Monographs of drugs

KP 9 21

Monographs, Part I

22 Monographs, Part I

KP 9 23

Acebutolol Hydrochloride

HClCH3CH2CH2 C

O

NH

C

O

CH3

OCH2CCH2NHCH(CH3)2

OH

H and enantiomer

C18H28N2O4HCl: 372.89

Acebutolol Hydrochloride, when dried, contains not less than 98.0% and not more than 102.0% of acebutolol hy-drochloride (C18H28N2O4 HCl). Description Acebutolol Hydrochloride is white to pale yellowish white crystal or crystalline powder. Acebutolol Hydrochloride is freely soluble in water, in methanol, in ethanol or in glacial acetic acid and practi-cally insoluble in ether. A solution of Acebutolol Hydrochloride (1 in 20) shows no optical rotation. Identification (1) Determine the absorption spectra of solutions of Acebutolol Hydrochloride and Acebutolol Hydrochloride RS, in 0.01mol/L hydrochloric acid TS (1 in 100000) as directed under the Ultraviolet-visible Spec-trophotometry: both spectra exhibit similar intensities of absorption at the same wavelengths.

(2) Determine the infrared spectra of Acebutolol Hy-drochloride and Acebutolol Hydrochloride RS, previous-ly dried, as directed in the potassium bromide disk me-thod under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wa-venumbers.

(3) A solution of Acebutolol Hydrochloride (1 in 100) responds to the Qualitative Tests for chloride. Melting Point Between 141 C and 145 C. Purity (1) Heavy metalsProceed with 1.0 g of Ace-butolol Hydrochloride according to Method 2 and per-form the test. Prepare the control solution with 1.0 mL of standard lead solution (not more than 10 ppm).

(2) ArsenicPrepare the test solution with 1.0 g of Acebutolol Hydrochloride according to Method 3 and perform the test (not more than 2 ppm).

(3) Related substancesDissolve 40 mg of Acebuto-lol Hydrochloride in 2 mL of methanol and use this solu-tion as the test solution. Pipet exactly 1 mL of the test so-lution and add methanol to make exactly 25 mL. Pipet exactly 1 mL of this solution, add methanol to make ex-actly 20 mL and use this solution as the standard solution. Perform the test with the test solution and the standard solution as directed under the Thin-layer Chromatogra-phy. Spot 5 L each of the test solution and the standard solution on a plate of silica gel for thin-layer chromato-

graphy. Develop the plate with the upper layer of a mix-ture of water, n-butanol and glacial acetic acid (5 : 4 : 1) to a distance of about 10 cm and air-dry the plate. Ex-amine under ultraviolet light (main wavelength: 365 nm). Any spot other than the principal spot from the test solu-tion is not more intense than the spot from the standard solution. Loss on Drying Not more than 1.0% (0.5 g, 105 C, 3 hours). Residue on Ignition Not more than 0.2% (1 g). Assay Weigh accurately about 0.25 g of Acebutolol Hydrochloride, previously dried, dissolve in 20 mL of glacial acetic acid, add 80 mL of acetic anhydride and ti-trate with 0.1 mol/L perchloric acid VS (potentiometric titration, Endpoint Detection Method in Titrimetry). Per-form a blank determination and make any necessary cor-rection.

Each mL of 0.1 mol/L perchloric acid VS = 37.289 mg of C18H28N2O4HCl

Packaging and Storage Preserve in well-closed con-tainers.

Aceclofenac

HN

O COOH

O

Cl

Cl

C16H13Cl2NO4: 354.19 Aceclofenac, when dried, contains not less than 99.0% and not more than 101.0% of aceclofenac (C16H13Cl2NO4). Description Aceclofenac is a white crystalline powder. Aceclofenac is freely soluble in acetone or in dimethyl-formamide, soluble in ethanol or in methanol, and practi-cally insoluble in water. Identification (1) Dissolve 10 mg of Aceclofenac in 10 mL of ethanol, and to 1 mL of this solution, add 0.2 mL of a mixture of equal volume of a solution of potassium ferricyamide (6 in 1000) and a solution of ferric chloride (9 in 1000). Allow to stand in the dark for 5 minutes, add 3 mL of a solution of hydrochloric acid (10 in 1000), and allow to stand in the dark for 15 minutes again: A blue color develops and a precipitate is formed. (2) Dissolve 50 mg of Aceclofenac in 100 mL of me-thanol, and to 2 mL of this solution, add methanol to


make 50 mL, and determine the absorption spectrum of this solution between 220 nm and 370 nm as directed under the Ultraviolet-visible Spectrophotometry: it exhi-bits a maximum at 275 nm. The specific absorbance at the maximum is 320 to 350. (3) Determine the infrared spectra of Aceclofenac and Aceclofenac RS as directed in the potassium bro-mide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Purity (1) Heavy metalsProceed with 2.0 g of Acec-lofenac according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of standard lead solution (not more than 10 ppm). (2) Related substancesDissolve 0.1 g of Aceclofe-nac, accurately weighed, in 50 mL of the mobile phase, and use this solution as the test solution. Dissolve diclo-fenac sodium RS, equivalent to 5 mg of diclofenac, in 50 mL of the mobile phase, and use this solution as the standard solution (1). Pipet 2 mL of the standard solution (1), add the mobile phase to make 50 mL, and use this solution as the standard solution (2). Pipet 5 mL of the standard solution (1), add 0.25 mL of the test solution, add the mobile phase to make 50 mL, and use this solu-tion as the standard solution (3). Perform the test with 10 L each of the test solution and the standard solution (2) as directed under the Liquid Chromatography according to the following conditions. Determine each peak area of these solutions: the area of each peak other than the peak of Aceclofenac from the test solution is not larger than the peak area of Aceclofenac from the standard solution (2) (not more than 0.2%), and the total area of each peak other than the peak of Aceclofenac from the test solution is not more than 2.5 times of the peak area of Aceclofe-nac from the standard solution (2) (not more than 0.5%). Omit the peak from the test solution, which peak area is less than 0.2 times of the peak area of the main peak from the standard solution (2). Operating conditions Detector: An ultraviolet absorption photometer (wa-velength: 275 nm). Column: A stainless steel column, about 4 mm in in-side diameter and about 15 cm in length, packed with oc-tadecylsilanized silica gel for liquid chromatography (5 m in particle diameter). Mobile phase: Adjust the pH of a mixture of acetoni-tile, tetrahydrofuran, and glacial acetic acid (1.2 in 1000) (225 : 225 : 550) to 3.5 with sodium hydroxide TS. Flow rate: 1 mL/minute System suitability:

System performance: When the procedure is run with 10 L of the standard solution (3) under the above operating conditions, Aceclofenac and diclofenac are eluted in this order with the resolution between their peaks being not less than 8.0.

Detection sensitivity: Adjust the detection sensitiv-ity so that the peak height of Aceclofenac and diclofenac

obtained from the standard solution (3) composes 50% of the full scale. Time span of measurement: About 10 times as long as the retention time of Aceclofenac. Loss on Drying Not more than 0.5% (1.0 g, between 100 C and 105 C) Residue on Ignition Not more than 0.1% (1.0 g). Assay Weigh accurately about 0.3 g of Aceclofenac, previously dried, dissolve in exact 40 mL of methanol, and titrate with 0.1 mol/L sodium hydroxide VS (poten-tiometric titration, Endpoint Detection Method in Titri-metry). Perform a blank determination, and make any necessary correction. Each mL of 0.1 mol/L sodium hydroxide VS = 35.419 mg of C16H13Cl2NO4 Packaging and Storage Preserve in light-resistant, well-closed containers

Acetaminophen

C

O

NH OHCH3

Paracetamol C8H9NO2: 151.16 Acetaminophen, when dried, contains not less than 98.0% and not more than 101.0% of acetaminophen (C8H9NO2). Description Acetaminophen is a white crystal or crys-talline powder. Acetaminophen is freely soluble in methanol or in etha-nol, sparingly soluble in water, and very slightly soluble in ether. Acetaminophen dissolves in sodium hydroxide TS. Identification Determine the infrared spectra of Ace-taminophen and Acetaminophen RS, previously dried, as directed in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Melting Point Between 169 C and 172 C. Purity (1) ChlorideDissolve 4.0 g of Acetamino-phen in 100 mL of water by heating, cool with shaking in ice-water, allow to stand until ordinary temperature is at-tained, add water to make 100 mL and filter. To 25 mL of the filtrate, add 6 mL of dilute nitric acid and water to make 50 mL and perform the test using this solution as the test solution. Prepare the control solution with 0.40

KP 9 25

mL of 0.01 mol/L hydrochloric acid VS (not more than 0.014%).

(2) SulfateTo 25 mL of the filtrate, obtained in (1), add 1 mL of dilute hydrochloric acid and water to make 50 mL and perform the test using this solution as the test solution. Prepare the control solution with 0.40 mL of 0.005 mol/L sulfuric acid VS (not more than 0.019%).

(3) Heavy metalsProceed with 2.0 g of Acetami-nophen according to Method 4 and perform the test. Pre-pare the control solution with 2.0 mL of standard lead so-lution (not more than 10 ppm).

(4) ArsenicPrepare the test solution with 1.0 g of Acetaminophen according to Method 3 and perform the test using Apparatus B (not more than 2 ppm).

(5) Related substancesDissolve 50 mg of Aceta-minophen in 1 mL of methanol, add the mobile phase to make 50 mL and use this solution as the test solution. Pi-pet exactly 1 mL of the test solution, add the mobile phase to make exactly 200 mL and use this solution as the standard solution. Perform the test with 10 L each of the test solution and the standard solution as directed under the Liquid Chromatography according to the fol-lowing conditions. Determine each peak area of both so-lutions by the automatic integration method: the total area of all peaks other than the peak area of Acetamino-phen from the test solution is not larger than the peak area of Acetaminophen from the standard solution. Operating conditions

Detector: An ultraviolet absorption photometer (wa-velength: 225 nm).

Column: A stainless steel column, about 4 mm in in-side diameter and about 15 cm in length, packed with oc-tadecylsilanized silica gel for liquid chromatography (5 m in particle diameter).

Column temperature: A constant temperature of about 40 C.

Mobile phase: A mixture of 0.05 mol/L monobasic potassium phosphate TS, pH 4.7 and methanol (4:1).

Flow rate: Adjust the flow rate so that the retention time of Acetaminophen is about 5 minutes.

System Suitability System performance: Dissolve 10 mg each of Ace-

taminophen and p-aminophenol in 1 mL of methanol, add the mobile phase to make 50 mL. To 1 mL of this so-lution add the mobile phase to make 10 mL. When the procedure is run with 10 L of this solution under the above operating conditions. p-Aminophenol and Aceta-minophen are eluted in this order with the resolution be-tween their peaks being not less than 7.

Detection sensitivity: Adjust the detection sensitiv-ity so that the peak height of Acetaminophen obtained from 10 L of the standard solution is about 15% of the full scale.

Time span of measurement: About 6 times as long as the retention time of Acetaminophen after the solvent peak. Loss on Drying Not more than 0.3% (0.5 g, 105 C, 2

hours). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 20 mg each of Acetami-nophen and Acetaminophen RS, previously dried, dis-solve in 2 mL of methanol and add water to make exactly 100 mL. Pipet exactly 3 mL each of these solutions, add water to make exactly 100 mL and use these solutions as the test solution and the standard solution, respectively. Determine the absorbance, TA and SA , of the test so-lution and the standard solution, respectively, at the wa-velength of maximum absorption at about 244 nm as di-rected under the Ultraviolet-visible Spectrophotometry, using water as the blank.

Amount (mg) of acetaminophen (C8H9NO2) = amount (mg) of Acetaminophen RS

S

T

AA

Packaging and Storage Preserve in light-resistant, tight containers

Acetaminophen Tablets Paracetamol Tablets Acetaminophen Tablets contain not less than 90.0% and not more than 110.0% of the labeled amount of acetami-nophen (C8H9NO2: 151.17). Method of Preparation Prepare as directed under Tab-lets, with Acetaminophen. Identification (1) The retention time of main peak of the test solution and the standard solution for Assay is the same.

(2) Weigh a portion of powdered Acetaminophen Tablets, equivalent to 50 mg of Acetaminophen accord-ing to labeled amount, add 50 mL of methanol and mix, filter and use this filtrate as the test solution. Separately, weigh 5 mg of Acetaminophen RS, add methanol to make 5 mL and use this solution as the standard solution. Perform the test with the test solution and the standard solution as directed under Thin-layer Chromatography. Spot 5 L each of the test solution and the standard solu-tion on a plate of silica gel with fluorescent indicator for thin-layer chromatography. Develop the plate with the upper layer of a mixture of dichloromethane and metha-nol (4 : 1) to a distance of about 10 cm and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm). The fR values of the spots from the test solu-tion and the standard solution are the same. Dissolution Test Perform the test with 1 tablet of Ace-taminophen Tablets at 50 revolutions per minute accord-


ing to Method 2 under the Dissolution Test, using 900 mL of diluted phosphate buffer solution, pH 5.8, as the dissolution solution. Take the dissolution solution 30 mi-nutes after starting the test, make any necessary dilution of the filtrate by adding the dissolution solution and use this solution as the test solution. Separately, weigh accu-rately about sufficient quantity of Acetaminophen RS, previously dried in a dessicator (silica gel for 18 hours) and dissolve in the test solution, to make the same con-centration as the test solution and use this solution as the standard solution. Determine the absorbances of the test solution and the standard solution at 243 nm as directed under Ultraviolet-visible Spectrophotometry. The dissolution rate of Acetaminophen Tablets in 30 mi-nutes should be not less than 80%.

Phosphate buffer solution, pH 5.8To 50 mL of 0.2 mol/L dibasic potassium phosphate TS, add 3.6 mL of 0.2 mol/L of sodium hydroxide TS and add water to make 200 mL. Uniformity of Dosage Units It meets the requirement. Assay Weigh accurately and powder not less than 20 Acetaminophen Tablets. Weigh accurately equivalent to about 0.1 g of Acetaminophen, add 100 mL of mobile phase, shake for 10 minutes, then shake strongly for 5 minutes, add mobile phase to make 200 mL, pipet exact-ly 5 mL of this solution, add mobile phase to make 250 mL and filter through a membrane filter with pore size of not more than 0.5 m. Discard the first 10 mL of the fil-trate, and use the subsequent filtrate as the test solution. Separately, weigh accurately about 20 mg of Acetamino-phen RS, previously dried in 105 C for 2 hours, dis-solves in mobile phase to make exactly 100 mL, pipet exactly 5 mL of this solution, add mobile phase to make exactly 100 mL and use this solution as the standard so-lution. Perform the test with 10 L each of the test solu-tion and the standard solution as directed under the Liq-uid Chromatography according to the following condi-tions and determine, TA and SA , of the peak area of Acetaminophen.

Amount (mg) of acetaminophen (C8H9NO2)

= amount (mg) of Acetaminophen RS 5S

T

AA

Operating conditions

Detector: An ultraviolet absorption spectrophotome-ter (wavelength: 243 nm).

Column: A stainless steel column, about 4 mm in in-side diameter and about 30 cm in length, packed with oc-tadecylsilanized silica gel for liquid chromatography (5 m to 10 m in particle diameter).

Mobile phase: A mixture of water and methanol (3 : 1).

Flow rate: 1.5 mL/minute. System suitability

System performance: When the procedure is run with 10 L of the standard solution under the above op-erating condition, the symmetry factor of the peak of acetaminphen is not more than 2.0.

System repeatability: When the test is repeated 6 times with 10 L of the standard solution under the above operating conditions, the relative standard devia-tion of the peak areas is not more than 2.0%. Packaging and Storage Preserve in tight containers.

Acetazolamide

N N

SHNC

O

CH3 S

O

O

NH2

C4H6N4O3S2: 222.25 Acetazolamide contains not less than 98.0% and not more than 102.0% of acetazolamide (C4H6N4O3S2), cal-culated on the dried basis. Description Acetazolamide is a white to pale yello-wish white, crystalline powder, is odorless and has a slight bitter taste. Acetazolamide is slightly soluble in ethanol, very slightly soluble in water, and practically insoluble in eth-er.

Melting pointAbout 255 C (with decomposition) Identification (1) To 0.1 g of Acetazolamide, add 5 mL of sodium hydroxide TS, then add 5 mL of a solution of 0.1 g of hydroxylamine hydrochloride and 50 mg of cu-pric sulfate in 10 mL of water: a pale yellow color devel-ops. Then heat this solution for 5 minutes: a deep yellow color is produced gradually.

(2) To 20 mg of Acetazolamide, add 2 mL of dilute hydrochloric acid, boil for 10 minutes, cool and add 8 mL of water: this solution responds to the Qualitative Tests for primary aromatic amines.

(3) To 0.2 g of Acetazolamide, add 0.5 g of granu-lated zinc and 5 mL of diluted hydrochloric acid (1 in 2): the gas evolved darkens moistened lead acetate paper. Purity (1) Clarity and color of solutionDissolve 1.0 g of Acetazolamide in 10 mL of sodium hydroxide TS: the solution is clear and colorless to pale yellow.

(2) ChlorideTo 1.5 g of Acetazolamide, add 75 mL of water and warm at 70 C for 20 minutes with occa-sional shaking. After cooling, filter and to 25 mL of the filtrate, add 6 mL of dilute nitric acid and water to make 50 mL. Perform the test using this solution as the test so-lution. Prepare the control solution with 0.20 mL of 0.01 mol/L hydrochloric acid VS (not more than 0.014%).

(3) SulfateTo 25 mL of the filtrate obtained in (2),

KP 9 27

add 1 mL of dilute hydrochloric acid and water to make 50 mL. Perform the test using this solution as the test so-lution. Prepare the control solution with 0.40 mL of 0.005 mol/L sulfuric acid VS (not more than 0.038%).

(4) Heavy metalsProceed with 1.0 g of Acetazola-mide according to Method 2 and perform the test. Pre-pare the control solution with 2.0 mL of standard lead so-lution (not more than 20 ppm).

(5) Silver-reducing substancesWet 5 g of Acetazo-lamide with 5 mL of aldehyde-free ethanol and add 125 mL of water, 10 mL of nitric acid and exactly 5 mL of 0.1 mol/L silver nitrate VS. Stir for 30 minutes while protected from light, filter through a glass filter (G3) and wash the residue on the glass filter with two 10 mL vo-lumes of water. Combine the filtrate with the washings, to the solution, add 5 mL of ferric ammonium sulfate TS and titrate with 0.1 mol/L ammonium thiocyanate VS: not less than 4.8 mL of 0.1 mol/L ammonium thiocyanate VS is consumed. Loss on Drying Not more than 0.5% (0.5 g, 105 C, 3 hours). Residue on Ignition Not more than 0.1% (0.5 g). Assay Weigh accurately about 0.15 g of Acetazolamide and dissolve in 400 mL of water in a water-bath. After cooling, add water to make exactly 1000 mL. Pipet ex-actly 5 mL of the solution, add 10 mL of 1 mol/L hy-drochloric acid TS and then add water to make exactly 100 mL. Determine the absorbance A of this solution at the wavelength of maximum absorption at about 265 nm as directed under the Ultraviolet-visible Spectrophotome-try.

Amount (mg) of acetazolamide (C4H6N4O3S2)

= A

474 200000

Packaging and Storage Preserve in light-resistant, well-closed containers.

Acetohexamide

C

O

CH3 S

O

O

NH C

O

NH

C15H20N2O4S: 324.40 Acetohexamide, when dried, contains not less than 98.0% and not more than 101.0% of acetohexamide (C15H20N2O4S). Description Acetohexamide is a white to yellowish white powder. Acetohexamide is freely soluble in dimethylformamide,

sparingly soluble in acetone, slightly soluble in methanol or in ethanol, and practically insoluble in water.

Melting pointAbout 185 C (with decomposition) Identification (1) Dissolve 0.10 g each of Acetohex-amide and Acetohexamide RS in 100 mL of methanol. To 5 mL each of these solutions, add 20 mL of 0.5 mol/L hydrochloric acid TS and 75 mL of methanol and pipet exactly 10 mL each of these solutions and dilute with methanol to exactly 50 mL. Determine the absorption spectra of these solutions as directed under the Ultravio-let-visible Spectrophotometry, using methanol as the blank, respectively: both spectra exhibit similar intensi-ties of absorption at the same wavelengths.

(2) Determine the infrared spectra of Acetohex-amide and Acetohexamide RS, previously dried, as di-rected in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Purity (1) ChlorideDissolve 1.5 g of Acetohex-amide in 40 mL of dimethylformamide, add 6 mL of di-lute nitric acid and dimethylformamide to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution as follows: to 0.45 mL of 0.01 mol/L hydrochloric acid VS, add 6 mL of dilute ni-tric acid and dimethylformamide to make 50 mL (not more than 0.011%).

(2) SulfateDissolve 2.0 g of Acetohexamide in 40 mL of dimethylformamide and add 1 mL of dilute hy-drochloric acid and dimethylformamide to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution as follows: to 0.40 mL of 0.005 mol/L sulfuric acid VS, add 1 mL of dilute hy-drochloric acid and dimethylformamide to make 50 mL (not more than 0.010%).

(3) Heavy metalsProceed with 1.0 g of Acetohex-amide according to Method 2 and perform the test. Pre-pare the control solution with 2.0 mL of standard lead so-lution (not more than 20 ppm).

(4) Related substances (i) Cyclohexylamine Dis-solve exactly 1.0 g of Acetohexamide in exactly 30 mL of 0.5 mol/L sodium hydroxide TS, add exactly 5 mL of hexane, shake vigorously for 60 minutes, allow to stand for 5 minutes, and use the upper layer as the test solution. Separately, dissolve about 50 mg of Cyclohexylamine RS, accurately weighed, in 0.5 mol/L sodium hydroxide TS to make exactly 50 mL. Pipet exactly 2 mL of this so-lution, and add 0.5 mol/L sodium hydroxide TS to make exactly 300 mL. Pipet 30 mL of this solution, add exactly 5 mL of hexane, shake vigorously for 60 minutes, allow to stand for 5 minutes, and use the upper layer as the standard solution. Perform the test with exactly 2 L each of the test solution and standard solution as directed under Gas Chromatography according to the following conditions, and determine the peak area of cyclohexyla-mine by the automatic integration method: the peak area of cyclohexylamine is not more than that with the stan-dard solution.



Detector: A hydrogen flame-ionization detector. Column: A fused-silica column 0.53 mm in inside di-

ameter and 30 cm in length, coated the inner surface with methylsilicone polymer for Gas Chromatography 1.5 m in thickness.


Injection port temperature: A constant temperature of about 150 C.

Detector temperature: A constant temperature of about 210 C.

Carrier gas: Helium Flow rate: Adjust the flow rate so that the retention

time of cyclohexylamine is about 4 minutes. System suitability

System performance: When the procedure is run with 2 L of the standard solution under the above oper-ating conditions, the number of theoretical plates of the peak of cyclohexylamine is not less than 8000.

System repeatability: When the test is repeated 6 times with 2 L of the standard solution under the above operating conditions, the relative standard deviation of the peak area of cyclohexylamine is not more than 5.0%.

(ii) DicyclohexylureaDissolve 1.0 g of Acetohex-amide, accurately weighed, in exactly 10 mL of 0.5 mol/L sodium hydroxide TS, add exactly 20 mL of me-thanol, shake, then add exactly 5 mL of diluted hydroch-loric acid (1 in 10), shake vigorously for 15 minutes, and centrifuge. Filter 10 mL or more of the supernatant liquid through a membrane filter with pore size of not larger than 0.5 m. Discard the first 5 mL of the filtrate, and use the subsequent filtrate as the test solution. Separately, weigh accurately about 50 mg of dicyclohexylurea RS, dissolve with methanol to make exactly 100 mL. Pipet exactly 2 mL of this solution, add methanol to make ex-actly 100 mL, pipet exactly 20 mL of this solution, add exactly 10 mL of 0.5 mol/L sodium hydroxide TS, shake, then add exactly 5 mL of diluted hydrochloric acid (1 in 10), shake, and use this solution as the standard solution. Perform the test with exactly 50 L each of the test solu-tion and the standard solution as directed under Liquid Chromatography according to the following conditions, and determine the peak area of dicyclohexylurea by the automatic integration method: the peak area of dicyclo-hexylurea obtained with the test solution is not more than that with the standard solution. Operating conditions


Column: A stainless steel column 4.6 mm in inside diameter and 25 cm in length, packed with octadecylsila-nized silica gel for Liquid Chromatography (5 m in par-ticle diameter).


Mobile phase: Dissolve 0.5 g of sodium hydroxide in

1000 mL of 0.05 mol/L sodium dihydrogen phosphate TS, and adjust to pH 6.5 with 0.5 mol/L sodium hydrox-ide TS. To 500 mL of this solution add 500 mL of aceto-nitrile.

Flow rate: Adjust the flow rate so that the retention time of dicyclohexylurea is about 10 minutes.

System suitability System performance: When the procedure is run

with 50 L of the standard solution under the above op-erating conditions, the number of theoretical plates of the peak of dicyclohexylurea is not less than 10000.

System repeatability: When the test is repeated 6 times with 50 L of the standard solution under the above operating conditions, the relative standard devia-tion of the peak area of dicylohexylurea is not more than 2.0%.

(iii) Other related substancesDissolve 0.1 g of Ace-

tohexamide in 10 mL of acetone and use this solution as the test solution. Pipet exactly 1 mL of this solution, add acetone to make exactly 20 mL. Pipet exactly two 1-mL portions of this solution, add acetone to make exactly 10 mL and 25 mL, respectively, and use these solutions as the standard solutions (1) and (2). Perform the test with these solutions as directed under the Thin-layer Chroma-tography. Spot 10 L each of the test solution and the standard solutions (1) and (2) on a plate of silica gel with fluorescent indicator for thin-layer chromatography and dry the plate. Then, develop the plate with a mixture of ethyl acetate, methanol, cyclohexane and strong ammo-nia water (6 : 2 : 1 : 1) to a distance of about 10 cm and dry the plate with air. Examine under ultraviolet light (main wavelength: 254 nm): any spot other than the prin-cipal spot from the test solution is not more intense than that from the standard solution (1) and the number of spots being more intense than that from the standard so-lution (2) is not more than 4. Loss on Drying Not more than 1.0% (1 g, 105 C, 4 hours). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.3 g of Acetohexamide, previously dried, dissolve in 30 mL of dimethylforma-mide, add 10 mL of water and titrate with 0.1 mol/L so-dium hydroxide VS (potentiometric titration, Endpoint Detection Method in Titrimetry). Perform a blank deter-mination using a solution prepared by adding 19 mL of water to 30 mL of dimethylformamide and make any necessary correction.

Each mL of 0.1 mol/L sodium hydroxide VS = 32.440 mg of C15H20N2O4S


KP 9 29

Acetylcholine Chloride for Injection

ClH3C N

CH3

CH3

CH2CH2OCOCH3

C7H16ClNO2: 181.66 Acetylcholine Chloride for Injection is a preparation for injection which is dissolved before use. Acetylcholine Chloride for Injection contains not less than 98.0% and not more than 102.0% of acetylcholine chloride (C7H16ClNO2) and not less than 19.3% and not more than 19.8% of chlorine (Cl: 35.45), calculated on the dried ba-sis. Acetylcholine Chloride for Injection contains not less than 93.0% and not more than 107.0% of the labeled amount of acetylcholine chloride (C7H16ClNO2). Method of Preparation Prepare as directed under In-jections. Description Acetylcholine Chloride for Injection is a white crystal or crystalline powder. Acetylcholine Chloride for Injection is very soluble in water, freely soluble in ethanol. Acetylcholine Chloride for Injection is extremely hy-groscopic. Identification (1) Determine the infrared spectra of Acetylcholine Chloride for Injection and Acetylcholine Chloride RS, previously dried, as directed in the potas-sium bromide disk method under the Infrared Spectro-photometry: both spectra exhibit similar intensities of ab-sorption at the same wavenumbers.

(2) A solution of Acetylcholine Chloride for Injection in water (1 in 10) responds to the Qualitative Tests (2) for chloride. Melting Point Between 149 C and 152 C. Seal Ace-tylcholine Chloride for Injection in a capillary tube for melting point determination immediately after drying both the sample and the tube at 105 C for 3 hours and determine the melting point. Purity (1) Clarity and color of solutionDissolve 1.0 g of Acetylcholine Chloride for Injection in 10 mL of water: the solution is clear and colorless.

(2) AcidityDissolve 1.0 g of Acetylcholine Chlo-ride for Injection in 10 mL of freshly boiled and cooled water, and add 1 drop of bromthymol blue TS, and use this solution as the test solution. To the test solution add 0.30 mL of 0.01 mol/L sodium hydroxide VS: the solu-tion is blue in color.

(3) Heavy metalsProceed with 2.0 g of Acetylcho-

line Chloride for Injection according to Method 1 and perform the test. Prepare the control solution with 2.0 mL of standard lead solution (not more than 10 ppm). Sterility Test It meets the requirement. Foreign Insoluble Matter Test It meets the require-ment. Insoluble Particulate Matter Test for Injections It meets the requirement. Uniformity of Dosage Units It meets the requirement. Loss on Drying Not more than 1.0% (1 g, 105 C, 3 hours). Residue on Ignition Not more than 0.1% (1 g). Assay (1) Acetylcholine chlorideWeigh accurately the contents of not less than 10 Acetylcholine Chloride for Injections. Weigh accurately about 0.5 g of the con-tents, dissolve in 15 mL of water, then add exactly 40 mL of 0.1 mol/L sodium hydroxide VS, stopper loosely and heat on a water-bath for 30 minutes. Cool quickly and ti-trate the excess sodium hydroxide with 0.05 mol/L sul-furic acid VS (indicator: 3 drops of phenolphthalein TS). Perform a blank determination and make any necessary correction.

Each mL of 0.1 mol/L sodium hydroxide VS = 18.166 mg of C7H16ClNO2

(2) ChlorineTitrate the solution, which has been ti-

trated in (1), with 0.1 mol/L silver nitrate VS (indicator: 3 drops of fluorescein sodium TS).

Each mL of 0.1 mol/L silver nitrate VS = 3.5453 mg of Cl

Packaging and Storage Preserve in hermetic contain-ers.

Acetylcysteine

HS

H3C NH

OH

O

O

C5H9NO3S: 163.20 Acetylcysteine, when dried, contains not less than 98.0% and not more than 102.0% of acetylcysteine (C5H9NO3S).


Description Acetylcysteine is a white, crystalline powder. Acetylcysteine is freely soluble in water or ethanol, and practically insoluble in dichloromethane. Identification (1) Determine the infrared spectra of Acetylcysteine and Acetylcysteine RS, respectively, as directed in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Specific Optical Rotation 20D][ : Between +21 and +27 Weigh accurately about 1.25 g of Acetylcysteine, dissolve in 1 mL of disodium ethylenediaminetetraace-tate solution (1 in 100) and 7.5 mL of sodium hydroxide solution (1 in 25), and add phosphate buffer solution, pH 7.0, to make 25 mL, and determine the optical rotation of this solution.

pH 7.0 phosphate buffer solutionAdd 50 mL of 1 mol/L monobasic potassium phosphate TS and 29.5 mL of 1 mol/L sodium hydroxide solution to a volumetric flask, adjust to a pH of 7.0 by adding water, and add wa-ter again to make 100 mL. pH Dissolve 1.0 g of Acetylcysteine in 100 mL of freshly boiled and cooled water: the pH of this solution is between 2.0 and 2.8. Purity Heavy metals Proceed with 2.0 g of Acetyl-cysteine according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of lead standard solution (not more than 10 ppm). Loss on Drying Not more than 0.1% (1 g, in vacuum at the pressure not exceeding 0.67 kPa, 70 C, 4 hours). Residue on Ignition Not more than 0.5% (2 g, 600 C). Assay Weigh accurately about 1.0 g of Acetylcysteine, previously dried, dissolve in freshly prepared sodium metabisulfite solution (1 in 2000) to make exactly 100 mL. Pipet exactly 10 mL of this solution, add exactly 10 mL of the internal standard solution, then add sodium metabisulfite solution (1 in 2000) to make exactly 200 mL, and use this solution as the test solution. Separately, dissolve about 1.0 g of Acetylcysteine RS, accurately weighed, in sodium metabisulfite solution (1 in 2000) to make exactly 100 mL. Pipet exactly 10 mL of this solu-tion, add exactly 10 mL of the internal standard solution, then add sodium metabisulfite solution (1 in 2000) to make exactly 200 mL, and use this solution as the stan-dard solution. Perform the test with 5 L each of the test solution and the standard solution as directed under the Liquid Chromatography according to the following con-ditions, and calculate the ratios, TQ and SQ , of the peak area of Acetylcysteine to that of the internal stan-dard, respectively.

Amount (mg) of Acetylcysteine (C5H9NO3S)

= amount (mg) of Acetylcysteine RS S

T

QQ

Internal standard solutionDissolve of 1 g of dl-

phenylalanine in freshly prepared sodium metabisulfite solution (1 in 2000) to make 200 mL. Operating conditions


Column: A stainless steel column, about 3.9 mm in inside diameter and about 30 cm in length, having octa-decylsilanized silica gel for liquid chromatography (3 m to 10 m in particle diameter).

Column temperature: A room temperature. Mobile phase: A solution of potassium dihydrogen

phosphate, pH 3.0 (6.8 in 1000). Flow rate: 1.5 mL/minute. System suitability

System performance: When the procedure is run with 5 L of the standard solution under the above oper-ating conditions, acetylcystein and dl-phenylalanine are eluted in this order with the resolution between their peaks being not less than 6.0.

System repeatability: When the test is repeated 6 times with 5 L of the standard solution under the above operating conditions, the relative standard deviation of the ratios of the peak area is not more than 2.0%. Packaging and Storage Preserve in tight containers.

Acrinol Hydrate

NH2N

NH2

OCH2CH3

CH3CHCO2H

OH

H2O

Ethacridine Lactat C15H15N3OC3H6O3H2O: 361.39 Acrinol Hydrate, contains not less than 98.5% and not more than 101.0% of acrinol (C15H15N3OC3H6O3 : 343.38), calculated on the anhydrous basis. Description Acrinol Hydrate is a yellow, crystalline powder. Acrinol Hydrate is freely soluble in hot water, sparingly soluble in water, and slightly soluble in ethanol.

pHThe pH of an aqueous solution of Acrinol Hy-drate (1 in 100) is between 5.5 and 7.0.

Melting pointAbout 245 C (with decomposition) Identification (1) Determine the absorption spectra of solutions of Acrinol Hydrate and Acrinol Hydrate RS, in

KP 9 31

water (3 in 250000) as directed under Ultraviolet-visible Spectrophotometry: both spectra exhibit similar intensi-ties of absorption at the same wavelengths.

(2) Determine the infrared spectra of Acrinol Hydrate and the Acrinol Hydrate RS as directed in the potassium bromide disk method under the Infrared Spectrophoto-metry: both spectra exhibit similar intensities of absorp-tion at the same wavenumbers.

(3) To 5 mL of a solution of Acrinol Hydrate in water (1 in 100), add 5 mL of dilute sulfuric acid, shake well, allow to stand for about 10 minutes at room temperature and filter: the filtrate responds to the Qualitative Tests for lactate. Purity (1) ChlorideDissolve 1.0 g of Acrinol Hy-drate in 80 mL of water by warming in a water-bath, cool and add 10 mL of sodium hydroxide TS and water to make 100 mL. Shake well, allow to stand for 30 minutes, filter, to 40 mL of the filtrate, add 7 mL of dilute nitric acid and water to make 50 mL and perform the test using this solution as the test solution. Prepare 50 mL of the control solution with 4 mL of sodium hydroxide TS, 7 mL of dilute nitric acid, 0.30 mL of 0.01 mol/L hydroch-loric acid VS and water (not more than 0.026%).

(2) Heavy metalsProceed with 1.0 g of Acrinol Hydrate according to Method 2 and perform the test. Prepare the control solution with 2.0 mL of standard lead solution (not more than 20 ppm).

(3) Volatile fatty acidsDissolve 0.5 g of Acrinol Hydrate in a mixture of 20 mL of water and 5 mL of di-lute sulfuric acid, shake well, filter and heat the filtrate: no odor of volatile fatty acids is perceptible.

(4) Related substancesDissolve 10 mg of Acrinol Hydrate in 25 mL of the mobile phase, and use this solu-tion as the test solution. Pipet exactly 1 mL of the test so-lution, add the mobile phase to make exactly 100 mL, and use this solution as the standard solution (1). Pipet exactly 1 mL of standard solution (1), add the mobile phase to make exactly 10 mL, and use this solution as the standard solution (2). Perform the test with exactly 10 L each of the test solution and the standard solutions (1) and (2) as directed under Liquid Chromatography ac-cording to the following conditions, and determine each peak area by the automatic integration method: the area of any peak other than acrinol obtained with the test so-lution is not larger than 3 times the peak area of acrinol obtained with the standard solution (2), and the total area of all peaks other than acrinol obtained with the test solu-tion is not larger than the peak area of acrinol with the standard solution (1).




Column temperature: A constant temperature of

about 25 C. Mobile phase: Dissolve 7.8 g of sodium dihydrogen

phosphate in 900 mL of water, adjust to pH 2.8 with phosphoric acid, and add water to make 1000 mL. To 700 mL of this solution add 300 mL of acetonitrile for Liquid Chromatography, and add 1.0 g of sodium 1-octanesulfonate to dissolve.

Flow rate: Adjust the flow rate so that the retention time of acrinol is about 15 minutes.

System suitability Test for required detectability: Confirm that the

peak area of acrinol obtained with 10 L of the standard solution (2) is equivalent to 7 to 13% of that with 10 L of the standard solution (1).

System performance: When the procedure is run with 10 L of the standard solution (2) under the above operating conditions, the number of theoretical plates and the symmetry factor of the peak of acrinol are not less than 5000 and not more than 2.0, respectively.

System repeatability: When the test is repeated 6 times with 10 L of the standard solution (1) under the above operating conditions, the relative standard devia-tion of the peak area of acrinol is not more than 1.5%.

Time span of measurement: About 3 times as long as the retention time of acrinol beginning after the sol-vent peak. Water Between 4.5and 5.5% (0.2 g, volumetric titra-tion, direct titration) Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.27 g of Acrinol Hy-drate, dissolve in 5 mL of formic acid, add 60 mL of a mixture of acetic anhydride and glacial acetic acid (1 : 1), and titrate immediately with 0.1 mol/L perchloric acid VS (potentiometric titration, Endpoint Detection Method in Titrimetry). Perform a blank determination in the same manner, and make any necessary correction.

Each mL of 0.1 mol/L perchloric acid VS = 34.34 mg of acrinol (C15H15N3OC3H6O3)

Packaging and Storage Preserve in light-resistant, tight containers.

Acyclovir

HN

N N

N

O

OH

O

H2N

C8H11N5O3: 225.21 Acyclovir contains not less than 98.0% and not more


than 101.0% of acyclovir (C8H11N5O3), calculated on the anhydrous basis. Description Acyclovir is a white crystalline powder. Acyclovir is freely soluble in dimethylsulfoxide, slightly soluble in water, and very slightly soluble in ethanol. Acyclovir dissolves in dilute hydrochloric acid. Identification (1) Determine the infrared spectra of Acyclovir and Acyclovir RS, respectively, as directed in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensi-ties of absorption at the same wavenumbers.

(2) The retention time of main peak of the test solu-tion for Assay and the standard solution is the same. Water Not more than 6.0% (0.5 g, volumetric trtration, direct titration) Purity (1) Related substancesDissolve a certain amount of Acyclovir, accurately weighed, in dimethyl-sulfoxide to contain about 10 mg per mL of Acyclovir, and use this solution as the test solution. Pipet exactly 1 mL of this solution, add dimethylsulfoxide to make ex-actly 100 mL, and use this solution as the standard solu-tion. Perform the test with the test solution and the stan-dard solution as directed under the Thin-layer Chromato-graphy. Spot 5 L each of the test solution and the stan-dard solution on a plate of silica gel with fluorescent in-dicator for thin-layer chromatography. Develop the plate with a mixture of chloroform, methanol, and strong am-monia water (80 : 20 : 2) to a distance of about 15 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 and 366 nm): the spots other than principal spot from the test solution are not more intense than the spot from the standard solution (not more than 1%)

(2) GuanineDissolve about 0.1 g of Acyclovir, ac-curately weighed, in water to make exactly 200 mL. Pi-pet exactly 10 mL of this solution, add 0.01 mol/L so-dium hydroxide TS to make exactly 50 mL, and use this solution as the test solution. Separately, dissolve about 8.8 mg of Guanine RS, accurately weighed, in 50 mL of 0.1 mol/L sodium hydroxide TS, add water to make ex-actly 500 mL. Pipet exactly 2 mL of this solution, add 0.01 mol/L sodium hydroxide TS to make exactly 50 mL, and use this solution as the standard solution. Perform the test with 20 L each of the test solution and the stan-dard solution as directed under the Liquid Chromatogra-phy according to the following conditions, and calculate the peak areas of guanine, TA and SA , for the test so-lution and the standard solution, respectively (not more than 0.7%).

Amount (g) of guanine (C5H5N5O) = S

T

AAC 1000

C: Concentration of the standard solution (g/mL),

Residue on Ignition Not more than 0.1% (1.0 g). Assay Dissolve about 0.1 g of Acyclovir, accurately weighed, in 20 mL of 0.1 mol/L sodium hydroxide TS, and add water to make exactly 200 mL. Pipet exactly 10 mL of this solution, add 0.01 mol/L sodium hydroxide TS to make exactly 50 mL, and use this solution as the test solution. Separately, dissolve about 25 mg of Acyc-lovir RS, accurately weighed, in 5 mL of 0.1 mol/L so-dium hydroxide TS, add water to make exactly 50 mL. Pipet exactly 10 mL of this solution, add 0.01 mol/L so-dium hydroxide TS to make exactly 50 mL, and use this solution as the standard solution. Perform the test with 20 L each of the test solution and the standard solution as directed under the Liquid Chromatography according to the following conditions, and calculate the peak areas of acyclovir, TA and SA , for the test solution and the standard solution, respectively.

Amount (g) of acyclovir (C8H11N5O3)

= S

T

AAC 1000

C: Concentration of Acyclovir RS in the standard so-lution (g/mL)



Column: A stainless steel column, about 4.2 mm in inside diameter and about 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (3 m to 10 m in particle diameter).

Mobile phase: Glacial acetic acid solution (1 in 1000). Flow rate: 3 mL/minute. System suitability

System performance: When the procedure is run with 40 L of the mixture of equal volumes of the stan-dard solution in the Purity (2) under Acyclovir and the standard solution in Assay Acyclovire RS under the above operating conditions, Acyclovir and guanine are eluted in this order with the resolution between their peaks being not less than 2.0.

System repeatability: When the test is repeated 6 times with 20 L of the standard solution under the above operating conditions, the relative standard devia-tion of the peak areas is not more than 2.0%. Packaging and Storage Preserve in tight containers.

KP 9 33

Adenosine

HO

N

NN

N

NH2

O

OHHO

HH

C10H13N5O4 : 267.24 Adenosine contains not less than 99.0% and not more than 101.0% of adenosine (C10H13N5O4), calculated on the dried basis. Description Adenosine is a colorless crystalline powd-er and produces adenine and D-ribose by hydrolysis. Adenosine is freely soluble in water, sparingly soluble in hot water, and slightly soluble in ethanol.

Identification Determine the infrared spectra of Ade-nosine and Adenosine RS, previously dried, as directed in the paste method under the Infrared Spectrophotome-try, respectively: both spectra exhibit similar intensities of absorption at the same wavenumbers. Melting Point Between 233 and 238 C Specific Optical Rotation 20D][ : Between -68 to -72 (after drying, 0.4 g, sodium hydroxide solution (1 in 10), 20 mL, 100 mm). Purity (1) Acidity or alkalinitySuspend 1 g of Adeno-sine in 20 mL carbon dioxide free water. Stir for 30 seconds, and pass through a coarse filter. To each of two 10 mL portions of the filtrate add 0.1 mL of bromocresol purple TS. Not more than 0.3 mL of 0.01 N sodium hy-droxide is required to produce a blue-violet color in one portion, and not more than 0.1 mL of 0.01 N hydrochlor-ic acid is required to produce a yellow color in the other portion.

(2) ChlorideSuspend 0.75 g of Adenosine in 15 mL of water. Stir for 30 seconds, pass through a coarse filter, and use the filtrate as the test solution. Prepare a chloride standard solution by diluting 1 mL of sodium chloride solution (231 mg in 1000 mL) with 100 mL of water. To the test solution and 10 mL of the chloride standard solution add 1 mLof nitric acid and 1 mL of sil-ver nitrate TS, dilute each solution with water to 40 mL, and mix. Allow the solutions to stand for 5 minutes, pro-tected from light. When viewed against a dark back-ground, the test solution is not more turbid than the stan-dard solution (not more than 0.007%).

(3) SulfateSuspend 0.75 g of Adenosine in 15 mL

of water. Stir for 30 seconds, pass through a coarse filter, and use the filtrate as the test solution. Prepare a sulfate standard solution by adding 0.15 mL of 0.01 mol/L sul-furic acid to 15 mL of water. To the test solution and the standard solution add 2 mL of barium chloride TS and 1 mL of 3 mol/L hydrochloric acid, dilute each solution with water to 30 mL, and mix. Allow the solutions to stand for 5 minutes: the test solution is not more turbid than the standard solution (not more than 0.02%).

(4) Ammonia Suspend 0.5 g of Adenosine in 10 mL of water. Stir for 30 seconds, pass through a coarse filter. Dilute the filtrate with water to 15 mL, mix, and use the filtrate as the test solution. Dilute 1 mL of am-monium chloride solution (314 mg in 1000 mL) with 100 mL of water. Mix 2 mL of this ammonia standard solu-tion with 13 mL of water, and use this solution as the ref-erence solution. To the test solution and reference solu-tion add 0.3 mL of alkaline mercuric-potassium iodide TS, cap the test tubes, and allow to stand for about 5 mi-nutes : the test solution does not exhibit a more intense yellow color than that of the reference solution (not more than 0.0004%).

(5) Heavy metalsProceed with 1.0 g of Adenosine according to Method 2 and perform the test. Prepare the control solution with 1.0 mL of standard lead solution (not more than 10 ppm).

(6) Related substancesWeigh accurately 25 mg of Adenosine and dissolve in mobile phase and add to make exactly 25 mL and use this solution as the test so-lution. Perform the test with exactly with 20 L of the test solution as directed under Liquid Chromatography according to the following conditions, and determine the percentage of each impurity in the portion of Adenosine taken by the peak area percentage method: not more than 0.2% of adenine is found; and not more than 0.5% of to-tal impurities is found. Operating conditions


Column: A stainless steel column about 4.6 mm in inside diameter and about 25 cm in length, packed with octadecylsilanized silica gel for Liquid Chromatography (5 m in particle diameter).

Mobile phase: A mixture of sulfate buffer and a solu-tion (1 in 10000) of sodium azide (60:40)

Flow rate: 1.5 mL/minute System suitability

System performance: Weigh accurately each 20 mg of adenosine and 20 mg of inosine and dissolve in mobile phase to make 100 mL volume. When the proce-dure is run with 20 L of this solution under the above operating condition, the resolution between adenosine and inosine is not less than 9.0 and the symmetry factor is not more than 2.5.

System repeatability: Weigh 20 mg each of adeno-sine and inosine, dissolve in mobile phase to make 100 mL. When the test is repeated 5 times with 20 L of this solution under the above operating conditions, the rela-


tive standard deviation of the peak area is not more than 2.0%.

Time span of measurement: Adjust the run time to at least twice the retention time of the major peak.

Sulfate bufferDissolve 6.8 g of potassium hydro-gen sulfate and 3.4 g of tetrabutylammonium hydrogen sulfate in water, dilute with water to 1000 mL, and mix. Adjust with 2 N potassium hydroxide to a pH of 6.5. Loss on Drying Not more than 0.5% (1 g, 105 C, 2 hours). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.5 g of Adenosine, pre-viously dried, dissolve in 50 mL of glacial acetic acid and titrate with 0.1 mol/L perchloric acid VS (potenti-ometric titration, Endpoint Detection Method in Titrime-try). Perform a blank determination and make any neces-sary correction.

Each mL of 0.1 mol/L perchloric acid VS = 26.724 mg of C10H13N5O4

Packaging and Storage Preserve in tight containers.

Ajmaline

NN

CH3H

H

CH2CH3

H

H

OH

H

HOH

H

C20H26N2O2: 326.43 Ajmaline, when dried, contains not less than 96.0% and not more than 101.0% of ajmaline (C20H26N2O2). Description Ajmaline is a white to pale yellow, crys-talline powder, is odorless and has a bitter taste. Ajmaline is freely soluble in acetic anhydride or in chlo-roform, sparingly soluble in methanol, in ethanol, in ace-tone or in ether, and very slightly soluble in water. Ajmaline dissolves in dilute hydrochloric acid.

Melting pointAbout 195 C (with decomposition). Identification (1) Dissolve 50 mg of Ajmaline in 5 mL of methanol and use this solution as the test solution. Add 3 mL of nitric acid to 1 mL of the test solution: a deep red color develops.

(2) Spot the test solution of (1) on filter paper and spray Dragendorff's TS: an orange color develops.

Absorbance %1cm 1E (249 nm): Between 257 and 271 (after drying, 2 mg, ethanol, 100 mL).

%1cm 1E (292 nm): Between 85 and 95 (after drying, 2 mg, ethanol, 100 mL). Specific Optical Rotation 20D][ : Between + 136 and + 151 (after drying, 0.5 g, chloroform, 50 mL, 100 mm). Purity Related substancesDissolve 0.1 g of Ajma-line in 10 mL of chloroform and use this solution as the test solution. Pipet exactly 1 mL of this solution, add chloroform to make exactly 100 mL and use this solution as the standard solution. Perform the test with the test so-lution and the standard solution as directed under the Thin-layer Chromatography. Spot 10 L each of the test solution and the standard solution on a plate of silica gel with fluorescence indicator for thin-layer chromatogra-phy. Develop the plate with a mixture of chloroform, acetone and diethylamine (5 : 4 : 1) to a distance of about 10 cm and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): any spot other than the principal spot from the test solution is not more intense than the spot from the standard solution. Loss on Drying Not more than 1.0% (0.6 g, in vacuum, 80 C, 3 hours). Residue on Ignition Not more than 0.2% (0.5 g). Assay Weigh accurately about 0.3 g of Ajmaline, pre-viously dried, dissolve in 50 mL of acetic anhydride and 50 mL of acetone for nonaqueous titration and titrate with 0.05 mol/L perchloric acid VS (potentiometric titra-tion, Endpoint Detection Method in Titrimetry). Perform a blank determination and make any necessary correction.

Each mL of 0.05 mol/L perchloric acid VS = 16.322 mg of C20H26N2O2

Packaging and Storage Preserve in light-resistant, well-closed containers.

Ajmaline Tablets Ajmaline Tablets contain not less than 90.0% and not more than 110.0% of the labeled amount of ajmaline (C20H26N2O2: 326.43). Method of Preparation Prepare as directed under Tab-lets, with Ajmaline. Identification (1) Shake a quantity of powdered Ajma-line Tablets, equivalent to 0.10 g of Ajmaline according to the labeled amount, with 30 mL of chloroform and fil-

KP 9 35

ter. Evaporate the filtrate in a water-bath to dryness. With the residue, proceed as directed in the Identification un-der Ajmaline.

(2) Dissolve 10 mg of the residue of (1) in 100 mL of ethanol. To 10 mL of this solution, add ethanol to make 50 mL and determine the absorption spectrum of the so-lution as directed under the Ultraviolet-visible Spectro-photometry: it exhibits maxima between 247 nm and 251 nm and between 291 nm and 294 nm and a minimum be-tween 269 nm and 273 nm. Dissolution Test Perform the test with 1 tablet of Aj-maline Tablets at 100 revolutions per minute according to Method 2 under the Dissolution Test, using 900 mL of diluted phosphate buffer solution, pH 6.8, (1 in 2) as the dissolution solution. Take 20 mL or more of the dis-solved solution 60 minutes after start of the test and filter through a membrane filter with pore size of not more than 0.8 m. Discard the first 10 mL of the filtrate and use the subsequent filtrate as the test solution. Separately, weigh accurately about 28 mg of Ajmaline RS, previous-ly dried in vacuum at 80 C for 3 hours, dissolve in di-luted phosphate buffer solution, pH 6.8, (1 in 2) to make exactly 500 mL and use this solution as the standard so-lution. Determine the absorbances, TA and SA , of the test solution and the standard solution, respectively, at 288 nm as directed under the Ultraviolet-visible Spectro-photometry. The dissolution rate of Ajmaline Tablets in 60 minutes is not less than 75%.

Dissolution rate (%) with respect to the labeled

amount of ajmaline (C20H26N2O2) = 1801 CA

AWS

TS

SW : Amount (mg) of Ajmaline RS,

C: Labeled amount (mg) of ajmaline (C20H26N2O2) in 1 tablet. Uniformity of Dosage Units It meets the requirement. Assay Weigh accurately and powder, not less than 20 Ajmaline Tablets. Weigh accurately a portion of the powder, equivalent to about 0.3 g of ajmaline (C20H26N2O2), add 15 mL of strong ammonia water and extract with four 25 mL volumes of chloroform. Com-bine the chloroform extracts, wash with 10 mL of water, add 5 g of anhydrous sodium sulfate, shake well and fil-ter, wash the container and the residue with two 10 mL volumes of chloroform and filter. Evaporate the com-bined filtrate in a water-bath to dryness, dissolve the re-sidue in 50 mL of acetic anhydride and 50 mL of acetone for nonaqueous titration and titrate with 0.05 mol/L per-chloric acid VS (potentiometric titration, Endpoint De-tection Method in Titrimetry). Perform a blank determi-nation and make any necessary correction.

Each mL of 0.05 mol/L perchloric acid VS

= 16.322 mg of C20H26N2O2 Packaging and Storage Preserve in light-resistant, well-closed containers.

Albendazole

N

N HN OCH3

OSH3C

C12H15N3O2S: 265.33 Albendazole, when dried, contains not less than 98.0% and not more than 102.0% of albendazole (C12H15N3O2S). Description Albendazole is white to pale yellow powder. Albendazole is freely soluble in anhydrous formic acid, very slightly soluble in ether or methylene chloride and practically insoluble in ethanol or water. Identification (1) Perform the test as directed in the Related substances: the principal spots from the test solu-tion and the standard solution show the same fR value.

(2) Determine the infrared spectra of Albendazole and Albendazole RS, previously dried, as directed in the potassium bromide disk method under the Infrared Spec-trophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Purity Related substancesDissolve 50 mg of Alben-dazole in 3 mL of glacial acetic acid, add glacial acetic acid to make 5 mL and use this solution as the test solu-tion. Separately, weigh accurately a portion of Albenda-zole RS, dissolve in the glacial acetic acid to contain 5 mg per mL and use this solution as the standard solution. Pipet 1.0 mL of the standard solution, dilute with glacial acetic acid to make exactly 100 mL and use this solution as the diluted standard solution. Perform the test with the these solutions as directed under the Thin-layer Chroma-tography. Spot 10 L each of the test solution, the stan-dard solution and the diluted standard solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of chloroform, glacial actic acid and ether (60 : 10 : 10) to a distance of about 15 cm and air-dry the plate. Examine under ultraviolet light (main wa-velength: 254 nm): any spot other than the principal spot from the test solution is not larger and not more intense than the spot from the standard solution. (not more than 0.5%) Loss on Drying Not more than 0.5% (105 C, 4 hours). Residue on Ignition Not more than 0.2% (1 g).


Assay Weigh accurately about 0.25 g of Albendazole, previously dried, dissolve in 100 mL of glacial acetic ac-id, and warm if necessary. After cooling, add 1 drop of solvent blue 19 in glacial acetic acid solution (1 in 200), and titrate with 0.1 mol/L perchloric acid VS until the color of the solution changes to violet. Perform a blank determination, and make any necessary correction.

Each mL of 0.1 mol/L perchloric acid VS = 26.533 mg of C12H15N3O2S.


Albumin Tannate Tannalubin Albumin Tannate is a compound of tannic acid and a protein. The label states the origin of the protein of Albumin Tannate. Description Albumin Tannate is a pale brown powder. Albumin Tannate is odorless, or has a faint, characteris-tic odor. Albumin Tannate is practically insoluble in water or in ethanol. Albumin Tannate dissolves in sodium hydroxide TS or sodium carbonate TS with turbidity. Identification (1) To 0.1 g of Albumin Tannate, add 10 mL of ethanol and heat in a water-bath for 3 minutes with shaking. After cooling, filter and to 5 mL of the fil-trate, add 1 drop of ferric chloride TS: a blue-purple to bluish black color is produced. On standing, a bluish black precipitate is produced.

(2) To 0.1 g of Albumin Tannate, add 5 mL of nitric acid: an orange-yellow color develops. Purity (1) AcidShake 1.0 g of Albumin Tannate with 50 mL of water for 5 minutes and filter. To 25 mL of the filtrate, add 1.0 mL of 0.1 mol/L sodium hydrox-ide VS and 2 drops of phenolphthalein TS: a red color develops.

(2) FatsTo 2.0 g of Albumin Tannate, add 20 mL of petroleum benzine, shake vigorously for 15 minutes and filter. Evaporate 10 mL of the filtrate on a water-bath: the weight of the residue is not more than 50 mg. Loss on Drying Not more than 6.0% (1 g, 105 C, 3 hours). Residue on Ignition Not more than 1.0% (0.5 g). Digestion Test To 1.00 g of Albumin Tannate, add 0.25 g of saccharated pepsin and 100 mL of water, shake

well and allow to stand for 20 minutes at 40 1 C in a water-bath. Add 1.0 mL of dilute hydrochloric acid, shake and allow to stand for 3 hours at 40 1 C. Cool rapidly to ordinary temperature and filter. Wash the resi-due with three 10 mL volumes of water, dry in a desicca-tor (silica gel) for 18 hours and dry at 105 C for 5 hours: the weight of the residue is 0.50 g to 0.58 g. Packaging and Storage Preserve in light-resistant, tight containers.

Aldioxa

N

HN OAl(OH)2

O

HNC

O

H2N Dihydroxyaluminum Allantoinate C4H7AlN4O5: 218.10 Aldioxa is a condensation product of allantoin and alu-minum hydroxide. When dried, Aldioxa contains not less than 65.3% and not more than 74.3% of allantoin (C4H6N4O3: 158.12) and not less than 11.1% and not more than 13.0% of aluminum (Al: 26.98). Description Aldioxa is a white powder, is odorless and tasteless. Aldioxa is practically insoluble in water, in ethanol or in ether. Aldioxa dissolves in dilute hydrochloric acid or in dilute nitric acid.

Melting pointAbout 230 C (with decomposition). Identification (1) To 0.2 g of Aldioxa, add 10 mL of dilute hydrochloric acid, boil for 5 minutes and add 10 mL of a solution of phenylhydrazine hydrochloride (1 in 100). After cooling, mix well with 0.5 mL of potassium ferricyanide TS and shake with 1 mL of hydrochloric ac-id: a red color develops.

(2) To 0.2 g of Aldioxa, add 10 mL of dilute hydroch-loric acid, dissolve by warming and cool: the solution re-sponds to the Qualitative Tests for aluminum salt. Purity (1) ChlorideTo 0.10 g of Aldioxa, add 6 mL of dilute nitric acid, boil to dissolve with shaking for 5 minutes, cool and add water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution with 0.40 mL of 0.01 mol/L hydrochlor-ic acid VS (not more than 0.142%).

(2) SulfateTo 0.20 g of Aldioxa, add 6 mL of di-lute hydrochloric acid, boil to dissolve with shaking for 5 minutes, cool and add water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution with 1.0 mL of 0.005 mol/L sulfuric acid VS (not more than 0.240%).

(3) NitrateTo 0.10 g of Aldioxa, add carefully 5

KP 9 37

mL of water and 5 mL of sulfuric acid, dissolve by shak-ing, cool and superimpose 2 mL of ferrous sulfate TS: no brown ring is produced at the zone of contact.

(4) Heavy metalsTo 1.0 g of Aldioxa, add 3mL of hydrochloric acid and 3 mL of water, heat gently to boil with shaking and evaporate in a water-bath to dryness. To the residue, add 30 mL of water, shake under warm-ing, cool, filter and to the filtrate, add 2 mL of dilute acetic acid and water to make 50 mL. Perform the test using this solution as the test solution. Prepare the con-trol solution as follows: to 3 mL of hydrochloric acid add 3 mL of water, evaporate in a water-bath to dryness and add 2.0 mL of standard lead solution, 2 mL of dilute acetic acid and water to make 50 mL (not more than 20 ppm).

(5) ArsenicPrepare the test solution with 1.0 g of Aldioxa according to Method 2 and perform the test (not more than 2 ppm). Loss on Drying Not more than 4.0% (1 g, 105 C, 2 hours). Assay (1) AllantoinWeigh accurately about 0.1 g of Aldioxa, previously dried, dissolve in 50 mL of dilute sulfuric acid by heating, cool and add water to make ex-actly 100 mL. Pipet exactly 10 mL of this solution and perform the test as directed under the Nitrogen Determi-nation.

Each mL of 0.005 mol/L sulfuric acid VS = 0.39529 mg of C4H6N4O3

(2) AluminumWeigh accurately about 0.2 g of Al-

dioxa, previously dried, dissolve carefully in 50 mL of dilute hydrochloric acid by heating, cool and add dilute hydrochloric acid to make exactly 100 mL. Pipet exactly 4 mL of this solution, add water to make exactly 25 mL and use this solution as the test solution. Separately, pipet a suitable quantity of aluminum standard stock solution, dilute with water so that each mL of the solution contains not less than 16.0 g and not more than 64.0 g of alu-minum (Al: 26.98) and use this solution as the standard solution. Perform the test with the test solution and the standard solution as directed under the Atomic Absorp-tion Spectrophotometry according to the following con-ditions and calculate the aluminum content of the test so-lution from the calibration curve obtained from the ab-sorbance of the standard solution.

Gas: Combustible gas- Acetylene.

Supporting gas- Nitrous oxide. Lamp: An aluminum hollow cathode lamp. Wavelength: 309.2 nm.


Alfacalcidol

CH3

CH3

H

H

H3C

H

HOCH2

OH

CH3

C27H44O2 : 400.64

Alfacalcidol contains not less than 97.0% and not more than 102.0% of alfacalcidol (C27H44O2). Description Alfacalcidol is a white crystals. Alfacalcidol is freely soluble in ethanol, soluble in fatty oils, and practically insoluble in water. Alfacalcidol is sensitive to air, heat and light. A reversible isomerisation to pre-alfacalcidol takes place in solution, and the activity is due to both compounds. Identification (1) Determine the infrared spectra of Al-facalcidol and Alfacalcidol RS, previously dried, as di-rected in the potassium bromide disk method under the Infrared Spectrophotometry, respectively: both spectra exhibit similar intensities of absorption at the same wa-venumbers.

(2) Examine the chromatograms obtained in the assay. The principal peak in the chromatogram obtained with the test solution is same in retention time as the principal peak in the chromatogram obtained with standard solu-tion (1). Purity Related substancesExamine by liquid chro-matography as described under Assay. Calculate the per-centage content of related substances, other than pre-alfacalcidol, that are eluted within twice the retention time of alfacalcidol from the areas of the peaks in the chromatogram obtained with the test solution by the normalisation procedure. The content of any individual related substance is not more than 0.5% and the total area of all the related substances is not more than 1.0%. Dis-regard any peak not more than 0.1%. Assay Carry out the assay as rapidly as possible, avoid-ing exposure to light and air. Weigh accurately about 1.0 mg of Alfacalcidol, dissolve in mobile phase to make ex-actly 10 mL and use this solution as the test solution. Separately, weigh accurately 1.0 mg of Alfacalcidol RS and dissolve in mobile phase without heating to make exactly 10 mL and use this solution as the standard solu-tion (1). To 1.0 mL of the standard solution (1) add mo-bile phase to make exactly 100 mL and use this solution as the standard solution (2). Heat 2 ml of the standard so-lution (1) in a water-bath at 80 C under a reflux con-denser for 2 hours and cool and use this solution as the


standard solution (3). Perform the test with 100 L each of the test solution and the standard solutions (1) and (2) as directed under Liquid Chromatography according to the following conditions, and determine each peak area,

TA and SA of alfacalcidol, by the automatic integra-tion method.

Amount (mg) of alfacalcidol (C27H44O2)

= amount (mg) of Alfacalcidol RS S

T

AA



Column: A stainless steel column about 4 mm in in-side diameter and about 25 cm in length, packed with oc-tadecylsilanized silica gel for Liquid Chromatography (5 m in particle diameter).

Mobile phase: the mixture of acetonitrile, water and 9 mol/L ammonia water (800 : 200 : 1).

Flow rate: 2.0 mL/minute. System suitability

System performance: When the procedure is run with 100 L of the standard solution (3) under the above operating condition, the retention time for pre-alfacalcidol, relative to alfacalcidol, is about 1.3 with the resolution between the peaks due to pre-alfacalcidol and alfacalcidol being not less than 4.0

System repeatability: When the test is repeated 6 times with 100 L of the standard solution (3) under the above operating conditions, the relative standard devia-tion of the peak areas of alfacalcidol is not more than 1.0%. Packaging and Storage Preserve in a tight container, under nitrogen, protected from light, at a temperature of 2 C to 8 C. The contents of an opened container are to be used immediately.

Alfuzosin Hydrochloride

N

N NHN

O

O

NH2

H3CO

H3CO

CH3

HCl

H

and enantiomer

C19H27N5O4HCl : 425.91

Alfuzosin Hydrochloride contains not less than 98.5% and not more than 101.0% of alfuzosin hydrochloride (C19H27N5O4HCl), calculated on the anhydrous basis.

Description Alfuzosin Hydrochloride is a white crys-talline powder. Alfuzosin Hydrochloride is freely soluble in water, spa-ringly soluble in ethanol, and practically insoluble in dichloromethane. Alfuzosin Hydrochloride is hygroscopic. Identification (1) Determine the infrared spectra of Al-fuzosin Hydrochloride and Alfuzosin Hydrochloride RS, previously dried, as directed in the potassium bromide disk method under the Infrared Spectrophotometry, re-spectively: both spectra exhibit similar intensities of ab-sorption at the same wavenumbers.

(2) To 0.5 g of Alfuzosin Hydrochloride add 25 mL of water. The diluted solution of 1 mL of this solution by 1 mL of water responds to the Qualitative Tests (2) for chlorides. pH The pH of the solution of 0.5 g of Alfuzosin Hy-drochloride in 25 mL of water is between 4.0 and 6.0. Specific Optical Rotation 20D][ : Between -0.10 and +0.10 (calculated on the anhydrous basis, 0.2 g, water, 10 mL, 100 mm) Purity Related substancesWeigh accurately 20.0 mg of Alfuzosin Hydrochloride, dissolve in mobile phase to make exactly 100 mL and use this solution as test so-lution. Pipet exactly 1.0 mL of the test solution, add mo-bile phase to make exactly 50 mL, pipet 5.0 mL of this solution, add mobile phase to make exactly 20 mL and use this solution as the standard solution (1). Separately, weigh accurately 5 mg of Alfuzosin Impurity I {N-[3-[(4-Amino-6,7-dimethoxyquinolin-2-yl)(methyl)amino] propyl]furan-2-carboxamide} RS, dissolve in mobile phase to make 25 mL, pipet exactly 1 mL of this solution, add 1 mL of the test solution and then add mobile phase to make exactly 100 mL and use this solution as the standard solution (2). Perform the test with exactly 20 L each of the test and the standard solution (2) as directed under Liquid Chromatography according to the follow-ing conditions, and determine each peak area by the au-tomatic integration method: the area of any peak other than the principal peak from the test solution is not greater than 0.6 times the area of the principal peak from the standard solution (1) (0.3%); the total area of all peaks other than the principal peak is not greater than the area of the principal peak with the standard solution (1) (0.5%). Disregard any peak with an area less than 0.025 times that of the principal peak from the standard solu-tion (1). Operating conditions



KP 9 39

Mobile phase: The mixture of sodium perchlorate so-lution, acetonitrile and tetrahydrofuran (80 : 20 : 1).

Flow rate: 1.5 mL/minute System suitability

System performance: Perform the test with 20 l of standard solution (2) according to the above condi-tions. Adjust the sensitivity of the system so that the height of the two peaks in the chromatogram obtained is at least 50% of the full scale of the recorder. The test is not valid unless the resolution between the peaks corres-ponding to alfuzosin and alfuzosin related substance I is at least 3.0.

Sodium perchlorate solutionMix 5 mL of perchlor-

ic acid and 900 mL of water, adjust pH to 3.5 with 8.5w/v% sodium hydroxide VS and add water to make 1000 mL. Water Not more than 2.0% (0.5 g, volumetric titration, direct titration) Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.3 g of Alfuzosin Hy-drochloride, dissolve in the mixture of 40 mL of glacial acetic acid and 40 mL of acetic anhydride and titrate with 0.1 mol/L perchloric acid VS (potentiometric titra-tion, Endpoint Detection Method in Titrimetry). Perform a blank determination and make any necessary correction.

Each mL of 0.1 mol/L perchloric acid VS = 42.59 mg of C19H28ClN5O4.

Packaging and Storage Preserve in light-resistent, tight containers.

Alimemazine Tartrate

S

N

CH2CHCH2N

CH3CH3

CH3 CH(OH)CO2H

CH(OH)CO2H

2

(C18H22N2S)2C4H6O6 : 746.98 Alimemazine Tartrate, when dried, contains not less than 98.0% and not more than 101.0% of alimemazine tartrate (C18H22N2S)2 C4H6O6). Description Alimemazine Tartrate is a white powder, is odorless and has a bitter taste. Alimemazine Tartrate is freely soluble in water or in gla-cial acetic acid, sparingly soluble in ethanol, and practi-cally insoluble in ether.

pH The pH of a solution of Alimemazine Tartrate

(1 in 50) is between 5.0 and 6.5. Alimemazine Tartrate is gradually colored by light. Identification (1) To 2 mL of a solution of Alimema-zine Tartrate (1 in 100), add 1 drop of ferric chloride TS: a red-brown color is produced and immediately a yellow precipitate is formed.

(2) Dissolve 1 g of Alimemazine Tartrate in 5 mL of water, add 3 mL of sodium hydroxide TS, extract with two 10 mL volumes of ether [use the aqueous layer ob-tained in the Identification (4)]. Shake the combined eth-er extracts with 3 g of anhydrous sodium sulfate, filter and evaporate the ether with the aid of a current of air. Dry the residue in a desiccator (in vacuum, P2O5) for 16 hours: it melts between 66 C and 70 C.

(3) Determine absorption spectra of solutions of Ali-memazine Tartrate and Alimemazine Tartrate RS, in wa-ter (1 in 100000) as directed under the Ultraviolet-visible Spectrophotometry: both spectra exhibit similar intensi-ties of absorption at the same wavelengths.

(4) The aqueous layer, obtained in the Identification (2), when neutralized with dilute acetic acid, responds to the Qualitative Tests (1) and (2) for tartrate. Melting Point Between 159 C and 163 C. Purity (1) Clarity and color of solution Dissolve 1.0 g of Alimemazine Tartrate in 20 mL of water: the so-lution is clear and colorless.

(2) Heavy metalsProceed with 1.0 g of Alimema-zine Tartrate according to Method 2 and perform the test. Prepare the control solution with 2.0 mL of standard lead solution (not more than 20 ppm).

(3) ArsenicPrepare the test solution with 1.0 g of Alimemazine Tartrate according to Method 3 and per-form the test. Use a solution of magnesium nitrate in ethanol (1 in 5) (not more than 2 ppm). Loss on Drying Not more than 0.5% (1 g, 105 C, 3 hours). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.8 g of Alimemazine Tartrate, previously dried, dissolve in 50 mL of glacial acetic acid and titrate with 0.1 mol/L perchloric acid VS until the color of the solution changes from red through brown to green-brown (indicator: 2 mL of -naphtholbenzeine TS). Perform a blank determination and make any necessary correction.

Each mL of 0.1 mol/L perchloric acid VS = 37.349 mg of (C18H22N2S)2C4H6O6

Packaging and Storage Preserve in light-resistant, tight containers.


Allantoin

NH2

ONH

NHHN

O

O

C4H6N4O3 : 158.12 Allantoin, when dried, contains not less than 98.5% and not more than 101.0% of allantoin (C4H6N4O3). Description Allantoin is a white crystalline powder. Allantoin is slightly soluble in water and very slightly so-luble in ethanol. Allantoin dissolves in sodium hydroxide TS.

Melting Point About 225 C (decomposition) Identification (1) Boil 20 mg with a mixture of 1 mL of 2 mol/L sodium hydroxide TS and 1 mL of water. Al-low to cool. Add 1 mL of 2 mol/L hydrochloric acid TS. To 0.1 mL of the solution add 0.1 mL of a solution of po-tassium bromide (1 in 10), 0.1 mL of a solution of resor-cinol (1 in 50) and 3 mL of sulfuric acid. Heat for 5 min to 10 min on a water-bath. A dark blue color develops, which becomes red after cooling and pouring into about 10 mL of water.

(2) Determine the infrared spectra of Allantoin and Allantoin RS, previously dried, as directed in the potas-sium bromide disk method under the Infrared Spectro-photometry, respectively: both spectra exhibit similar in-tensities of absorption at the same wavenumbers.

(3) The principal spots in the chromatograms ob-tained with test solution (2) and the standard solution (1) in Related substances under Purity have the same fR values. Specific Optical Rotation 20D][ : Between -0.10 and +0.10 (0.2 g, water, 20 mL, 100 mm) Purity (1) Acidity or alkalinityTo a 10 mL solution of about 50 mg of Allantoin in carbon dioxide-free water, add 0.1 mL of methyl red TS and 0.2 mL of 0.01 mol/L sodium hydroxide TS: the solution is yellow. Add 0.4 mL of 0.01 mol/L hydrochloric acid TS: the solution is red.

(2) Reducing substancesMix 1.0 g of Allantoin with 10 mL of water by shaking for 2 minutes and filter. Add 1.5 mL of 0.02 mol/L potassium permanganate TS: the solution must remain violet for at least 10 min.

(3) Potassium permangate Related substances Weigh accurately about 0.10 g of Allantoin, dissolve in 5 mL of water with heating. After cool add methanol to

make exactly 10 mL and use this solution as test solution (1). Pipet 1 mL of the test solution (1), add a mixture of methanol and water (1:1) to make exactly 10 mL and use this solution as the test solution (2). Separately, weigh accurately about 10 mg of Allantoin RS, add a mixture of methanol and water (1 : 1) to make exactly 10 mL and use this solution as the standard solution (1). Weigh ac-curately about 10 mg of urea RS, add water to make ex-actly 10 mL, pipet 1 mL of this solution, add methanol to make exactly 10 mL and use this solution as the standard solution (2). Mix 1 mL each of the standard solution (1) and the standard solution (2) and use this solution as the standard solution (3). Perform the test with these solu-tions as directed under the Thin-layer Chromatography. Spot 10 L of the test solution (1) and 5 L each of the test solution (2), the standard solution (1), the standard solution (2) and the standard solution (3) on a plate of si-lica gel with fluorescent indicator for thin-layer chroma-tography. Develop the plate with a mixture of 1-butanol, water and glacial acetic acid (60 : 25 : 15) to a distance of about 10 cm and air-dry the plate. Spray evenly the plate with a solution of 0.1 g dimethylaminobenzalde-hyde in 20 mL of a mixture of methanol and hydrochlor-ic acid (3 : 1). Dry the plate in a current of hot air. Ex-amine under daylight after 30 min: any spot frorm the test solution (1), other than the principal spot, is not more intense than the spot from standard solution (2) (0.5%). The test is not valid unless the chromatogram from stan-dard solution (3) shows two clearly separated principal spots. Loss on Drying Not more than 0.1% (2 g, 105 C, constant mass). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 1.2 g of Allantoin, pre-viously dried, add 40 mL of water to dissolve. Titrate with 0.1 mol/L sodium hydroxide VS (potentiometric ti-tration, Endpoint Detection Method in Titrimetry). Per-form a blank determination and make any necessary cor-rection.

Each mL of 0.1 mol/L sodium hydroxide VS

= 15.812 mg of C4H6N4O3 Packaging and Storage Preserve in well-closed con-tainers

Allopurinol

N

NN

HN

OH

C5H4N4O: 136.11

KP 9 41

Allopurinol, when dried, contains not less than 98.0% and not more than 101.0% of allopurinol (C5H4N4O). Description Allopurinol is a white to pale yellowish white crystal or crystalline powder and is odorless. Allopurinol is slightly soluble in dimethylformamide, very slightly soluble in water, and practically insoluble in ethanol or in ether. Allopurinol dissolves in sodium hydroxide TS or in am-monia TS.

Melting pointNot lower than 320 C (with decom-position) Identification (1) Dissolve 0.1 g of Allopurinol in 50 mL of water by warming. To 5 mL of this solution, add 1 mL of ammonia TS and 1 mL of silver nitrate TS: a white precipitate is produced.

(2) Determine the absorption spectra of solutions of Allopurinol and Allopurinol RS, in water (1 in 200000) as directed under Ultraviolet-visible Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavelengths.

(3) Determine the infrared spectra of Allopurinol and Allopurinol RS as directed in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensities of absorption at the same wavenumbers. Purity (1) Clarity and color of solutionDissolve 0.5 g of Allopurinol in 10 mL of sodium hydroxide TS: the solution is clear and has no more color than Color Matching Fluid D.

(2) SulfateTo 2.0 g of Allopurinol, add 100 mL of water and boil for 5 minutes. Cool, add water to make 100 mL and filter. To 25 mL of the filtrate, add 1 mL of dilute hydrochloric acid and water to make 50 mL and perform the test using this solution as the test solution. Prepare the control solution with 0.40 mL of 0.005 mol/L sulfuric acid VS (not more than 0.038%).

(3) Heavy metalsProceed with 1.0 g of Allopurinol according to Method 2 and perform the test. Prepare the control solution with 2.0 mL of standard lead solution (not more than 20 ppm).

(4) ArsenicPrepare the test solution with 1.0 g of Allopurinol according to Method 3 and perform the test (not more than 2 ppm).

(5) Related substancesDissolve 50 mg of Allopu-rinol in 10 mL of ammonia TS and use this solution as the test solution. Pipet exactly 1 mL of this solution, add ammonia TS to make exactly 200 mL and use this solu-tion as the standard solution. Perform the test with the test solution the standard solution as directed under the Thin-layer Chromatography. Spot 5 L each of the test solution and the standard solution on a plate of cellulose with fluorescent indicator for thin-layer chromatography. Develop the plate with ammonia TS saturated with n-butanol to a distance of about 10 cm and air-dry the plate. Examine under ultraviolet light (main wavelength: 254

nm): any spot other than the principal spot from the test solution is not more intense than the spot from the stan-dard solution. Loss on Drying Not more than 0.5% (1 g, 105 C, 4 hours). Residue on Ignition Not more than 0.1% (1 g). Assay Weigh accurately about 0.16 g of Allopurinol, previously dried, dissolve in 70 mL of dimethylforma-mide by warming. Cool and titrate with 0.1 mol/L tetra-methylammonium hydroxide VS (potentiometric titration, Endpoint Detection Method in Titrimetry). Separately to 70 mL of dimethylformamide, add 12 mL of water, per-form a blank determination with this solution and make any necessary correction.

Each mL of 0.1 mol/L tetramethylammonium hydroxide VS = 13.611 mg of C5H4N4O

Packaging and Storage Preserve in tight containers.

Allopurinol Tablets Allpurinol Tablets contain not less than 93.0% and not more than 107.0% of the labeled amount of allopurinol (C5H4N4O : 136.11). Method of Preparation Prepare as directed under Tab-lets, with Allopurinol. Identification To a quantity of powdered Allopurinol Tablets, equivalent to 50 mg of Allopurinol according to the labeled amount, add 10 mL of 0.1 mol/L sodium hy-droxide VS, mix thoroughly and extract. After filtration, make the filtrate acidic with 1 mol/L acetic acid. Collect the precipitate, wash few times with 3 mL of dehydrated ethanol, 4 mL of anhydrous ether, dry in air for 15 mi-nutes and dry at 105 C for 3 hours. Determine the infra-red spectra of the residue and Allopurinol RS as directed in the potassium bromide disk method under the Infrared Spectrophotometry: both spectra exhibit similar intensi-ties of absorption at the same wavenumbers. Dissolution Test Perform the test with 1 tablet of Allo-purinol Tablets at 75 revolutions per minute according to Method 2 under the Dissolution Test, using 900 mL of 0.1 mol/L hydrochloric acid as the dissolution solution. Take a volume of the dissolved solution 45 minutes after starting the test and filter through a membrane filter, di-lute with dissolution solution and use this solution as the test solution. Separately, weigh accurately a portion of Allopurinol RS, dissolve in the dissolution solution to make the same concentration with the test solution and use this solution as the standard solution. Determine the


absorbances, TA and SA , of the test solution and the standard solution, respectively, at approximately 250 nm as directed under the Ultrviolet-visible Spectrophotome-try. The dissolution rate of Allopurinol Tablets in 45 minutes should be not less than 75%. Uniformity of Dosage Units It meets the requirement. Assay Weigh accurately and powder not less than 20 tablets of Allopurinol Tablets. Weigh accurately a portion of the powder, equivalent to about 50 mg of allopurinol (C5H4N4O), add exactly 10 mL of 0.1 mol/L sodium hy-droxide VS, shake for 10 minutes and add water to make exactly 50 mL (perform the following assay as soon as possible). After centrifugation, discard 10 mL of the first filtrate, collect exactly 4 mL of the subsequent filtrate, add exactly 2.0 mL of the internal standard solution and the mob

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