(im'' i pen' em).
1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-(1-hydroxyethyl)-3-[[2-(iminomethyl)amino]ethyl]thio]-7-oxo-, monohydrate, [5R-[5,6(R*)]]-.
(5R,6S)-3-[[2-(Formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate [74431-23-5].
Anhydrous 299.35 [64221-86-9].
» Imipenem contains the equivalent of not less than 98.0 percent and not more than 101.0 percent of imipenem monohydrate (C12H17N3O4S·H2O).
Packaging and storage Preserve in Containers for Sterile Solids as described under Injections 1, and store in a cold place.
Labeling Where it is intended for use in preparing injectable dosage forms, the label states that it is sterile.
USP Reference standards 11
USP Endotoxin RS
USP Imipenem Monohydrate RS
Identification, Infrared Absorption 197M.
Specific rotation 781S: between +84 and +89.
Test solution: 5 mg per mL, in a pH 7 buffer. Prepare the pH 7 buffer solution as follows. Dissolve 5 g of monobasic potassium phosphate and 11 g of dibasic potassium phosphate in 900 mL of water, adjust with phosphoric acid or 5 N sodium hydroxide to a pH of 7, dilute with water to 1000 mL, and mix.
Crystallinity 695: meets the requirements.
Bacterial endotoxins 85 (where the label states that Imipenem is sterile) It contains not more than 0.17 USP Endotoxin Unit per mg.
Sterility 71 (where the label states that Imipenem is sterile) It meets the requirements when tested as directed for Membrane Filtration under Test for Sterility of the Product to be Examined, 6 g of specimen dissolved in 200 mL of Fluid A being used.
Loss on drying (see Thermal Analysis 891)[noteThe quantity taken for the determination may be adjusted, if necessary, for instrument sensitivity. Weight loss occurring at temperatures above about 160, indicative of decomposition, is not to be interpreted as Loss on drying. ] Determine the percentage of volatile substances by thermogravimetric analysis on an appropriately calibrated instrument, using 5 to 10 mg of Imipenem, accurately weighed. Heat the specimen under test at a rate of 20 per minute under vacuum. Record the thermogram to 200, and calculate the weight loss at the plateau or inflection point at about 150: it loses not less than 5.0% and not more than 8.0% of its weight.
Residue on ignition 281: not more than 0.2%.
Heavy metals, Method II 231: not more than 0.002%.
Internal standard solution Add 1 mL of n-propyl alcohol to 2000 mL of water, and mix.
Standard preparation Transfer 1.0 mL of acetone and 2.0 mL of isopropyl alcohol to a 1000-mL volumetric flask, dilute with water to volume, and mix. Transfer 1.0 mL of this solution and 5.0 mL of Internal standard solution to a 25-mL volumetric flask, dilute with water to volume, and mix. Each mL of this Standard preparation contains 31.6 µg of acetone and 63.2 µg of isopropyl alcohol.
Test preparation Transfer about 250 mg of Imipenem, accurately weighed, to a 10-mL volumetric flask, add 4.0 mL of 1 N ammonium hydroxide, and dissolve by swirling. Add 2.0 mL of Internal standard solution, dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621)The gas chromatograph is equipped with a flame-ionization detector and a 3-mm × 1.8-m column containing 10% phase G16 on support S5. The column temperature is programmed to operate at 70 for 8 minutes, then to increase at a rate of 32 per minute to 170, and to maintain the temperature at 170 for 8 minutes. The injection port is maintained at 200, the detector is maintained at 250, and helium is used as the carrier gas at a flow rate of about 19 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the relative retention times are about 0.3 for acetone, 0.5 for isopropyl alcohol, and 1.0 for n-propyl alcohol, and the relative standard deviation of each of the ratios of the response of the respective analyte peak to the response of the n-propyl alcohol peak for replicate injections is not more than 5%.
Procedure [noteUse peak areas where peak responses are indicated. ] Separately inject equal volumes (about 2 µL) of the Standard preparation and the Test preparation into the chromatograph, using the solvent (water) flush technique, record the chromatograms, and measure the responses for the acetone, isopropyl alcohol, and n-propyl alcohol peaks. Calculate the percentages of acetone and isopropyl alcohol in the portion of Imipenem taken by the same formula:
(C / W)(RU / RS)in which C is the concentration, in µg per mL, of the appropriate analyte in the Standard preparation; W is the quantity, in mg, of Imipenem taken to prepare the Test preparation; and RU and RS are the ratios of the peak response of each of the corresponding analytes to the peak responses of n-propyl alcohol obtained from the Test preparation and the Standard preparation, respectively. Add the percentages of acetone and isopropyl alcohol found: the total is not more than 0.25%.
Mobile phase Dissolve 0.54 g of monobasic potassium phosphate in 3600 mL of water, adjust with 0.5 N sodium hydroxide or 0.5 M phosphoric acid to a pH of 6.8 ± 0.1, dilute with water to make 4000 mL of solution, and mix. Filter this solution through a filter of 0.5-µm or finer porosity, and degas. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation Dissolve an accurately weighed quantity of USP Imipenem Monohydrate RS in Mobile phase to obtain a solution having a known concentration of about 0.4 mg per mL. Store this solution in an ice bath, and discard after 8 hours.
Assay preparation Transfer about 100 mg of Imipenem, accurately weighed, to a 250-mL volumetric flask, dissolve in and dilute with Mobile phase to volume, and mix. Store this solution in an ice bath, and discard the unused portion after 8 hours.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 300-nm detector and a 4.6-mm × 30-cm column that contains packing L1, and is maintained at a temperature of 30 ± 1.0. The flow rate is about 1.5 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency determined from the analyte peak is not less than 600 theoretical plates, and the relative standard deviation for replicate injections is not more than 1.0%.
Procedure Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of imipenem monohydrate (C12H17N3O4S·H2O) in the portion of Imipenem taken by the formula:
(317.36 / 299.35)(0.25CP)(rU / rS)in which 317.36 and 299.35 are the molecular weights of imipenem monohydrate and anhydrous imipenem, respectively; C is the concentration, in mg per mL, of USP Imipenem Monohydrate RS in the Standard preparation; P is the content, in µg per mg, of anhydrous imipenem (C12H17N3O4S) in USP Imipenem Monohydrate RS; and rU and rS are the imipenem peak responses obtained from the Assay preparation and the Standard preparation, respectively.
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