezil hydrochloride. The observed mobilities at different pHs were well in agreement with the regressed values from Eq. (17). The obtained pKa value is 9.2, which is consistent with the result via the UV method (9.1). Similar results were reported for weak acids, amphoteric compounds, as well as peptides with seven ionic groups (20). 

Cholinesterase inhibitors donepezil hydrochloride galantamine hydrobromide rivastigmine tartrate... 

Donepezil hydrochloride is a white powder and is freely soluble in water, soluble in chloroform, sparingly soluble in glacial acetic acid and in ethanol, slightly soluble in acetonitrile, very slightly soluble in ethyl acetate, and insoluble in n-hexane [2],... 

Donepezil hydrochloride (E2020) is the second drug approved by the US FDA for the treatment of mild to moderate Alzheimer s diseases (AD). It is a new class of acetylcholinesterase (AChE) inhibitor having an... 

The donepezil hydrochloride has been charchaterized by differential scanning calorimetry DSC, which exhibits a significant endo peak around 229.85 °C [19]. The DSC thermogram of donepezil hydrochloride is substantially depicted as in Fig. 3.12. 

FIGURE 3.11 X-Ray powder diffraction pattern of donepezil hydrochloride [20]. 

To establish a sensitive and specific liquid chromatography-mass spectrometry (time-of-flight) [LC-MS (TOF)] method for the determination of donepezil in human plasma after an oral administration of 5 mg donepezil hydrochloride tablet [29]. Alkalized plasma was extracted with isopropa-nol-n-hexane (3 97) and loratadine was used as internal standard (IS). Solutes were separated on a Cis column with a mobile phase of metha-nokacetate buffer (pH 4.0) (80 20). Detection was performed on a TOF mass spectrometry equipped with an electrospray ionization interface and operated in positive-ionization mode. Donepezil quantitation was realized by computing the peak area ratio (donepezil-loratadine) (donepezil m/z 380 [M + H]+ and loratadine m/z 383[M + H]+) and comparing them with calibration curve (r = 0.9998). The linear calibration curve was obtained in the concentration range of 0.1-15 jUg/1. The detection limit of donepezil was 0.1 /zg/1. The average recovery was more than 90%. The intra- and inter-run precision was measured to be below 15% of RSD... 

A selective, sensitive, and rapid hydrophilic interaction liquid chromatography with electrospray ionization tandem mass spectrometry was developed for the determination of donepezil in human plasma [32], Donepezil was twice extracted from human plasma using methyl-ferf-butyl ether at basic pH. The analytes were separated on an Atlantis HILIC Silica column with the mobile phase of acetonitrile ammonium formate (50 mM, pH 4.0) (85 15, v/v) and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r = 0.9994) over the concentration range of 0.10-50.0 ng/ ml and the lower limit of quantification was 0.1 ng/ml using 200 /d plasma sample. The CV and relative error for intra- and inter-assay at four quality control levels were 2.7% to 10.5% and —10.0% to 0.0%, respectively. There was no matrix effect for donepezil and cisapride. The present method was successfully applied to the pharmacokinetic study of donepezil after oral dose of donepezil hydrochloride (10 mg tablet) to male healthy volunteers. 

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed [33] and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the IS. The collision-induced transition m/z 380 > 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 —> 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1 to 20.0 ng/ml. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/ml. The intra- and inter-day precisions were below 10.2% and the accuracy was between 2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non-compartmental pharmacokinetic model was used to fit the donepezil plasma concentration-time curve. Maximum plasma concentration was... 

To establish chiral separation method for donepezil hydrochloride enantiomers by capillary electrophoresis (CE) and to determine the two enantiomers in plasma [39], alkalized plasma was extracted by isopropa-nol-n-hexane (3 97) and L-butefeina was used as the IS. Enantioresolution was achieved using 2.5% sulfated-beta-cyclodextrin as chiral selector in 25 mmol/1 triethylammonium phosphate solution (pH 2.5) on the uncoated fused-silica capillary column (70 cm x 50 fim i.d.). The feasibility of the method to be used as quantitation of donepezil HC1 enantiomers in rabbit plasma was also investigated. Donepezil HC1 enantiomers were separated at a baseline level under the above condition. The linearity of the response was evaluated in the concentration range from 0.1 to 5 mg/1. The linear regression analysis obtained by plotting the peak area ratio (A(s)/A(i)) of the analyte to the IS versus the concentration (C) showed excellent correlation coefficient The low limit of detection was 0.05 mg/1. The inter- and intra-day precisions (RSD) were all less than 20%. Compared with chiral stationary phase by HPLC, the CE method is simple, reliable, inexpensive, and suitable for studying the stereoseletive pharmacokinetics in rabbit. 

It has been demonstrated that AD is associated with a relative decrease in the activity of the cholinergic system in the cerebral cortex and other areas of the brain. Studies suggest that donepezil hydrochloride exerts its... 

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3-4 h. Oral administration of Aricept produces highly predictable plasma concentrations with plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 h, thus administration of multiple single-daily doses results in gradual approach to steady state. Approximate steady state is achieved within 3 weeks after the initiation of therapy. Once at steady state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day. Neither food nor time of administration (morning versus evening dose) affect the absorption of donepezil hydrochloride [46-51]. 

The steady-state volume of distribution is 12 1/kg. Donepezil hydrochloride is approximately 96% bound to human plasma proteins. The distribution of donepezil hydrochloride in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 h after the administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the label remained unrecovered. This suggests that donepezil and/or its metabolites may persist in the body for more than 10 days. 

N. Mahesh, G.A. Kumar, D. Ramesh, M. Sivakumaran, Process for the preparation of donepezil hydrochloride, United State Patent Application, US 2007/0191610 Al. 

M.S. Reddy, S. Eswaraiah, M.V. Thipparmachar, E.R. Chandrashekar, P.A. Kumar, United States Patent Application Publication, Novel crystalline form-VI of donepezil hydrochloride and process for the preparation thereof, United State of Patents, US2004/ 0229914A1. 

S.S. Abbas, Y.M. Fayez, L.-S. Abdel Fattah, Stability indicating methods for determination of donepezil hydrochloride according to ICH guidelines, Chem. Pharm. Bull. 54 (2006) 1447-1450. 

K. Stella, M. Stella, A. Pandora, A. Morfis, B. Antonios, K. Maria, New gradient high-performance liquid chromatography method for determination of donepezil hydrochloride assay and impurities content in oral pharmaceutical formulation, J. Chromatogr. A 1189 (2008) 392-397. 

K. Nakashima, K. Itoh, M. Kono, M.N. Nakahima, M. Wada, Determination of donepezil hydrochloride in human and rat plasma, blood and brain microdialysates by HPLC with a short C30 column, J. Pharm. Biomed. Anal. 41 (2006) 201-206. 

Y. Lu, H. Wen, W. Li, Y. Chi, Z. Zhang, Determination of donepezil hydrochloride (E2020) in plasma by liquid chromatography-mass spectrometry and its application to pharmacokinetic studies in healthy, young, Chinese subjects, J. Chromatogr. Sci. 42 (2004) 234-237. 

J.F. Reyes, R. Vargas, D. Kumar, E.I. Cullen, C.A. Perdomo, R.D. Pratt, Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients, Br. J. Clin. Pharmacol. 58 (2004) 9-17. 

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