头孢卡品酯

430JP XV
Cefcapene Pivoxil Hydrochloride Hydrate /O‹cial Monographs solution and the mobile phase to make 50mL,and use these solutions as the sample solution and standard solution.Per-form the test with 10m L each of the sample solution and stan-dard solution as directed under Liquid Chromatography <2.01>according to the following conditions,and determine the ratios,Q T and Q S ,of the peak area of cefbuperazone to that of the internal standard.
Amount [m g (potency)]of cefbuperazone (C 22H 29N 9O 9S 2)＝W S ×(Q T /Q S )×1000
W S :Amount [mg (potency)]of Cefbuperazone Reference
Standard Internal standard solution —A solution of acetonitrile in the mobile phase (1in 4000).Operating conditions —
Detector:An ultraviolet absorption photometer (wave-length:254nm).
Column:A stainless steel column 4.6mm in inside di-ameter and 15cm in length,packed with octadecylsilanized silica gel for liquid chromatography (5m m in particle di-ameter).
Column temperature:A constant temperature of about 259C.
Mobile phase:Dissolve 2.0g of tetra-n -propylammonium bromide in 1000mL of a mixture of water,acetonitrile and acetic acid-sodium acetate buŠer solution,pH 5.0(83:13:4).Flow rate:Adjust the ‰ow rate so that the retention time of cefbuperazone is about 16minutes.System suitability —
System performance:When the procedure is run with 10m L of the standard solution under the above operating conditions,the internal standard and cefbuperazone are elut-ed in this order with the resolution between these peaks being not less than 3.
System repeatability:When the test is repeated 6times with 10m L of the standard solution under the above operating conditions,the relative standard deviation of the ratios of the peak area of cefbuperazone to that of the internal standard is not more than 1.0z .
Containers and storage Containers—Hermetic containers.Storage—In a cold place.
Cefcapene Pivoxil Hydrochloride Hydrate
セフカペン
ピボキシル塩酸塩水和物
C 23H 29N 5O 8S 2.HCl.H 2O:622.11
2,2-Dimethylpropanoyloxymethyl (6R ,7R )-7-[(2Z )-2-(2-aminothiazol-4-yl)pent-2-enoylamino]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-caboxylate monohydrochloride monohydrate [147816-24-8]
Cefcapene Pivoxil Hydrochloride Hydrate contains not less than 722m g (potency)and not more than 764m g (potency)per mg,calculated on the anhydrous ba-sis.The potency of Cefcapene Pivoxil Hydrochloride Hydrate is expressed as mass (potency)of cefcapene (C 17H 19N 5O 6S 2:453.49).
Description Cefcapene Pivoxil Hydrochloride Hydrate oc-curs as a white to pale yellowish white,crystalline powder or mass.It has slightly a characteristic odor.
It is freely soluble in N ,N -dimethylformamide and in methanol,soluble in ethanol (99.5),slightly soluble in water,and practically insoluble in diethyl ether.
Identiˆcation (1)Determine the infrared absorption spec-tra of Cefcapene Pivoxil Hydrochloride Hydrate and Cefca-pene Pivoxil Hydrochloride Reference Standard as directed in the paste method under Infrared Spectrophotometry <2.25>,and compare these spectra:both spectra exhibit simi-lar intensities of absorption at the same wave numbers.(2)Determine the spectrum of a solution of Cefcapene Pivoxil Hydrochloride Hydrate in deuterated methanol for nuclear magnetic resonance spectroscopy (1in 50)as directed under Nuclear Magnetic Resonance Spectroscopy <2.21>(1H),using tetramethylsilane for nuclear magnetic resonance spectroscopy as an internal reference compound:it exhibits a triplet signal A at around d 6.3ppm,and a single signal B at around d 6.7ppm,and the ratio of integrated intensity of each signal,A:B,is about 1:1.
(3)Dissolve 10mg of Cefcapene Pivoxil Hydrochloride Hydrate in 2mL of a mixture of water and methanol (1:1),and add 1drop of silver nitrate TS:a white precipitate is formed.
Absorbance <2.24>E 1z
1cm (265nm):255–285(30mg calcu-lated on the anhydrous basis,a mixture of acetate buŠer solu-tion,pH 5.5and methanol (1:1),2000mL).
Optical rotation <2.49>[a ]20D :＋51–＋549
(0.1g calculated on the anhydrous basis,methanol,10mL,100mm).Purity (1)Heavy metals <1.07>—Proceed with 2.0g of Cefcapene Pivoxil Hydrochloride Hydrate according to Method 4,and perform the test.Prepare the control solution with 2.0mL of Standard Lead Solution (not more than 10ppm).
(2)Related substance I—Dissolve an amount of Cefca-pene Pivoxil Hydrochloride Hydrate,equivalent to about 10mg (potency),in 2mL of methanol,add a mixture of water and methanol (1:1)to make 50mL,and use this solution as the sample solution.Perform the test with 30m L of the sam-ple solution as directed under Liquid Chromatography <2.01>according to the following conditions,and determine each peak area by the automatic integration method.If necessary,compensate the base-line by performing in the same manner as the test with 30m L of a mixture of water and methanol (1:1).Measure the amount of the peak other than cefcapene pivoxil by the area percentage method:the amounts of the peaks,having the relative retention times of about 1.5and about 1.7with respect to cefcapene pivoxil,are not more than 0.2z ,respectively.The amount of the peak other than the peaks mentioned above is not more than 0.1z ,and the total of them is not more than 1.5z .Operating conditions —
431 JP XV O‹cial Monographs/Cefcapene Pivoxil Hydrochloride Hydrate
Detector:An ultraviolet absorption photometer
(wavelength:265nm).
Column:A stainless steel column 4.6mm in inside di-
ameter and15cm in length,packed with octadecylsilanized
silica gel for liquid chromatography(5m m in particle di-
ameter).
Column temperature:A constant temperature of about
209C.
Mobile phase A:Dissolve5.99g of potassium dihydrogen
phosphate in water to make1100mL.To this solution add a
solution prepared by dissolving1.89g of tetra-n-pentylam-
monium bromide in methanol to make1000mL.
Mobile phase B:A mixture of methanol and water(22:3).
Flowing of the mobile phase:Control the gradient by mix-
ing the mobile phase A and B as directed in the following ta-
ble.
Time after injection of sample(min)Mobile phase
A(vol z)
Mobile phase
B(vol z)
0–20982
20–4098ª502ª50
40–505050 Flow rate:0.8mL per minute.
Time span of measurement:About2.5times as long as the retention time of cefcapene pivoxil.
System suitability—
Test for required detectability:To exactly1mL of the sam-ple solution add a mixture of water and methanol(1:1)to make exactly100mL,and use this solution as the solution for system suitability test.Pipet1mL of the solution for system suitability test,and add the mixture of water and methanol (1:1)to make exactly10mL.Conˆrm that the peak area of cefcapene pivoxil obtained from30m L of this solution is e-quivalent to7to13z of that of cefcapene pivoxil obtained from30m L of the solution for system suitability test.
System performance:Dissolve10mg of Cefcapene Pivoxil Hydrochloride Hydrate and10mg of propyl parahydrox-ybenzoate in25mL of methanol,and add water to make50 mL.To5mL of this solution add the mixture of water and methanol(1:1)to make50mL.When the procedure is run with30m L of this solution under the above operating condi-tions,cefcapene pivoxil and propyl parahydroxybenzoate are eluted in this order with the resolution between these peaks being not less than7.
System repeatability:When the test is repeated3times with 30m L of the solution for system suitability test under the above operating conditions,the relative standard deviation of the peak area of cefcapene pivoxil is not more than4.0z.
(3)Related substance II—Dissolve an amount of Cefca-pene Pivoxil Hydrochloride Hydrate,equivalent to about2 mg(potency),in N,N-dimethylformamide for liquid chro-matography to make20mL,and use this solution as the sam-ple solution.Perform the test with20m L of the sample solu-tion as directed under Liquid Chromatography<2.01>ac-cording to the following conditions,and determine each peak area by the automatic integration method:the total area of the peaks which appear earlier than cefcapene pivoxil is not more than1.7z of the total area of the peaks other than the solvent.
Operating conditions—
Detector:An ultraviolet absorption photometer (wavelength:280nm).
Column:A stainless steel column7.8mm in inside di-ameter and30cm in length,packed with styrene-divinylben-zene copolymer for liquid chromatography.
Column temperature:A constant temperature of about 259C.
Mobile phase:A solution of lithium bromide in N,N-dimethylformamide for liquid chromatography(13in5000).
Flow rate:Adjust the‰ow rate so that the retention time of cefcapene pivoxil is about22minutes.
Time span of measurement:About1.8times as long as the retention time of cefcapene pivoxil.
System suitability—
Test for required detection:To exactly1mL of the sample solution add N,N-dimethylformamide for liquid chro-matography to make exactly100mL,and use this solution as the solution for system suitability test.Pipet3mL of the so-lution for system suitability test,and add N,N-dimethylfor-mamide for liquid chromatography to make exactly10mL. Conform that the peak area of cefcapene pivoxil obtained from20m L of this solution is equivalent to20to40z of that of cefcapene pivoxil obtained from20m L of the solution for system suitability test.
System performance:When the procedure is run with20 m L of the sample solution under the above operating condi-tions,the number of theoretical plates of the peak of cefca-pene pivoxil is not less than12,000steps.
System repeatability:When the test is repeated6times with 20m L of the solution for system suitability test under the above operating conditions,the relative standard deviation of the peak areas of cefcapene pivoxil is not more than4.0z.
Water<2.48>Not less than2.8z and not more than3.7z (0.5g,volumetric titration,back titration).
Assay Weigh accurately an amount of Cefcapene Pivoxil Hydrochloride Hydrate and Cefcapene Pivoxil Hydrochlo-ride Reference Standard,equivalent to about20mg(poten-cy),and dissolve each in a mixture of water and methanol (1:1)to make exactly50mL.Pipet10mL each of these solu-tions,add exactly10mL of the internal standard solution and the mixture of water and methanol(1:1)to them to make 50mL,and use these solutions as the sample solution and standard solution,respectively.Perform the test with10m L each of the sample solution and standard solution as directed under Liquid Chromatography<2.01>according to the fol-lowing conditions,and determine the ratios,Q T and Q S,of the peak area of cefcapene pivoxil to that of the internal stan-dard of these solutions.
Amount[m g(potency)]of cefcapene(C17H19N5O6S2)
＝W S×(Q T/Q S)×1000
W S:Amount[mg(potency)]of Cefcapene Pivoxil Hydrochloride Reference Standard
Internal standard solution—A solution of p-benzylphenol in a mixture of water and methanol(1:1)(7in4000). Operating conditions—
Detector:An ultraviolet absorption photometer (wavelength:265nm).
Column:A stainless steel column 3.0mm in inside di-ameter and7.5cm in length,packed with octadecylsilanized silica gel for liquid chromatography(3m m in particle di-ameter).
432JP XV Cefcapene Pivoxil Hydrochloride Fine Granules/O‹cial Monographs
Column temperature:A constant temperature of about 409C.
Mobile phase:Dissolve 1.56g of sodium dihydrogen-phosphate dihydrate and1.22g of sodium1-decanesulfonate in water to make1000mL.To700mL of this solution add 300mL of acetonitrile and100mL of methanol.
Flow rate:Adjust the‰ow rate so that the retention time of cefcapene pivoxil is about5minutes.
System suitability—
System performance:Dissolve0.2g of Cefcapene Pivoxil Hydrochloride Hydrate in10mL of methanol,and warm in a water bath at609C for20minutes.After cooling,pipet1mL of this solution,and add exactly10mL of the internal stan-dard solution and the mixture of water and methanol(1:1)to make50mL.When the procedure is run with10m L of this solution under the above operating conditions,cefcapene pivoxil,trans-cefcapene pivoxil and the internal standard are eluted in this order,the ratios of the retention time of trans-cefcapene pivoxil and the internal standard to that of cefca-pene pivoxil are about1.7and2.0,respectively,and the reso-lution between the peaks of trans-cefcapene pivoxil and the internal standard is not less than1.5.
System repeatability:When the test is repeated5times with 10m L of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area of cefcapene pivoxil to that of the internal standard is not more than1.0z.
Containers and storage Containers—Tight containers.
Storage—Light-resistant,at a temperature not exceeding 59C.
Cefcapene Pivoxil Hydrochloride Fine Granules
セフカペンピボキシル塩酸塩細粒
Cefcapene Pivoxil Hydrochloride Fine Granules contains not less than90.0z and not more than 110.0z of cefcapene(C17H19N5O6S2:453.49).
Method of preparation Prepare toˆnely granulated form as directed under Powders,with Cefcapene Pivoxil Hydrochlo-ride Hydrate.
Identiˆcation Powder Cefcapene Pivoxil Hydrochloride Fine Granules.To a portion of the powder,equivalent to10 mg(potency)of Cefcapene Pivoxil Hydrochloride Hydrate, add40mL of methanol,shake vigorously,and add methanol to make50mL.To4mL of this solution add methanol to make50mL,andˆlter through a membraneˆlter with a pore size of0.45m m.Determine the absorption spectrum of the ˆltrate as directed under Ultraviolet-visible Spectrophoto-metry<2.24>:it exhibits a maximum between264nm and268 nm.
Purity(1)Related substances I—Powder Cefcapene Pivoxil Hydrochloride Fine Granules.To a portion of the powder,equivalent to5mg(potency)of Cefcapene Pivoxil Hydrochloride Hydrate,add1mL of methanol,and shake. Add25mL of a mixture of water and methanol(1:1),shake vigorously for5minutes,andˆlter through a membraneˆlter with a pore size of0.45m m.Discard theˆrst3mL of the ˆltrate,and use the subsequentˆltrate as the sample solution. Perform the test with30m L of the sample solution as directed under Liquid Chromatography<2.01>according to the fol-lowing conditions.Determine each peak area by the automat-ic integration method.If necessary,compensate the base-line by performing in the same manner as the test with30m L of a mixture of water and mothod(1:1).Calculate the amount of the peaks other than the peak of cefcapene pivoxil by the area percentage method:the amount of the substance,having the relative retention time of about1.3with respect to cefcapene pivoxil,is not more than0.4z,the amount of the trans-isomer of cefcapene pivoxil,having the relative retention time of about1.5,is not more than1.1z,the amount of the substance other than that mentioned above is not more than 0.3z,and the total of these substances is not more than2.8 z.
Operating conditions—
Proceed as directed in the Purity(2)under Cefcapene Pivoxil Hydrochloride Hydrate.
System suitability—
Proceed as directed in the Purity(2)under Cefcapene Pivoxil Hydrochloride Hydrate.
(2)Related substances II—Powder Cefcapene Pivoxil Hydrochloride Fine Granules.To a portion of the powder, equivalent to2mg(potency)of Cefcapene Pivoxil Hydrochloride Hydrate,add20mL of N,N-dimethylfor-mamide for liquid chromatography,shake vigorously for10 minutes,andˆlter through a membraneˆlter with a pore size of0.45m m.Discard theˆrst3mL of theˆltrate,and use the subsequentˆltrate as the sample solution.Perform the test with20m L of the sample solution as directed under Liquid Chromatography<2.01>according to the following condi-tions,and determine each peak area by the automatic integra-tion method:the total area of the peaks eluted before that of cefcapene pivoxil is not more than4.0z of the total area of all peaks other than the solvent peak.
Operating conditions—
Proceed as directed in the Purity(3)under Cefcapene Pivoxil Hydrochloride Hydrate.
System suitability—
Proceed as directed in the Purity(3)under Cefcapene Pivoxil Hydrochloride Hydrate.
Water<2.48>Not more than1.4z(0.5g,volumetric titra-tion,back titration).Perform the test without pulverizing the sample,and handling the sample under a relative humidity of less than30z.
Uniformity of dosage units<6.02>The granules in single-u-nit container meet the requirement of the Mass variation test. Dissolution Being speciˆed separately.
Particle size<6.03>It meets the requirement of theˆne granules of the Powders.
Assay Weigh accurately an amount of Cefcapene Pivoxil Hydrochloride Fine Granules,equivalent to about0.2g (potency)of and Cefcapene Pivoxil Hydrochloride Hydrate, add100mL of the mixture of water and methanol(1:1), shake vigorously for10minutes,add the mixture of water and methanol(1:1)to make exactly200mL,and centrifuge at 3000rpm for5minutes.Filter the supernatant liquid through a membraneˆlter with a pore size of0.45m m,discard theˆrst 1mL of theˆltrate,pipet the subsequent2mL of theˆltrate,。