Parts per billion of nitrite in microcrystalline cellulose by ion chromatography mass spectrometry with isotope labeled internal standard.

Regulatory authorities like the U.S. Food and Drug Administration (FDA) have set strict specification levels for N-nitrosamines in finished drug products. Nitrite is a potential precursor for the formation of probable carcinogenic N-nitrosamines when secondary or tertiary amines are also present in the active pharmaceutical ingredient (API) synthesis or drug formulation process. An accurate and sensitive determination of nitrite will be useful when a drug product manufacturer chooses to investigate the reaction kinetics between nitrite and amines or to select appropriate excipients for its drug formulation. Pharmaceutical excipient manufacturers may also need an accurate nitrite measurement to investigate the nitrite content in their excipients. This study details the development and validation of an ion chromatography mass spectrometry (IC-MS) method for trace nitrite determination in microcrystalline cellulose materials, one of the important pharmaceutical excipients used in many drug formulations. MS operated under selected ion monitoring mode was used to solve the commonly encountered interference issue with conductivity detection, and nitrite isotope internal standard was employed to address the ion suppression issue with MS detection. The installation of an after-column "jumper" to flush water with an auxiliary pump through the MS when it is not used for data collection avoided sensitivity loss due to trace salt accumulation in the ion source. Validation of the optimized method was satisfactory, with linearity of nitrite in the concentration range of 0.02-7.50 ppm (µg/g) having a regression coefficient of > 0.999, precision of RSD < 9.5% at 0.03 ppm and RSD < 3.4% at 0.4 ppm and recovery of 92.0-103.0%. The limit of detection and limit of quantitation were 0.005 and 0.016 ppm, respectively.

Trace-level quantification of ethylene oxide and 2-chloroethanol in low-viscosity hydroxypropyl methylcellulose with solid phase microextraction and GC-MS.

Ethylene oxide (EtO) is naturally present in numerous food products but recently EtO and its degradation product of 2-chloroethanol (2-CE) have been reported in amounts exceeding the maximum residue limit in Europe. The reports include hard capsules for dietary supplements made from low viscous hydroxypropyl methylcellulose (HPMC). The European council (EC) has proposed a generalized method for spices, seeds, and capsules utilizing QuEChERS, solid phase extraction (SPE), and GC-MS/MS to accommodate the need for analyte specificity, trace-level analysis, and higher throughput. HPMC has unique solvation properties and, without care, can potentially be transferred to the instrument. The current work presents the development of two methods specific for EtO and 2-CE in low viscous HPMC using solid phase microextraction (SPME) and GC-MS. Method optimization for solvation, SPME settings, and GC-MS settings are presented along with validation based on standard addition. Both methods present a high degree of specificity and limits of detection (EtO 6.7 µg/kg and 2-CE 12 µg/kg), comparable to those obtained with the EC method. Apart from sampling, the methods were fully automated and rely on low cost GC-MS instrumentation, widely available. Analyzed samples did not contain EtO or 2-CE, and method development was done with spiked samples. Contamination from plastic containers and analytical carry-over are shown as possible sources of EtO and 2-CE.

Elimination of N,O-bis(trimethylsilyl)trifluoroacetamide interference by base treatment in derivatization gas chromatography mass spectrometry determination of parts per billion of alcohols in a food additive.

A novel base treatment followed by liquid-liquid extraction was developed to remove the interference of excess derivatization reagent BSTFA [N,O-Bis(trimethylsilyl)trifluoroacetamide] and its byproducts for trace determination of 1-chloro-2-propanol and 2-chloro-1-propanol in a food additive. The corresponding trimethylsilyl derivatives were analyzed by gas chromatography mass spectrometry (GC/MS) detection in selective ion monitoring mode. Due to a large volume splitless injection needed for achieving the required sensitivity, excess BSTFA in the derivatization sample solution interfered with the trimethylsilyl derivatives of the analytes of interest, making their quantitation not attainable. Efforts were made to decompose BSTFA while keeping the trimethylsilyl derivatives intact. Water or aqueous sulfuric acid treatment converted BSTFA into mainly N-trimethylsilyltrifluoroacetamide, which partitions between aqueous and organic layers. In contrast, aqueous sodium hydroxide decomposed BSTFA into trifluoroacetic acid, which went entirely into the aqueous layer. No BSTFA or its byproduct N-trimethylsilyltrifluoroacetamide or trifluroacetamide was found in the organic layer where the derivatized alcohols existed, which in turn completely eliminated their interference, enabling accurate and precise determination of parts per billion of the short-chain alcohols in the food additive. Contrary to the conventional wisdom that a trimethylsilyl derivative is susceptible to hydrolysis, the derivatized short-chain alcohols were found stable even in the presence of 0.17N aqueous sodium hydroxide as the improved GC/MS method was validated successfully, with a satisfactory linearity response in the concentration range of 10-400ng/g (regression coefficient greater than 0.999), good method precision (<4%), good recovery (90-98%), and excellent limit of detection (3ng/g) and limit of quantitation (10ng/g).