Tizanidine is an agonist at
α2-adrenergic receptor sites and reduces spasticity by increasing presynaptic
inhibition of motor neurons. Tizanidine hydrochloride is an imidazoline
derivative, which acts as agonist on centrally located α2 receptors and this
leads to myotonolytic effects on skeletal muscle. It is structurally and
pharmacologically similar to clonidine and other α2-adrenergic agonists. The
correct mechanism of tizanidine in decreasing muscle tone and frequency of
spasm is not clearly understood. About 53% to 66% of the dose administered is
being absorbed through the gastrointestinal tract after oral administration the
peak plasma concentration is reached within 1 to 2 h. Bioavailability of
Tizanidine is about 34% to 40% half-life is 2.5 h. The drug is widely
distributed throughout the body and 30% of drug binds to plasma proteins.
Releases 80% or more of the tizanidine in
20 minutes or less after administration of the drug since most patients does
not like to hold a tablet or lozenge under the tongue for longer periods. More
preferably the composition or dosage form releases 80% or more tizanidine in 5
minutes or less. Optimum dose of
tizanidine is 2 mg to 4 mg; Toxic dose of tizanidine is 60 mg and 120 mg.
If the total dose cross 30 mg/day in divided doses
it may be lethal and may cause hepatic injury. (6)
CONCLUSION:
Mucoadhesive drug delivery system prolong the
residence time of the dosage form at the site of application or absorption.
Mucoadhesive drug delivery system has high drug loading capacity. The main
advantages of the buccal route of administration over the traditional oral
route are that drug degradation in the stomach is avoided, first-pass
metabolism is avoided, and therapeutic drug levels of drug can be achieved
rapidly, due the buccal cavity provides a highly vascular mucous membrane site
for the administration of drugs. Tizanidine undergoes rapid and
extensive first pass metabolism in the liver (approximately 95% of a dose),
leading to the oxidation of the imidazoline moiety, aromatic system, and the
sulfur atom. This leads to lower bioavailability of Tizanidine. In order to
overcome such extensive first-pass metabolism, the drug is selected as suitable
candidate for bioadhesive buccal drug delivery
MONOGRAPHS
TIZANIDINE
HYDROCHLORIDE:
C9H8ClN5S · HCl 290.17
2,1,3-Benzothiadiazol-4-amine, 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-, monohydrochloride;
5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole
monohydrochloride [64461-82-1].
DEFINITION
Tizanidine Hydrochloride contains
NLT 98.0% and NMT 102.0% of C9H8ClN5S · HCl, calculated on the dried basis.
IDENTIFICATION
·
A.INFRARED ABSORPTION (197K)
·
B. The retention time of the major peak of
the Sample solution corresponds
to that of the Standard solution, as obtained in the Assay.
·
C. IDENTIFICATION TESTS—GENERAL: Choride (191):
A solution of 10 mg/mL in water meets the requirements of the silver
nitrate precipitate test.
ASSAY
PROCEDURE
Solution
A:
6.8 mg/mL of monobasic potassium phosphate. Adjust with 5.3N potassium
hydroxide to a pH of 7.5 ± 0.05.
Mobile
phase:
Acetonitrile and Solution A (20:80)
System
suitability solution:
46 mg/mL of USP Tizanidine Hydrochloride RS and 0.12 mg/mL of USP Tizanidine
Related
Compound C RS in Mobile phase
Standard
solution:
0.046 mg/mL of USP Tizanidine Hydrochloride RS in Mobile phase
Sample
solution:
0.046 mg/mL of Tizanidine Hydrochloride in Mobile phase.
Chromatographic
system:
(See Chromatography á621ñ,
System Suitability.)
Mode: LC
Detector: UV 230 nm
Column: 4.6-mm ´ 15-cm;
packing L7
Column
temperature:
35°
Flow
rate:
1 mL/min
Injection
size:
20 mL
System
suitability
Sample: Standard solution
[NOTE—The relative retention
times for tizanidine related compound C and tizanidine are 0.5 and 1.0,
respectively.]
Suitability
requirements
Resolution: NLT 13.0
between tizanidine and tizanidine related compound C
Tailing
factor: NMT
1.6 for tizanidine
Relative
standard deviation:
NMT 2.0%
Analysis
Samples: Standard solution and Sample solution Calculate the
percentage of C9H8ClN5S · HCl in the portion of Tizanidine Hydrochloride taken:
Result
= (rU/rS) ´ (CS/CU) ´ 100
rU = peak response of tizanidine
from the Sample solution.
rS= peak response of tizanidine
from the Standard solution
CS = concentration of USP
Tizanidine Hydrochloride RS in the Standard
solution (mg/mL)
CU = concentration of the Sample solution (mg/mL)
Acceptance criteria: 98.0%–102.0%
IMPURITIES
Inorganic
Impurities
·
RESIDUE ON
IGNITION (281): NMT
0.1%
·
HEAVY METALS (231): NMT 20 ppm
Organic
Impurities
PROCEDURE
Solution A: Water and
phosphoric acid (44:6)
Buffer: 3.5 mg/mL of
sodium 1-pentanesulfonate. Adjust with Solution A or 1 N sodium
hydroxide to a pH of 3.0 ± 0.05.
Mobile phase: Acetonitrile
and Buffer (20:80)
Tizanidine
related compound A solution: 0.1 mg/mL of USP Tizanidine Related
Compound A RS in methanol
Tizanidine
related compound B solution: 0.1 mg/mL of USP Tizanidine Related
Compound B RS in methanol
Tizanidine
related compound C solution: 0.1 mg/mL of USP Tizanidine Related
Compound C RS in methanol
System
suitability solution:
Transfer 23mg of USP Tizanidine Hydrochloride RS to a 100-mL volumetric flask.
Add 20.0 mL of Mobile phase and
10.0 mL each of Tizanidine related
compound A solution, Tizanidine related compound B solution, and Tizanidine related compound C solution.
Sonicate to dissolve the USP Tizanidine Hydrochloride RS, and dilute with Mobile phase to volume.
Standard
solution:
0.046 mg/mL of USP Tizanidine Hydrochloride RS in Mobile phase
Sample
solution:
1.14 mg/mL of Tizanidine Hydrochloride in Mobile phase
Chromatographic
system
(See Chromatography á621ñ,
System Suitability.)
Mode: LC
Detector: UV 230nm
Column:
4.6-mm
´ 25-cm; packing L1
Column
temperature:
50°
Flow
rate:
1 mL/min
Injection
size:
10 mL
System
suitability
Samples: System suitability solution and Standard solution
[NOTE—the relative retention
times are listed in Impurity Table 1.]
Suitability
requirements
Resolution: NLT 4.0 between
tizanidine and tizanidine related compound C, System suitability solution; NLT 4.0 between
tizanidine and tizanidine related compound B, System suitability solution
Column
efficiency:
NLT 5000 theoretical plates Standard
solution
Tailing
factor:
NMT 2.0, Standard solution
Relative
standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples: Standard solution and Sample solution Calculate the
percentage of each impurity in the portion of Tizanidine Hydrochloride taken:
Result=
(rU/rS) ´ (CS/CU) ´ (Mr1/Mr2) ´ (1/F) ´ 100
rU = peak area for each impurity
in the Sample solution
rS = peak area of tizanidine in
the Standard solution
CS = concentration of USP
Tizanidine Hydrochloride RS in the Standard
solution (mg/mL)
CU = concentration of tizanidine
hydrochloride in the Sample solution (mg/mL)
Mr1 = molecular weight of
tizanidine, 253.71
Mr2 = molecular weight of
tizanidine hydrochloride 290.17
F = relative response factor in Impurity Table 1
Acceptance
criteria
Individual impurities: See Impurity Table 1.
Total impurities: NMT 0.3%
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