Accessed from 128.83.63.

20 by nEwp0rt1 on Tue Nov 29 03:32:07 EST 2011

4876 Tioconazole / Official Monographs USP 35

rS = peak response of the related compound from more than 0.5% of its weight. If labeled as attenuation grade,
the Standard solution ignite 4 g of titanium dioxide, accurately weighed, at 800 ± 25°
WI = weight of the respective USP Reference Standard to constant weight: it loses not more than 13% of its weight.
taken to prepare the Standard solution (mg) Water-soluble substances—Suspend 4.0 g in 50 mL of
WU = weight of Tioconazole taken to prepare the water, mix, and allow to stand overnight. Transfer to a 200-mL
Sample solution (mg) volumetric flask, add 2 mL of ammonium chloride TS, and mix.
Acceptance criteria: The limit of each related compound is If the Titanium Dioxide does not settle, add another 2-mL por-
NMT 1.0%. tion of ammonium chloride TS. Allow the suspension to settle,
dilute with water to volume, mix, and filter through a double
SPECIFIC TESTS thickness of fine-porosity filter paper, discarding the first 10 mL
• WATER DETERMINATION, Method I 〈921〉: NMT 0.5% of the filtrate. Collect 100 mL of the clear filtrate, transfer to a
ADDITIONAL REQUIREMENTS tared platinum dish, evaporate on a hot plate to dryness, and
• PACKAGING AND STORAGE: Preserve in tight containers. ignite at a dull red heat to constant weight: the residue weighs
• USP REFERENCE STANDARDS 〈11〉 not more than 5 mg (0.25%).
USP Tioconazole RS Acid-soluble substances—Suspend 5.0 g in 100 mL of 0.5 N
USP Tioconazole Related Compound A RS hydrochloric acid, and heat on a steam bath for 30 minutes,
1-[2,4-Dichloro-β-[(3-thenyl)-oxy]phenethyl]imidazole with occasional stirring. Filter through an appropriate filter me-
hydrochloride. dium until clear. Wash with three 10-mL portions of 0.5 N hy-
C16H14Cl2 N2OS · HCl 389.73 drochloric acid. Evaporate the combined filtrate and washings
USP Tioconazole Related Compound B RS to dryness, and ignite at a dull red heat to constant weight: the
1-[2,4-Dichloro-β-[(2,5-dichloro-3-thenyl)oxy]phenethyl] residue weighs not more than 25 mg (0.5%).
imidazole hydrochloride. Arsenic, Method I 〈211〉—Prepare the Test Preparation as fol-
C16H12Cl4N2OS · HCl 458.62 lows. Add 3.0 g to a 250-mL conical flask fitted with a ther-
USP Tioconazole Related Compound C RS mometer and a vapor outlet. Add 50 mL of water, 500 mg of
1-[2,4-Dichloro-β-[(5-bromo-2-chloro-3-thenyl)-oxy]- hydrazine sulfate, 500 mg of potassium bromide, 20 g of so-
phenethyl]imidazole hydrochloride. dium chloride, and 25 mL of sulfuric acid. Arrange to collect
C16H13BrCl2N2OS · HCl 468.63 the evolved vapors in 52 mL of water contained in the arsine
generator flask, then heat the test specimen to 90°, and main-
tain the temperature at 90° to 100° for 15 minutes. Add 3 mL
of hydrochloric acid to the solution in the generator flask: the
.

resulting solution meets the requirements of the test, the addi-

Titanium Dioxide tion of 20 mL of 7 N sulfuric acid specified for Procedure being
TiO2 79.87 omitted. The limit is 1 ppm.
Titanium oxide (TiO2). Assay—Accurately weigh about 300 mg of Titanium Dioxide,
Titanium oxide (TiO2) [13463-67-7]. transfer to a 250-mL beaker, and add 20 mL of sulfuric acid
and 7 to 8 g of ammonium sulfate. Mix, heat on a hot plate
» Titanium Dioxide contains not less than 99.0 until fumes of sulfur trioxide appear, and continue heating over
percent and not more than 100.5 percent of a strong flame until solution is complete or it is apparent that
TiO2, calculated on the dried basis. If labeled as the undissolved residue is siliceous matter. Cool, cautiously di-
lute with 100 mL of water, stir, heat carefully to boiling while
attenuation grade, then Titanium Dioxide con- stirring, and allow the insoluble matter to settle. Filter, transfer
tains not less than 99.0 percent and not more the entire residue to the filter, and wash thoroughly with cold
than 100.5 percent of TiO2, calculated on the ig- 2 N sulfuric acid. Dilute the filtrate with water to 200 mL, and
nited basis. Attenuation grade material may con- cautiously add about 10 mL of ammonium hydroxide.
Prepare a zinc amalgam column in a 25-cm Jones reductor
tain suitable coatings, stabilizers, and treatments tube, placing a pledget of glass wool in the bottom of the
to assist formulation. tube, and filling the constricted portion of the tube with zinc
NOTE—If labeled as attenuation grade, then all amalgam prepared as follows. Add 20- to 30-mesh zinc to mer-
tests and assays are conducted on uncoated, un- curic chloride solution (1 in 50), using about 100 mL of the
treated material. For UV attenuation grade, the solution for each 100 g of zinc, and after about 10 minutes,
decant the solution from the zinc, then wash the zinc by de-
test for Loss on drying does not apply. The FDA cantation. Wash the zinc amalgam column with 100-mL por-
requires the content of lead to be not more than tions of 2 N sulfuric acid until 100 mL of the washing does not
10 ppm, that of antimony to be not more than 2 decolorize 1 drop of 0.1 N potassium permanganate.
ppm, and that of mercury to be not more than 1 Place 50 mL of ferric ammonium sulfate TS in a 1000-mL
suction flask, and add 0.1 N potassium permanganate until a
ppm (21 CFR 73.1575). faint pink color persists for 5 minutes. Attach the Jones reductor
Packaging and storage—Preserve in well-closed containers. tube to the neck of the flask, and pass 50 mL of 2 N sulfuric
acid through the reductor at a rate of about 30 mL per minute.
Labeling—If intended for UV-attenuation, the material must be Pass the prepared titanium solution through the reductor at the
labeled as attenuation grade. If intended for UV-attenuation, same rate, and follow with 100 mL each of 2 N sulfuric acid
and any added coatings, stabilizers, or treatments are used, the and of water. During these operations, keep the reductor filled
labeling shall include the name and amount of the additives. with solution or water above the upper level of the amalgam.
Identification—To 500 mg add 5 mL of sulfuric acid, and Taking precautions against the admission of atmospheric oxy-
heat gently. After fumes of sulfur trioxide appear, continue gen, gradually release the suction, wash down the outlet tube
heating for a minimum of 10 seconds. Cool the suspension, of the reductor and the sides of the receiver, and titrate imme-
and cautiously dilute with water to 100 mL. Filter, and to 5 mL diately with 0.1 N potassium permanganate VS. Perform a
of the clear filtrate add a few drops of hydrogen peroxide TS: a blank determination, substituting 200 mL of 2 N sulfuric acid
yellow-red to orange-red color develops immediately. for the assay solution, and make any necessary correction. Each
Loss on drying 〈731〉—Dry it at 105° for 3 hours: it loses not mL of 0.1 N potassium permanganate is equivalent to 7.988
more than 0.5% of its weight. mg of TiO2.
Loss on ignition 〈733〉—Ignite 2 g, previously dried and accu-
rately weighed, at 800 ± 25° to constant weight: it loses not

Official from May 1, 2012

Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 128.83.63.20 by nEwp0rt1 on Tue Nov 29 03:32:07 EST 2011

USP 35 Official Monographs / Tizanidine 4877

Resolution solution—Transfer about 23 mg of USP Tizanidine

Tizanidine Hydrochloride
.

Hydrochloride RS to a 100-mL volumetric flask, add 20 mL of

Mobile phase and 10 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—Dissolve an accurately weighed quantity
of USP Tizanidine Hydrochloride RS in Mobile phase, and dilute
C9H8ClN5S · HCl 290.17 quantitatively, and stepwise if necessary, with Mobile phase to
2,1,3-Benzothiadiazol-4-amine, 5-chloro-N-(4,5-dihydro-1H- obtain a solution having a known concentration of about 0.046
imidazol-2-yl)-, monohydrochloride. mg per mL.
5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole Test solution—Transfer about 57 mg of Tizanidine Hydrochlo-
monohydrochloride [64461-82-1]. ride, accurately weighed, to a 50-mL volumetric flask, dissolve
in and dilute with Mobile phase to volume, and mix.
» Tizanidine Hydrochloride contains not less than
Chromatographic system (see Chromatography 〈621〉)—The
98.0 percent and not more than 102.0 percent liquid chromatograph is equipped with a 230-nm detector and
of C9H8ClN5S · HCl, calculated on the dried basis. a 4.6-mm × 25-cm column that contains packing L1. The flow
rate is about 1.0 mL per minute. The column temperature is
Packaging and storage—Preserve in tight containers, and maintained at 50°. Chromatograph the Resolution solution, and
store at room temperature. record the peak responses as directed for Procedure: the relative
USP Reference standards 〈11〉— retention times are given in Table 1; the resolution, R, between
USP Tizanidine Hydrochloride RS tizanidine and tizanidine related compound C is not less than
USP Tizanidine Related Compound A RS 4.0; and the resolution, R, between tizanidine and tizanidine
4-Amino-5-chloro-2,1,3-benzothiadiazole. related compound B is not less than 4.0. Chromatograph the
C6H4ClN3S 185.63 Standard solution, and record the peak responses as directed for
USP Tizanidine Related Compound B RS Procedure: the column efficiency is not less than 5000 theoreti-
N-Acetyltizanidine. cal plates; the tailing factor is not more than 2.0; and the rela-
C11H10ClN5OS 295.75 tive standard deviation for replicate injections is not more than
USP Tizanidine Related Compound C RS 2.0%.
1-Acetylimidazolidine-2-thione. Procedure—Inject equal volumes (about 10 µL) of the Stan-
C5H8N2OS 144.20 dard solution and the Test solution into the chromatograph, re-
Identification— cord the chromatograms, and measure the responses for the
major analyte peaks, disregarding the peaks due to the solvent.
A: Infrared Absorption 〈197K〉. Calculate the percentage of each impurity in the portion of
B: The retention time of the major peak in the chromato- Tizanidine Hydrochloride taken by the formula:
gram of the Assay preparation corresponds to that in the chro-
matogram of the Standard preparation, as obtained in the Assay. (253.71/290.17)100(CS / CT)(1/F)(rI / rS)
C: A solution of 10 mg per mL in water meets the require-
ments of the silver nitrate precipitate test for Chloride 〈191〉. in which 253.71 and 290.17 are the molecular weights of
pH 〈791〉: between 4.3 and 5.3, in a 1% (w/v) solution. tizanidine and tizanidine hydrochloride, respectively; CS and CT
are the concentration, in mg per mL, of tizanidine hydrochlo-
Loss on drying 〈731〉—Dry about 0.5 g of sample at 105° for ride in the Standard solution and the Test solution; F is the rela-
3 hours: it loses not more than 0.5% of its weight. tive response factor for each impurity relative to tizanidine and
Residue on ignition 〈281〉: not more than 0.1%. is given in Table 1; rI is the peak area for each impurity ob-
Heavy metals 〈231〉: 0.002%. tained from the Test solution; and rS is the peak area of
Related compounds— tizanidine obtained from the Standard solution. The limits for
the impurities are specified in Table 1.
Phosphoric acid solution—Transfer 6.0 mL of phosphoric acid
to a 50-mL volumetric flask, and dilute with water to volume.
Table 1
Buffer solution—Dissolve about 3.5 g of sodium 1-
pentanesulfonate in 1000 mL of water, and adjust with Phos- Relative Relative
phoric acid solution or 1 N sodium hydroxide to a pH of 3.0 ± Retention Response Limit
0.05. Compound Name Time Factor (%)
Mobile phase—Prepare a filtered and degassed mixture of Tizanidine related com- about 0.8 1.0 0.1
Buffer solution and acetonitrile (80:20). Make adjustments if nec- pound C
essary (see System Suitability under Chromatography 〈621〉). Tizanidine 1.0 — —
Tizanidine related compound A solution—Dissolve an accu- Tizanidine related com- about 1.4 1.1 0.1
rately weighed quantity of USP Tizanidine Related Compound A pound B
RS in methanol, and dilute quantitatively, and stepwise if neces- Tizanidine related com- about 10.2 1.1 0.1
sary, with methanol to obtain a solution having a known con- pound A
centration of about 0.1 mg per mL. Individual unknown — 1.0 0.1
Tizanidine related compound B solution—Dissolve an accu- Total — — 0.3
rately weighed quantity of USP Tizanidine Related Compound B
RS in methanol, and dilute quantitatively, and stepwise if neces-
sary, with methanol to obtain a solution having a known con- Assay—
centration of about 0.1 mg per mL. Buffer solution—Dissolve 6.8 g of monobasic potassium phos-
Tizanidine related compound C solution—Dissolve an accu- phate in 1000 mL of water, and adjust with 5.3 N potassium
rately weighed quantity of USP Tizanidine Related Compound C hydroxide to a pH of 7.5 ± 0.05.
RS in methanol, and dilute quantitatively, and stepwise if neces- Mobile phase—Prepare a filtered and degassed mixture of
sary, with methanol to obtain a solution having a known con- Buffer solution and acetonitrile (80:20). Make adjustments if nec-
centration of about 0.1 mg per mL. essary (see System Suitability under Chromatography 〈621〉).

Official from May 1, 2012

Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.