Analytical methods for the determination of drugs used in Alzheimer’s disease- A Review
Avuthu Sai Sheela, Mukthinuthalapati Mathrusri Annapurna*
Department of Pharmaceutical Analysis & Quality Assurance, Gandhi Institute of Technology and Management, GITAM Institute of Pharmacy, GITAM (Deemed to be) University, Visakhapatnam, AP-530045, India.
*Corresponding Author E-mail: mannapurna.mukthinuthalapati@gitam.edu
ABSTRACT:
Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. Alzheimer’s disease is the most common cause of dementia among elder adults. Till now there are no medications which cures Alzheimer's disease or alters the disease process in the brain. The exact causes of Alzheimer's disease are not understood. But scientists believe in most of the people, it is caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time. Problems with brain proteins leads to failure of normal functioning of brain which may disrupt the working of brain cells (neurons) which produces toxic events. Some of the drugs used are Donepezil, Rivastigmine, Galantamine, Memantine. A brief review of the analytical methods developed for the estimation of the above drugs was discussed in the present study.
KEYWORDS: Analytical methods, drugs, Alzheimer’s disease.
INTRODUCTION:
In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. The disease was named after Dr. Alois Alzheimer 1. The key symptom of Alzheimer's disease is memory loss. As the disease progresses, memory impairments worsen and other symptoms like repeating the statements again and again, forgetting conversations or events or appointments. Problems may include Depression, Apathy, Social withdrawal, Mood swings, Distrust in others, Irritability and aggressiveness, Changes in sleeping habits, Wandering, Loss of inhibitions. Two proteins are focused in the study of Alzheimer's disease. Beta-amyloid is a leftover fragment of a larger protein and these fragments cluster together and this disrupts cell-to-cell communication. Tau proteins play an important role in a neuron's internal support and transport system to carry nutrients and other essential materials. In Alzheimer's disease, tau proteins change shape and organize themselves into structures called neurofibrillary tangles. These tangles disrupt the transport system and are toxic to cells.
Alzheimer’s disease proceeds in seven stages- I, II, III, IV, V, VI and VII. In the first three stages an individual is not considered to have dementia but however a person is considered to have early-stage dementia in stage four. From stage IV to VII dementia progress and often psychomotor capabilities as well as ability to speak or communicate are also lost. Diagnosis of Alzheimer's disease will include different tests which include physical and neurological exam, lab tests, mental status and neuropsychological testing, brain imaging (Magnetic resonance imaging, Computerized tomography etc. Two types of drugs are currently used –i) Cholinesterase inhibitors - Donepezil, Galantamine and Rivastigmine) which work by preserving a chemical messenger that is depleted in the brain by Alzheimer's disease and ii) Memantine works in another brain cell and slows the progression of symptoms with moderate to severe Alzheimer's disease (Figure 1). In the present study the authors have reviewed the analytical methods published for the estimation of drugs used in the treatment of Alzheimer's disease.
Donepezil
Rivastigmine
Galantamine
Memantine
Figure 1: Chemical structures of drugs used in Alzheimer's disease
Donepezil (C24H29NO3) binds reversibly and inactivates the cholinesterases and there by inhibits the hydrolysis of acetylcholine and results in increase of acetylcholine concentration at cholinergic synapses. It is available with brand names Aricept, Act Donepezil, M-donepezil as tablets. Analytical methods were developed for the determination of Donepezil using HPLC3-14, LC-MS15-17 and Spectrophotometry18-24 (Table 1).
Rivastigmine (C14H22N2O2) is an acetylcholinesterase inhibitor25. It inhibits both butyryl cholinesterase and acetylcholinesterase (unlike donepezil, which selectively inhibits acetylcholinesterase) which would otherwise break down the brain neurotransmitter acetylcholine. It is available with brand names such as Exelon, Rivagem-3, Rivamer as capsule. Analytical methods were developed for the determination of Rivastigmine using HPLC26-32, spectrophotometry33-35 and TLC densitometry36 (Table 2).
Galantamine (C17H21NO3) is a phenanthrene alkaloid and a reversible competitive acetylcholinesterase inhibitor preventing the hydrolysis of acetycholine, leading to an increased concentration of acetylcholine at cholinergic synapses37. It is available with brand names such as Razadyne in tablet dosage form as it is consumed by oral route of administration. Analytical methods developed for the determination of Galantamine such as HPLC38-41 and Spectrophotometry42-45 were summarised in Table 3.
Memantine is chemically 3, 5-dimethyladamantan-1-amine (C12H21N) acts by blocking the current flow through channels of N-methyl-d-aspartate (NMDA) receptors-a glutamate receptor subfamily broadly involved in brain function46-47. Memantine is available as capsule and tablet with brand names Admenta, Namenda. Analytical methods developed for the determination of Memantine using HPLC48-53 and Spectrophotometry54-57 were discussed in Table 4.
Table 1: Review of analytical methods for the assay of Donepezil
|
Method |
Mobile phase (v/v) / Reagent |
Column |
Ref |
|
HPLC |
Methanol |
Uptisphere ODB C-18 |
3 |
|
HPLC |
Methanol: 0.02 M Phosphate buffer: triethylamine (50:50:0.5) |
C18 |
4 |
|
HPLC |
Methanol: Potassium dihydrogen orthophosphate solution pH adjusted to 2.5 ± 0.05 with o-phosphoric acid (40 : 60) |
Kromasil C18
|
5 |
|
HPLC |
0.1% Tri fluoro acetic acid in water: 0.1% Tri fluoro acetic acid in (70:30) Acetonitrile: Methanol (80:20) |
Waters Acquity C18 |
6 |
|
HPLC |
Methanol : 0.02M Phosphate buffer : Triethylamine (60:40:0.5) |
C18 |
7 |
|
HPLC |
Acetonitrile: 0.025 M Phosphate buffer (pH 7.0) (50 : 50) |
Phenomenex Luna C 18 |
8 |
|
HPLC |
Methanol: 0.02M Phosphate buffer: Tri ethylamine (50:40:10) |
C18 |
9 |
|
HPLC |
Methanol: .02M phosphate buffer (pH 7.5):Triethylamine ( 60: 40: 0.5) |
Keystone phenyl |
10 |
|
HPLC |
Acetonitrile: Water (50:50) |
Unisol C18 |
11 |
|
HPLC |
Potassium dihydrogen orthophosphate solution (pH adjusted to 2.5 with o-phosphoric acid): Methanol: Tri ethylamine (550: 450: 5) |
Inertsil C8 |
12 |
|
HPLC |
Ethanol: n-hexane: Triethylamine (20: 80: 0.3) |
Chiralcel-OJ-H |
13 |
|
HPLC |
Acetonitrile: Water (pH 3.5) (40: 60) |
C18 |
14 |
|
HPLC
LC- ESI-MS |
0.5 mM Monobasic potassium phosphate buffer (pH 3.0 with 0.5% of Tri ethylamine): Methanol (55:45) 0.2% Acetic acid (pH 3.2): Methanol (60:40) |
Phenomenex C18 |
15 |
|
LC-ESI- TOF-MS |
Methanol: Acetate buffer (pH 4.0) (80:20) |
C 18 |
16 |
|
LC-ESI- TOF-MS |
Methanol: Acetate buffer (pH 4.0) (80:20) |
C18 |
17 |
|
Spectrophotometryand Colorimetry |
Methanol |
- |
18 |
|
Spectrophotometry |
Phosphate buffer ( pH 7.4) |
- |
19 |
|
Spectrophotometry |
KMnO4 in alkaline medium |
- |
20 |
|
Spectrophotometry |
Acetonitrile and Water |
- |
21 |
|
Spectrophotometry (Ion-pair complex with Bromo cresol purple in phthalate buffer) |
Phthalate buffer solution. |
- |
22 |
|
Spectrophotometry (Ion-pair complex with azo-dye in acidic medium) |
De-ionized water. |
- |
23 |
|
Spectrophotometric method. (Derivative and AUC) |
Methanol: Water (30:70) |
- |
24 |
Table 2: Review of analytical methods for the assay of Rivastigmine
|
Method |
Mobile phase (v/v) / Reagent |
Column |
Ref |
|
HPLC |
Potassium dihydrogen phosphate buffer: Acetonitrile (70:30) |
C-18 |
26 |
|
HPLC |
Methanol : Water (90: 10) |
5C18-MS |
27 |
|
HPLC |
0.01 M Ammonium acetate (adjusted to pH 4.0 with ortho phosphoric acid): Acetonitrile (60:40) |
Thermo Hypersil C4 |
28 |
|
HPLC |
0.01 M Sodium-1-heptane sulphonate (pH: 3.0 with dilute phosphoric acid): Acetonitrile (72:28) |
Waters X Terra RP18 |
29 |
|
HPLC |
1-Octane sodium sulfonate (pH adjusted to 3.0 with ortho phosphoric acid): Acetonitrile (70 : 30) |
ODS, Xterra RP18 |
30 |
|
HPLC |
Methanol: Water: Acetonitrile (35:25:40) (pH 4.8). |
Symmetry Chromosil C18 |
31 |
|
HPLC |
Acetonitrile: 0.1% of ortho phosphoric acid (15:85) (pH 3.2 adjusted by Tri ethylamine) : Acetonitrile: 0.1% of ortho phosphoric acid (85:15) (pH3.2 adjusted by Tri ethylamine). |
Inertsil sprint C8 |
32 |
|
Spectrophotometry (Fluorescence) |
Triple distilled water |
- |
33 |
|
Spectrophotometry |
Water: Methanol (9:1) |
- |
34 |
|
Spectrophotometry |
- |
- |
35 |
|
Derivative spectroscopy Ratio derivative spectroscopy and TLC densitometry |
Methanol: Butanol: H2O: Ammonia (5:4:1:0.01)
|
- |
36 |
Table 3: Review of analytical methods for the assay of Galantamine
|
Method |
Mobile phase (v/v) / Reagent |
Column |
Ref |
|
HPLC |
0.05M disodium hydrogen phosphate dihydrate: Methanol (95:5):: Acetonitrile: Methanol (95:5) (75:25) |
Inertsil ODS-3V |
38 |
|
HPLC (Fluorescence detection) |
Acetonitrile: 10 mM o‐phosphoric acid (40:60) |
Inertsil C18 |
39 |
|
HPLC |
n-Hexane: 20% propionic acid in isopropanol Diethyl amine (80:20:0.2) |
Chiralpak AD-H |
40 |
|
HPLC |
1 mM Ammonium formate: Acetonitrile (30:70) |
Phenomenex C18 |
41 |
|
Spectrophotometry (first order derivative method) |
Distilled water |
- |
42 |
|
Spectrophotometry (fluorescence detection) |
Distilled water |
- |
43 |
|
Spectrophotometry |
Double distilled water |
- |
44 |
|
Spectrophotometry |
Double distilled water |
- |
45 |
Table 4: Review of analytical methods for the assay of Memantine
|
Method |
Mobile phase (v/v) / Reagent |
Column |
Ref |
|
HPLC |
Acetonitrile: Sodium dihydrogen phosphate (pH 2.5; 0.05 M) (70: 30) |
Nova-Pak C18 column |
48 |
|
HPLC |
Acetonitrile: phosphate buffer (80:20) |
Kromasil C18 column
|
49 |
|
HPLC |
n-Hexane: Ethyl acetate: Diethylamine (5:5:0.7) |
Aluminum plates pre-coated with silica gel G60F254. |
50 |
|
HPLC |
KH2PO4: Acetonitrile: Methanol (30:40:30) |
Inertsil ODS 3V |
51 |
|
HPLC (Refractive index detection) |
0.2% Diethyl amine (pH 6.0 adjusted with dilute o-phosphoric acid): Methanol (45:55) |
C18 |
52 |
|
HPLC (Evaporative Light Scattering Detection) |
Methanol: 0.1% tri fluro acetic acid buffer (50:50) |
Intersil ODS 3v |
53 |
|
Spectrophotometry |
Dichloromethane |
- |
54 |
|
Spectrophotometry |
Distilled water |
- |
55 |
|
Spectrophotometry
|
Bromo cresol green in potassium hydrogen phthalate buffer (pH 3) Picric acid in chloroform (Ion pair complex) |
- |
56 |
|
Spectrophotometry
Spectrofluorimetry |
4‐chloro‐7‐nitro‐2,1,3‐ benzoxadiazole in alkaline buffer and Acetone o‐phthalaldehyde/ N‐acetyl‐L‐cysteine |
- |
57 |
CONCLUSION:
A comprehensive information of various drugs and their detailed information regarding the mechanism, analytical methods developed by various authors and the key features of the methods were given in the present review article.
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Received on 06.10.2019 Modified on 28.10.2019
Accepted on 10.11.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2019; 12(11):5561-5565.
DOI: 10.5958/0974-360X.2019.00964.8