Upload
others
View
14
Download
0
Embed Size (px)
Citation preview
CHAPTER 2
ZOPICLONE
55
2.1. DRUG PROFILE
Zopiclone is a central nervous system depressant and belongs to non
benzodiazepine sedative and hypnotic. It is used to treat insomnia where sleep
initiation or sleep maintenance are prominent symptoms. Long term use is not
recommended as tolerance, dependence, addiction can occur with prolonged use.[1-2]
.
Zopiclone is a cyclopyrrone compound that has been reported to possess
hypnotic, muscle relaxant, and anticonvulsant properties analogous to benzodiazepine
compounds such as diazepam. Chemically [3]
it is 4-methyl-1piperazine-carboxylic
acid- 6-(5-chloro-2-pyridinyl)-6, 7dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester.
Zopiclone belongs to the group of medicines called central nervous system (CNS)
depressants. The therapeutic pharmacological properties of Zopiclone
include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties [4]
.
Zopiclone is known colloquially as a "Z-drug". Zopiclone, as traditionally sold
worldwide, is a racemic mixture of two stereoisomers, only one of which is active.[5-6]
It is recommended that Zopiclone be taken on an "as needed" basis. Daily or
continuous use of the drug is not usually advised.[7]
Zopiclone is a tranquillizer drug.
It works by causing a depression or tranquillisation of the Central Nervous System.
As Zopiclone is sedating it is marketed as a sleeping pill.
Figure 2.A: Structure of Zopiclone
56
Systematic (IUPAC) name : (RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-
dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-
methylpiperazine-1-carboxylate
Formula : C17H17ClN6O3
Molecular mass : 388.808 g/mol
Bioavailability : 52-59% bound to plasma protein
Metabolism : Various cytochrome P450 liver enzymes
Excretion : Urine
Routes : Oral tablets.
List of brand names of Zopiclone:
S.No.
BRAND
NAME
FORMULATION AVAILABLE
STRENGTH
MANUFACTURER
1 LYZOP TABLET 7.5mg Hetero
2 ZOLINOX TABLET 7.5mg Ranbaxy
3 ZOLIUM TABLET 7.5mg FDC
Table 2.1
Zopiclone, a benzodiazepine-like drug was introduced and initially promoted
as having less dependence and withdrawal than traditional benzodiazepine drugs.
However, Zopiclone may have an even greater addictive potential than
benzodiazepines and has been described as a "benzodiazepine in disguise".[8-10]
Tolerance to the effects of Zopiclone can develop after a few weeks. Long term use
should be avoided. Abrupt withdrawals particularly with prolonged and high doses
can in severe cases cause seizures and delirium.[11-12]
Publications in the British Medical Journal do not give any evidence to the
claim that Zopiclone has a low dependence potential. In fact, physical dependence and
recreational abuse and withdrawal syndromes similar to those seen in benzodiazepine
withdrawal are frequently encountered. Withdrawal symptoms included anxiety,
tachycardia, tremor, sweats, flushes, palpitations, derealisation, and further
57
insomnia.[13]
Suspected withdrawal convulsions during detoxification from Zopiclone
has been reported, however the individual was a high dose Zopiclone misuser.[14]
The risk of dependency on Zopiclone when used for less than 2 weeks or only
used occasionally is low.[15]
However, this is disputed by one study of low dose
Zopiclone taken for only 7 nights. It found that discontinuation of
Zopiclone caused significant rebound insomnia. Furthermore when midazolam taken
for 7 nights was discontinued no rebound insomnia occurred suggesting that
Zopiclone may have even more significant problems of tolerance and dependence
than the benzodiazepines.[16]
After 3 weeks of use mild to moderate rebound
withdrawal symptoms appear upon discontinuation of Zopiclone.[17]
Due to the risk of
tolerance and physical dependence, Zopiclone is only recommended for short term
(1–4 weeks max) relief of insomnia, or alternatively, long term infrequent use.[18]
Long-term Zopiclone users who have become physically dependent should not
discontinue their medication abruptly as severe withdrawal symptoms may occur such
as delirium.[19]
If Zopiclone has been taken for more than a few weeks then the
medication should be gradually reduced or preferably to cross over to an equivalent
dose of diazepam (Valium), which has a much longer half life which makes
withdrawal easier and then gradually taper their dosage over a period of several
months in order to avoid extremely severe and unpleasant withdrawal symptoms (e.g.,
inner restlessness, psychomotor agitation, abdominal pain, hypertension,
hallucinations, seizures, anxiety, depression, psychosis, etc.) which can last up to two
years after withdraw if the withdrawal is done too abruptly.[20-22]
After 4 weeks of nightly use of Zopiclone day time withdrawal related anxiety
begin to emerge in some users. However, the day time withdrawal anxiety does not
appear to be as intense as that seen with the much shorter acting triazolam which
provokes even more profound day time withdrawal anxiety symptoms in long term
users.[23]
According to the World Health Organization, Zopiclone, although molecularly
is not a benzodiazepine, binds unselectively with high affinity to the same
benzodiazepine sites that the benzodiazepine class of drugs do. The World Health
58
Organization also stated that Zopiclone is cross tolerant with benzodiazepines and one
can substitute one for the other. The withdrawal symptoms from Zopiclone reported
included anxiety, tachycardia, tremor, sweating, rebound insomnia, derealisation,
convulsions, palpitations and flushes.[24]
Zopiclone is cross tolerant with benzodiazepines.[25]
Alcohol has cross
tolerance with GABAA receptor positive modulators such as the benzodiazepines and
the nonbenzodiazepine drugs. For this reason alcoholics or recovering alcoholics may
be at increased risk of physical dependency on Zopiclone.
To withdraw from Zopiclone sleeping tablets cross over to an equivalent dose
of diazepam, the equivalency table by Professor Heather Ashton can be used.[26]
To
withdraw and reduce the intensity of withdrawal symptoms, including interdose
withdrawal symptoms, it is important that the blood levels of a drug remain constant
throughout a 24 hour period. This is not possible with Zopiclone as it is a short acting
drug; therefore users of Zopiclone should cross over to an equivalent dose of
diazepam to begin their dose taper.[27]
While it acts on the same benzodiazepine
receptors as the benzodiazepine family of drugs it is not classed as a benzodiazepine
(with which it shares a number of characteristics and effects) due to its differing
molecular structure. Zopiclone is classed as a cyclopyrrolone derivative.[28]
59
2.2. LITERATURE SURVEY
Several analytical methods have been reported for the determination of
Zopiclopne in pure drug, pharmaceutical dosage forms and in biological samples
using spcetrophotometry, liquid chromatography, electro kinetic chromatography high
performance thin layer chromatography either in single or in combined forms.
Beata Paw and Genowefa Misztal et al
[29] were developed a rapid, simple
and accurate chromatographic (HPLC) and spectrophotometric methods for the
determination of Zopiclone in tablets were elaborated. Acetonitrile was found to be a
suitable extraction solvent. The samples were chromatographed on Nova-Pak C18
column and UV detection at 304 nm. The elution was achieved isocratically with a
mobile phase of 0.067 M phosphate buffer pH 7.95 — acetonitrile (55:45, v/v).
Diazepam was applied as an internal standard. The method was validated for
precision, linearity, accuracy and limit of detection. The recovery (mean±SD) in
HPLC was 99.85±0.04% and in the UV-spectrophotometry 100.08±0.09%.
Hiren N
et al[30]
were developed a A simple, selective and sensitive
isocratic HPLC method with triple quadrupole mass spectrometry detection has been
developed and validated for simultaneous quantification of Zopiclone and its
metabolites in human plasma. The analytes were extracted using solid phase
extraction, separated on Symmetry shield RP8 column (150 mm × 4.6 mm i.d.,
3.5 μm particle size) and detected by tandem mass spectrometry with a turbo ion
spray interface. Metaxalone was used as an internal standard. The method had a
chromatographic run time of 4.5 min and linear calibration curves over the
concentration range of 0.5–150 ng/mL for both Zopiclone and N-desmethyl Zopiclone
and 1–150 ng/mL for Zopiclone-N-oxide. The intra-batch and inter-batch accuracy
and precision evaluated at lower limit of quantification and quality control levels were
within 89.5–109.1% and 3.0–14.7%, respectively, for all the analytes. The recoveries
calculated for the analytes and internal standard were ≥90% from spiked plasma
samples. The validated method was successfully employed for a comparative
bioavailability study after oral administration of 7.5 mg Zopiclone (test and reference)
to 16 healthy volunteers under fasted condition.
60
J. Van Bocxlaer et al [31]
were developed a new HPLC method for Zopiclone
(Imovane) in postmortem specimens by GC-MS and HPLC with diode-array
detection. Blood or stomach contents (1 ml) were mixed with 50 µl N-
allylnormetazocine (internal standard; 0.4 mg/ml in methanol) and thereafter with 1
ml ethanol, 1M-K2CO3 (5 drops, pH 9) and 2 ml H2O. The mixture was extracted
with 8 ml methyl tert-butyl ether/n-hexane (3:1). After mixing for 15 min, samples
were centrifuged for 10 min at 2500 g. The organic layer was evaporated at room
temperature under N2 and redissolved in 100 µl mobile phase. A 50 µl portion was
analyzed by HPLC on a 5 µm Hypersil BDS C18 column (15 cm × 4.6 mm i.d.),
1.5M-ammonium acetate/acetonitrile/ methanol/H2O (solvent A, 3:10:10:77; solvent
B, 3:40:40:17) as mobile phase with gradient elution from 5-50% B within 20 min (1
ml/min) and diode-array detection. Calibration graphs were linear from 0.9-10 µg/ml
Zopiclone and 2-40 µg/ml pentazocine. GC-MS analysis of liver samples was also
performed on a column (30 m × 0.25 mm i.d.) coated with DB-5 (0.25 µm) operated
with temperature programming from 150-270°C at 30°C/min and then to 290°C (held
for 5 min) at 1°C/min, He as carrier gas (0.8 ml/min) and mass-selective ion-trap
detection. Details of a liquid-liquid extraction procedure for extraction of the drugs
from the liver are presented. Without the use of these procedures, Zopiclone can be
easily overlooked during routine forensic screening
Gottfried Blaschke et al
[32] were report the preparative separation of
rac-Zopiclone using malic acid as the resolving agent. Furthermore, two different
methods for the analytical determination of Zopiclone enantiomers by HPLC on chiral
stationary phases are described. The benzodiazepine receptor binding of the isolated
enantiomers was investigated. Half-maximal inhibitory concentrations of (+)- and (−)-
Zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times
higher affinity of the (+)-enantiomer toward the receptor.
Lakshmana Rao et al [33]
were developed an A simple, rapid, sensitive
and precise HPLC method has been developed for the estimation of Zopiclone in pure
and tablet dosage form. In this method RP-C18 column (100mmx4.6mm I.D., 3µm
particle size) with mobile phase consisting of 0.02M phosphate buffer and acetonitrile
in the ratio of 55:45v/v in a isocratic mode was used. The detection wavelength is
61
304nm and the flow rate is 1ml/min. The linearity found in the range of 20-100µg/ml
and shows a correlation coefficient of 0.9913. The proposed method was validated by
determining sensitivity, linearity, accuracy and precision. This method is simple, fast,
accurate, precise and reproducible hence can be applied for the routine quality control
analysis of Zopiclone in pure and pharmaceutical dosage form.
Frank T.Peters et al [34]
were developed a Reliable analytical data are a
prerequisite for correct interpretation of toxicological findings in the evaluation of
scientific studies, as well as in daily routine work. Unreliable analytical data might
not only be contested in court, but could also lead to unjustified legal consequences
for the defendant or to wrong treatment of the patient. This is especially true in the
context of quality management and accreditation, which have become matters of
increasing relevance in analytical toxicology in recent years. In this paper, the author
tried in this chapter an important considerations in analytical method validation will
be discussed which may be used as guidance by scientists wishing to develop and
validate analytical methods. Therefore, new analytical methods to be used in forensic
and/or clinical toxicology require careful method development and thorough
validation of the final method.
62
2.3. EXPERIMENTAL
2.3.1. Instrumentation
Peak HPLC containing LC 20 AT pump, variable wavelength programmable
uv/vis detector and Rheodyne injector was employed for the investigation. The
chromatographic analysis was performed on a Chromosil C18 column (250 mm x 4.6
mm, 5μm) column. Degassing of the mobile phase was done by using a Loba
ultrasonic bath sonicator. A Denver balance was used for weighing the materials.
2.3.2. Chemicals and Solvents
The reference sample of Zopiclone (API) was obtained from Lupin,
Ahmadabad. The Formulation was procured from the local market. Acetonitrile,
Methanol, Tetra hydro furan (THF) and orthophosphoric acid used were of HPLC
grade and purchased from Merck Specialties’ Private Limited, Mumbai, India.
2.3.3. The buffer solution
About 1.0 mL of orthophosphoric acid was diluted to 1000 mL with water.
This solution was mixed and pH was adjusted to 5.8 with ortho phosphoric acid and
filtered through 0.45μ nylon filter.
2.3.4. The mobile phase
A mixture of Acetonitril: Methanol: THF: 0.1%OPA in the ratio of 45:20:5:30
v/v was prepared and used as mobile phase.
2.3.5. Standard solution of the drug
For analysis we 100 ppm standard solution was prepared in mobile phase.
Required concentrations were obtained from 100 ppm standard solution by proper
dilution.
2.3.6. Sample (tablet) solution
The formulation tablets of Zopiclone (ZOLINOX – 7.5mg) were crushed to
give finely powdered material. With Powder we prepared 70 ppm solution in mobile
phase and then filtered through Ultipor N66 Nylon 6, 6 membrane sample filter paper.
63
2.4. METHOD DEVELOPMENT
For developing the method [35-43]
, a systematic study of the effect of various
factors was undertaken by varying one parameter at a time and keeping all other
conditions constant. Method development consists of selecting the appropriate wave
length and choice of stationary and mobile phases. The following studies were
conducted for this purpose.
2.4.1. Detection wavelength
The spectrum of diluted solutions of the Zopiclone in mobile phase was
recorded separately on UV spectrophotometer. The peak of maximum absorbance
wavelength was observed. The spectra of the both Zopiclone were showed that a
wavelength was found to be 303 nm.
2.4.2. Choice of stationary phase
Preliminary development trials have performed with octadecyl columns with
different types, configurations and from different manufacturers. Finally the expected
separation and shapes of peak was succeeded Chromosil C18 column.
2.4.3. Selection of the mobile phase
In order to get sharp peak, low tailing factor and base line separation of the
components, we carried out a number of experiments by varying the composition of
various solvents and its flow rate. To effect ideal separation of the drug under
isocratic conditions, mixtures of solvents like methanol, water and Acetonitrile with
or without different buffers indifferent combinations were tested as mobile phases on
a C18 stationary phase. A mixture of Acetonitril: Methanol: THF : 0.1%OPA in the
ratio of 45:20:5:30 v/v was proved to be the most suitable of all the combinations
since the chromatographic peak obtained was better defined and resolved and almost
free from tailing.
2.4.4. Flow rate
Flow rates of the mobile phase were changed from 0.5 – 1.5 mL/min for
optimum separation. A minimum flow rate as well as minimum run time gives the
64
maximum saving on the usage of solvents. It was found from the experiments that 1.0
mL/min flow rate was ideal for the successful elution of the analyte.
2.4.5. Optimized chromatographic conditions
Chromatographic conditions as optimized above were shown in Table 2.2
These optimized conditions were followed for the determination of Zopiclone in bulk
samples and its combined tablet Formulations. The chromatograms of standard and
sample were shown in Figure 2.B
Mobile phase ACN45% ,MEOH ,20% ,THF 5% ,
0.1 %OPA 30%
Pump mode Isocratic
Mobile phase PH 4.5
Diluent The mobile phase
Column chromosil C18 column (250 mm x 4.6
mm, 5μ)
Column Temp Ambient
Wavelength 303 nm
Injection Volume 20 μl
Flow rate 1.0 mL/min
Run time 10 min
Retention Time 3.3 min
Table 2.2: Optimized chromatographic conditions for estimation Zopiclone
65
Figure 2.B: RP - HPLC Chromatogram of standard solution
66
2.5. VALIDATION OF THE PROPOSED METHOD
The proposed method [44-53]
was validated as per ICH guidelines. The
parameters studied for validation were specificity, linearity, precision, accuracy,
robustness, system suitability, limit of detection, limit of quantification, and solution
stability.
2.5.1. Specificity
The specificity of method was performed by comparing the chromatograms of
blank, standard and sample. It was found that there is no interference due to excipients
in the tablet formulation and also found good correlation between the retention times
of standard and sample. The specificity results are shown in Table 2.3
NAME OF THE SOLUTION Retention Time in Minutes
BLANK NO PEAKS
Zopiclone 3.03
Table 2.3: Specificity study
2.5.2 Linearity
Linearity was performed by preparing mixed standard solutions of Zoplicone
at different concentration levels including working concentration mentioned in
experimental condition i.e. 0.8µg/ml. Twenty micro liters of each concentration was
injected in duplicate into the HPLC system. The response was read at 303 nm and the
corresponding chromatograms were recorded. From these chromatograms, the mean
peak areas were calculated and linearity plots of concentration over the mean peak
areas were constructed individually. The regressions of the plots were computed by
least square regression method. Linearity results were presented in Table2.4
67
Figure 2.C: On X axis concentration of sample solution, On Y axis peak area
response Linearity results of Zopiclone:
Level Concentration of OLMESARTAN in µg/ml Mean peak area
Level -1 0.2 76001.1
Level -2 0.4 142422.3
Level -3 0.6 219516.2
Level -4 0.8 295425.0
Level -5 1.0 373769.3
Level -6 1.2 465371.4
Level-7 1.4 5381693.1
Range:
0.2 to 1.4
µg/ml
Slope
Intercept
Correlation coefficient
390754.9
0.029
0.9993
Table 2.4: Linearity Results
2.5.3. Precision
Precision is the degree of repeatability of an analytical method under normal
Operational conditions. Precision of the method was performed as intraday precision,
Inter day precision.
-100000
0
100000
200000
300000
400000
500000
600000
0 2 4 6 8
68
2.5.3.1: Intraday precision
To study the intraday precision, five replicate standard solution of Zopiclone
was injected. The percent relative standard deviation (% RSD) was calculated and it
was found to be 1.697, which are well within the acceptable criteria of not more than
2.0. Results of system precision studies are shown in Table 2.5.
SAMPLE
CONC(µg/ml) INJECTION No. PEAKS
AREA
R.S.D
(Acceptance
criteria 2.0)
Zopiclone
0.8
1 279249.2
1.697
2 277905.2
3 268011.3
4 273292.3
5 271282.8
Table 2.5: System Suitability (Intra Day)
2.5.5. Inter Day precision
To study the inter day precision, five replicate standard solution of Zopiclone
was injected on third day of sample preparation. The percent relative standard
deviation (% RSD) was calculated and it was found to be 1.743, which are well within
the acceptable criteria of not more than 2.0. Results of system precision studies are
shown in Table 2.6.
69
SAMPLE
CONC(µg/ml) INJECTION No. PEAKS
AREA
R.S.D
(Acceptance
criteria 2.0)
Zopiclone
0.8
1 290196.4
1.743
2 295425.0
3 295018.1
4 303377.6
5 291464.5
Table 2.6: System Precision (Inter Day)
2.5.6. Accuracy
The accuracy of the method was determined by standard addition method. A
known amount of standard drug was added to the fixed amount of pre-analyzed tablet
solution. Percent recovery was calculated by comparing the area before and after the
addition of the standard drug. The standard addition method was performed at 20%,
40% and 60% level. The solutions were analyzed in triplicate at each level as per the
proposed method. The percent recovery and % RSD was calculated and results are
presented in Table 2.7 Satisfactory recoveries ranging from 99.9 to 100.1 were
obtained by the proposed method. This indicates that the proposed method was
accurate.
70
LEVEL
Amount of
OLMESARTAN
spiked (µg/ml)
Amount of
OLMESARTAN
recovered(µg/ml)
%
Recovery
MEAN %
Recovery
%R.S.D
MEAN
%
R.S.D
20 %
1.2 1.19 99.16
0.484
1.2 1.18 98.33
1.2 1.19 99.16
40%
1.4 1.38 98.57
0.422
1.4 1.37 97.85
1.4 1.38 98.57
60%
1.6 1.56 97.5
1.099
1.6 1.56 97.5
1.6 1.59 99.37
98.44 0.668
Table 2.7: Percentage Recovery and %RSD
71
2.5.7. Robustness
The robustness study was performed by slight modification in flow rate of the
mobile phase, pH of the buffer and composition of the mobile phase. Zopiclone at
0.4µg/ml concentration was analyzed under these changed experimental conditions. It
was observed that there were no marked changes in chromatograms, which
demonstrated that the developed method was robust in nature. The results of
robustness study are shown in Table 2.8.
Condition Mean area % assay % difference
Unaltered 142422.3 100.0 0.0
Flow rate at 0.8 mL/min
Flow rate at 1.2mL/min
142874.5
141966.7
100.3
99.68
0.3
0.32
Mobile phase:
MeOH: water
82% 18%
78% 22%
142588.2
143120.6
100.11
100.49
0.11
0.49
pH of mobile phase at 4.8 143058.1 100.44 0.44
pH of mobile phase at 4.2 142688.0 100.1 0.1
Table 2.8: Robustness
72
2.5.8. System suitability
System suitability was studied under each validation parameters by injecting
six replicates of the standard solution. The system suitability parameters are given in
Table 2.9.
Parameter Tailing factor Theoretical plates
Specificity study 1.30 5557.18
Linearity study 1.45 4227.53
Precision study 0.99 2555.7
Table 2.9: System Suitability
2.5.9. Limit of detection and Limit of quantification
Limit of detection (LOD) is defined as the lowest concentration of analyte that
gives a detectable response. Limit of quantification (LOQ) is defined as the lowest
Concentration that can be quantified reliably with a specified level of accuracy and
Precision. For this study six replicates of the analyte at lowest concentration were
Measured and quantified. The LOD and LOQ of Zopiclone given in Table 2.10
Parameter Measured volume
Limit of Quantification 45ng/ml
Limit of Detection 10ng/ml
Table 2.10: LOQ and LOD
73
2.6. RESULTS AND DISCUSSION
To optimize the RP-HPLC parameters, several mobile phase compositions
were tried. A satisfactory separation and good peak symmetry was found in a mixture
of Acetonitril: Methanol: THF: 0.1%OPA in the ratio of 45:20:5:30 v/v and 1.0
mL/min flow rate proved to be better than the other mixtures in terms of resolution
and peak shape. The optimum wavelength for detection was set at 303nm at which
much better detector responses for drug was obtained. As it was shown in Fig. 2.B the
retention times were 3.30 min for Zopiclone. The number of theoretical plates was
found to be 5557.8, which indicates efficient performance of the column. A system
suitability test was applied to representative chromatograms for various parameters.
The results obtained were within acceptable limits and are represented in Table 2.9.
Thus, the system meets suitable criteria.
The calibration curve was obtained for a series of concentration in the range
of 0.2-1.4µg/ml and it was found to be linear. Seven points graphs was constructed
covering a concentration range 0.2-1.4µg/ml. The standard deviation of the slope and
intercept were low. The data of regression analysis of the calibration curves are shown
in Table 2.C.
The proposed method has been applied to the assay of T commercial tablets
containing Zopiclone. Sample was analyzed for five times after extracting the drug as
mentioned in assay sample preparation of the experimental section. The results
presented good agreement with the labeled content. Low values of standard deviation
denoted very good repeatability of the measurement. Thus it was showing that the
equipment used for the study was correctly and hence the developed analytical
method is highly repetitive. For the intermediate precision a study carried out by the
same author working on the same day on two consecutive days indicated a RSD of
1.697 & 1.743. This indicates good method precision.
The system suitability parameter like capacity factor, asymmetry factor, tailing
factor and number of theoretical plates were also calculated. It was observed that all
the values are within the limits. The statistical evaluation of the proposed method was
revealed its good linearity, reproducibility and its validation for different parameters
and let us to the conclusion that it could be used for the rapid and reliable
determination of Zopiclone in tablet formulation.
74
All these factors lead to the conclusion that the proposed method is accurate,
precise, simple, sensitive and rapid and can be applied successfully for the estimation
of Zopiclone in bulk and in pharmaceutical formulations without interference and
with good sensitivity
75
2.7. BIBILOGRAPHY
1. "What's wrong with prescribing hypnotics?‖; Drug Ther Bull; 2004, 42 (12):
89–93.
2. Touitou Y; "Sleep disorders and hypnotic agents: medical, social and
economical impact" (in French); Ann Pharm Fr; 2007; 65 (4): 230–8.
3. Budavari S; The Merck Index, 13th
Edn, Merck & Co., Inc., Whitehouse
Station, NJ. 2004; 10247.
4. Jonathan U; The Australian Drug Guide. Melbourne: Bookman Press Pvt.
Ltd.; 2000; p. 743.
5. Blaschke, G; Hempel, G; Müller We; "Preparative and analytical separation
of the Zopiclone enantiomers and determination of their affinity to the
benzodiazepine receptor binding site.‖; Chirality; 1993; 5(6): 419–21.
6. Fernandez, C; Maradeix, V; Gimenez, F; Thuillier, A; Farinotti, R;
"Pharmacokinetics of Zopiclone and its enantiomers in Caucasian young
healthy volunteers.‖; Drug metabolism and disposition: the biological fate of
chemicals 1993; 21(6): 1125–8.
7. Van, Der, Kleijn, E; "Effects of Zopiclone and temazepam on sleep, behaviour
and mood during the day"; European journal of clinical pharmacology; 1989;
36(3): 247–51.
8. Bramness JG, Olsen H; "Adverse effects of Zopiclone". Tidsskrift for den
Norske laegeforening; 1998; 118 (13): 2029–32.
9. Luty S, Sellman D; "Imovane—a benzodiazepine in disguise". N. Z. Med. J;
1993; 106 (959): 293.
10. Deveaux M, Chèze M, Pépin G; "The role of liquid chromatography-tandem
mass spectrometry (LC-MS/MS) to test blood and urine samples for the
toxicological investigation of drug-facilitated crimes". Ther Drug Monit,
2008; 30 (2): 225–8.
11. "Hypnotic dependence: zolpidem and Zopiclone too". Prescrire Int; 2001;
10 (51): 15.
12. Wong CP, Chiu PK, Chu LW. "Zopiclone withdrawal: an unusual cause of
delirium in the elderly". Age Ageing; 2005; 34(5): 526–7.
76
13. Ones IR, Sullivan G; "Physical dependence on Zopiclone: case reports"; BMJ;
1998; 316 (7125): 117.
14. Aranko, K; Henriksson, M; Hublin, C; Seppäläinen, Am; ―Misuse of
Zopiclone and convulsions during withdrawal"; Pharmacopsychiatry; 1991;
24 (4): 138–40.
15. Anderson, Aa; "Zopiclone and nitrazepam: a multicenter placebo controlled
comparative study of efficacy and tolerance in insomniac patients in general
practice‖; 1987; 10(1): 54–62.
16. Begg, Ej; Robson, Ra; Frampton, Cm; Campbell, Je; ―A comparison of
efficacy and tolerance of the short acting sedatives midazolam and
Zopiclone"; The New Zealand medical journal; 1992; 105 (944): 428–9.
17. Dorian, P; Sellers, Em; Kaplan, H; Hamilton, C; "Evaluation of Zopiclone
physical dependence liability in normal volunteers"; Pharmacology; 1983;
27(2): 228–34.
18. Mendelson WB, Jain B; "An assessment of short-acting hypnotics"; Drug Saf;
1995; 13(4): 257–70.
19. Harter C, Piffl-Boniolo E, Rave-Schwank M; "Development of drug
withdrawal delirium after dependence on zolpidem and zoplicone" (in
German); Psychiatr Prax; 1999; 26 (6): 309.
20. sanofi-aventis Canada Inc ;"IMOVANE (Zopiclone) Tablets, 5.0 mg and 7.5
mg".
21. Kahlert I; Brüne M; "A case of primary Zopiclone dependence"; Dtsch Med
Wochenschr; 2008; 126 (22): 653–4.
22. Heather Ashton; "Benzodiazepines: how they work and how to withdraw‖.
23. Fontaine, R; Beaudry, P; Le, Morvan, P; Beauclair, L; Chouinard, G;
"Zopiclone and triazolam in insomnia associated with generalized anxiety
disorder: a placebo-controlled evaluation of efficacy and daytime anxiety";
International clinical psychopharmacology; 1990; 5 (3): 173–83.
24. WHO (2006); "World Health Organisation - Assessment of Zopiclone";
who.int.http://www.who.int/medicines/areas/quality_safety/4.6ZopicloneCritR
eview.pdf.
77
25. Cohen, C; Sanger, Dj; ―Tolerance, cross-tolerance and dependence measured
by operant responding in rats treated with triazolam via osmotic pumps‖;
Psychopharmacology; 1994; 115 (1-2): 86–94.
26. EQUIVALENCY TABLE.
27. Explanation by Dr JG McConnell in his article called The
Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering
Using Diazepam.
28. Elie, R; Deschenes, Jp; "Efficacy and tolerance of Zopiclone in insomniac
geriatric patients"; International pharmacopsychiatry; 1982; 17(2): 179–87.
29. ―Determination of Zopiclone in tablets by HPLC and UV-spectrophotometry‖;
Journal of Pharmaceutical and Biomedical Analysis; 2000; 23(5): 819-823.
30. ―Validated method for simultaneous quantification of Zopiclone and its
metabolites, N-desmethyl Zopiclone and Zopiclone-N-oxide in human
plasma‖; Journal of Chromatography B; 2008; 864(1-2,15): 137-148.
31. J Anal Toxicol; ―Analysis of Zopiclone (Imovane) in postmortem specimens
by GC-MS and HPLC with diode-array detection‖; RSC Journals.; 1996;
20(1):52-4.
32. ―Preparative and analytical separation of the Zopiclone enantiomers and
determination of their affinity to the benzodiazepine receptor binding site‖;
Chirality; 1993; 5(6), 419–421.
33. ―RP-HPLC Method for the Estimation of Zopiclone in Tablet Dosage Form‖;
International Journal of Pharmaceutical Research; 2011; 3(1): 49-51.
34. Forensic Science International; 2007; 165(2): 216-224.
35. ―Q2A: Text on Validation of Analytical Procedures‖; International Conference
on Harmonization; Federal Register; 1995; 60(40): 11260–11262.
36. ―Q2B: Validation of Analytical Procedures: Methodology; Availability‖;
International Conference on Harmonization; Federal Register; 1997; 62(96):
27463–27467.
37. "Analytical Procedures and Methods Validation: Chemistry, Manufacturing
and Controls Documentation; Availability"; FDA; Federal Register (Notices);
2000; 65(169): 52776 – 52777.
38. www.fda.gov/cder/guidance/cmc3.pdf.
78
39. USP 25–NF 20; ―Validation of Compendial Methods Section (1225) (United
States Pharmacopeal Convention, Rockville, Maryland, USA, 2002)‖; 2256.
40. G.A. Shabir; ―Validation of HPLC Chromatography Methods for
Pharmaceutical Analysis‖; Understanding the Differences and Similarities
between Validation Requirements of FDA, the US Pharmacopeia and the ICH;
J. Chromatogr. A; 2003; 987(1-2): 57-66.
41. C.E. Wood; "Medicare Program; Changes to the Hospital Outpatient
Prospective"; Med. J. Aust; 1996; 165: 510–514.
42. A. Prentice; "Medical Management of Menorrhagia": Br. Med. J; 1999; 319,
1343–1345.
43. D.T. Baired and A.F. Glasier; "Hormonal Contraception"; New Engl. J. Med;
1993; 328: 1543–1549.
44. P.E. Belchetz; "Hormonal Treatment of Postmenopausal Women"; New Engl.
J. Med; 1994; 330: 1062–1071.
45. International Conference on Harmonization (ICH) of Technical Requirements
for the Registration of Pharmaceuticals for Human Use; ―Validation of
analytical procedures: definitions and terminology‖; Geneva (1996).
46. U.S. FDA; Title 21 of the U.S. Code of Federal Regulations:
21 CFR 211—Current good manufacturing practice for finished
pharmaceuticals.
47. U.S. FDA - Guidance for Industry (draft) Analytical Procedures and Methods
Validation: Chemistry, Manufacturing, and Controls and Documentation,
2000.
48. ISO/IEC 17025, General requirements for the competence of testing and
calibration laboratories, 2005.
49. International Conference on Harmonization (ICH) of Technical Requirements
for the Registration of Pharmaceuticals for Human Use, Validation of
analytical procedures: Methodology, adopted in 1996, Geneva.
50. U.S. EPA, Guidance for methods development and methods validation for the
Resource Conservation and Recovery Act (RCRA) Program, Washington,
D.C. (1995).http://www.epa.gov/sw-846/pdfs/methdev.pdf.
79
51. General Chapter 1225, Validation of compendial methods, United States
Pharmacopeia 30, National Formulary 25, Rockville, Md., USA, The United
States Pharmacopeial Convention, Inc., (2007).
52. U.S. FDA - Guidance for Industry, Bioanalytical Method Validation.
53. G. C. Hokanson, A life cycle approach to the validation of analytical methods
during pharmaceutical product development, Part I: The initial validation
process, Pharm. Tech., Sept. 1994, pp. 118–130.