Optimization of the Water-Insoluble Procedures for USP General Chapter Residual Solvents <467>

Abstract

Abstract. The water-insoluble procedures in US Pharmacopeia (USP) General Chapter Residual Solvents <467>, which are based on European Pharmacopoeia procedures, were optimized and modified before their inclusion in the chapter to improve their scope, performance, and ruggedness. The optimized procedures use a static headspace introduction system with a gas chromatograph equipped with a flame ionization detector. This article describes some of the key changes made to the USP published procedures, including use of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) as the solvent, addition of 5 mL of water and 1 mL of sample (dissolved in DMSO or DMF) to the headspace vial, use of a 3:1 GC split ratio, and use of new matrix-matched system suitability solutions. These procedures were verified with two different active pharmaceutical ingredients-hydroxyzine pamoate and prednisone. In the investigation, the more polar material (hydroxyzine pamoate) showed greater recoveries for the optimized procedures when prepared in DMSO. The less polar material (prednisone) typically had greater recoveries in DMF for the optimized procedures. During experimentation, insights into sample preparation, additional types of headspace instrumentation, solvent purity, and other parameters were also gained.

Impact of API (Active Pharmaceutical Ingredient) Source Selection on Generic Drug Products

“…The supplier evaluation samples should be analyzed using high quality standard materials. Further, API open part DMF evaluation would also confirm the assay results during API stability studies [30,31].…”

“…Genotoxic impurities and metal impurities have recently received special attention from both, the health authorities and the industry. Hence generic drug product manufacturers should give exclusive consideration to these impurities [22][23][24][25][26][27][28][29][30][31].…”

Block copolymer nanoassemblies

“…Any method, however, needs to be strictly controlled to avoid contamination of the sample with residual organic solvents following the United States Pharmacopeia (USP) regulations or relevant rules in other countries [13]. For instance, the USP guidelines mandate the tests of all drug formulations for the residual solvents levels by considering the tolerable daily intake used by the international program on chemical safety to describe exposure limits of toxic chemicals as well as the acceptable daily intake used by the World Health Organization (WHO) or other health organizations.…”

Headspace gas chromatographic analysis of residual solvents in pharmaceuticals: comparison of two matrix media

“…The nature of the matrix medium is of primary importance as has an essential influence on the amount of the analytes in the headspace and thus on the determination sensitivity. For residual solvents determination in pharmaceuticals, water [8], dimethylsulfoxide [9,15], N,N-dimethylacetamide [16], N,N-dimethylformamide (DMF) [15], benzyl alcohol [17], liquid paraffin [18] and ionic liquids [3,11] were suggested as matrix media. Recently, for residual solvents determination deep eutectic solvents (DESs) have been proposed [7,8,19].…”