Prabha Dwivedi

Mass Spectrometry: Recent Advances in Direct Open Air Surface Sampling/Ionization

1. Scope of this Review 2270 2. Ambient Ionization Techniques 2272 2.1. Solid−Liquid Extraction-Based Techniques 2272 2.1.1. Desorption Electrospray Ionization (DESI) 2272 2.1.2. Desorption Ionization by Charge Exchange (DICE) 2277 2.1.3. Easy Ambient Sonic-Spray Ionization (EASI) 2278 2.1.4. Liquid Micro Junction Surface Sampling Probe (LMJ-SSP) 2279 2.1.5. Liquid Extraction Surface Analysis (LESA) 2279 2.1.6. Nanospray Desorption Electrospray Ionization (nanoDESI) 2280 2.1.7. Desorption Atmospheric Pressure Photoionization (DAPPI) 2280 2.2. Plasma-Based Techniques 2281 2.2.1. Direct Analysis in Real Time (DART) 2282 2.2.2. Flowing Atmospheric-Pressure Afterglow (FAPA) 2286 2.2.3. Low Temperature Plasma (LTP) & Dielectric Barrier Discharge Ionization (DBDI) 2286 2.2.4. Chemical Sputtering/Ionization Techniques 2287 2.3. Two-Step Thermal/Mechanical Desorption/ Ablation (Non-Laser) Techniques 2288 2.3.1. Neutral Desorption Extractive Electrospray Ionization (ND-EESI) 2288 2.3.2. Beta Electron-Assisted Direct Chemical Ionization (BADCI) 2288 2.3.3. Atmospheric Pressure Thermal Desorption-Secondary Ionization (AP-TD/SI) 2289 2.3.4. Probe Electrospray Ionization (PESI) 2289 2.4. Two-Step Laser-Based Desorption Ablation Techniques 2290 2.4.1. Laser-Based Hybrid Techniques Coupled to ESI or Plasma Ionization 2290 2.4.2. Laser Electrospray Mass Spectrometry (LEMS) 2292 2.4.3. Laser Ablation Atmospheric Pressure Photoionization (LAAPPI) 2293 2.4.4. Laser Ablation Sample Transfer 2293 2.5. Acoustic Desorption Techniques 2294 2.5.1. Laser-Induced Acoustic Desorption (LIAD) 2294 2.5.2. Radiofrequency Acoustic Desorption Ionization (RADIO) 2295 2.5.3. Surface Acoustic Wave-Based Techniques 2295 2.6. Multimode Techniques 2296 2.6.1. Desorption Electrospray/Metastable-Induced Ionization (DEMI) 2296 2.7. Other Techniques 2296 2.7.1. Rapid Evaporative Ionization Mass Spectrometry (REIMS) 2296 2.7.2. Laser Desorption Ionization (LDI) 2297 2.7.3. Switched Ferroelectric Plasma Ionizer (SwiFerr) 2297 2.7.4. Laserspray Ionization (LSI) 2297 3. Remote Sampling 2298 3.1. Nonproximate Ambient MS 2298 3.2. Fundamentals of Neutral/Ion Transport 2298 3.3. Transport of Neutrals 2298 3.4. Transport of Ions 2299 4. Future Directions 2300 Author Information 2300 Corresponding Author 2300 Author Contributions 2300 Notes 2300 Biographies 2300 Acknowledgments 2301 References 2301

Falsified medicines in Africa: all talk, no action

Fil: Newton, Paul N. . Mahosot Hospital. Microbiology Laboratory. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit; Laos. Oxford University. Churchill Hospital. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health; Reino Unido. Oxford University. Churchill Hospital. Worldwide Antimalarial Resistance Network; Reino Unido

Quality of Antimalarials at the Epicenter of Antimalarial Drug Resistance: Results from an Overt and Mystery Client Survey in Cambodia

Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the countrys efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources.

Ambient mass spectrometry technologies for the detection of falsified drugs

Increased globalization of the pharmaceutical market has facilitated the unobstructed and fast spread of poor-quality medicines. Poor-quality medicines include spurious/falsely-labeled/falsified/counterfeit drugs (those that are deliberately and fraudulently mislabeled with respect to content and/or origin), substandard drugs (legitimate drugs that do not meet their quality specifications), and degraded medicines (good quality pharmaceuticals that suffered from deterioration caused by improper storage or distribution). Consumption of poor-quality pharmaceuticals is likely to increase morbidity and mortality. Moreover, poor-quality drugs can also contribute to the development of resistance to anti-infective medicines and decrease the quality of health care received by patients. To assess the true prevalence of poor quality drugs, tiered technology approaches enabling the testing of drug samples collected at points of sale are required, thus ensuring public health standards. High throughput and high resolution ambient mass spectrometry techniques allow investigation of pharmaceuticals with minimal or no sample preparation, thus possessing capabilities to survey a large number of drug samples for their authenticity.

A Repeat Random Survey of the Prevalence of Falsified and Substandard Antimalarials in the Lao PDR: A Change for the Better

In 2003, a stratified random sample survey was conducted in the Lao Peoples Democratic Republic (Laos) to study the availability and quality of antimalarials in the private sector. In 2012, this survey was repeated to allow a statistically valid analysis of change through time. The counterfeit detection device 3 (CD-3) was used to assess packaging quality in the field and HPLC and mass spectroscopy analysis chemical analysis performed. The availability of oral artesunate monotherapies had significantly decreased from 22.9% (22) of 96 outlets in southern Laos in 2003 to 4.8% (7) of 144 outlets in 2012 (P < 0.0001). All the samples collected in the 2012 survey contained the correct active pharmaceutical ingredients (APIs) in contrast to the 21 (84%) falsified artesunate samples found in the 2003 survey. Although none of the medicines found in 2012 survey had evidence for falsification, 25.4% (37) of the samples were outside the 90–110% pharmacopeial limits of the label claim, suggesting that they were substandard or degraded. Results obtained from this survey show that patients are still exposed to poorly manufactured drugs or to ineffective medicines such as chloroquine. The quality of artemisinin-based combination therapies (ACTs) used in Laos needs to be monitored, since falsified ACTs would have devastating consequences in public health.

Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained.

Desorption atmospheric pressure photoionization and direct analysis in real time coupled with travelling wave ion mobility mass spectrometry

RATIONALE Ambient mass spectrometry (MS) is a tool for screening analytes directly from sample surfaces. However, background impurities may complicate the spectra and therefore fast separation techniques are needed. Here, we demonstrate the use of travelling wave ion mobility spectrometry in a comparative study of two ambient MS techniques. METHODS Desorption atmospheric pressure photoionization (DAPPI) and direct analysis in real time (DART) were coupled with travelling wave ion mobility mass spectrometry (TWIM-MS) for highly selective surface analysis. The ionization efficiencies of DAPPI and DART were compared. Test compounds were: bisphenol A, benzo[a]pyrene, ranitidine, cortisol and α-tocopherol. DAPPI-MS and DART-TWIM-MS were also applied to the analysis of chloroquine from dried blood spots, and α-tocopherol from almond surface, and DAPPI-TWIM-MS was applied to analysis of pharmaceuticals and multivitamin tablets. RESULTS DAPPI was approximately 100 times more sensitive than DART for bisphenol A and 10-20 times more sensitive for the other compounds. The limits of detection were between 30-290 and 330-8200 fmol for DAPPI and DART, respectively. Also, from the authentic samples, DAPPI ionized chloroquine and α-tocopherol more efficiently than DART. The mobility separation enabled the detection of species with low signal intensities, e.g. thiamine and cholecalciferol, in the DAPPI-TWIM-MS analysis of multivitamin tablets. CONCLUSIONS DAPPI ionized the studied compounds of interest more efficiently than DART. For both DAPPI and DART, the mobility separation prior to MS analysis reduced the amount of chemical noise in the mass spectrum and significantly increased the signal-to-noise ratio for the analytes.

Ion mobility and liquid chromatography/mass spectrometry strategies for exhaled breath condensate glucose quantitation in cystic fibrosis studies

RATIONALE Cystic fibrosis related diabetes (CFRD) is an important complication of cystic fibrosis (CF) because it causes acceleration in the decline in lung function. Monitoring concentrations of key metabolites such as glucose in airway lining fluid is necessary for improving our understanding of the biochemical mechanisms linking diabetes and CF. Targeted-metabolomic strategies for glucose quantitation in exhaled breath condensate (EBC) from healthy individuals are presented. METHODS Three different electrospray ionization mass spectrometry (ESI-MS)-based methods were developed for EBC sample interrogation and glucose quantitation without derivatization. Two methods utilized ultra-high-performance liquid chromatography (UHPLC) coupled to either time-of-flight (TOF) MS or triple quadrupole (QqQ) tandem MS (MS/MS). A third approach involved direct-infusion traveling wave ion mobility spectrometry (TWIMS) with TOF-MS detection. UHPLC/QqQ-MS/MS was used for urea quantitation as the EBC dilution marker. Matrix effects were mitigated using isotopically labeled glucose and urea as internal standards. RESULTS All the developed methods allowed glucose and urea quantitation in EBC with high accuracy and precision. The UHPLC/TOF-MS and UHPLC/QqQ-MS/MS methods provided similar analytical figures of merit. UHPLC/QqQ-MS/MS provided the highest sensitivity and the lowest limit of detection (LOD) of 1.5 nM in EBC for both glucose and urea. The TWIMS-TOF-MS-based method provided the highest sample throughput capability; however, the glucose LOD was ~3-fold higher than with the two chromatographic methods. CONCLUSIONS Mass spectrometric methods for the quantitative analysis of trace EBC glucose levels are reported and compared for the first time. The analytical figures of merit demonstrate the applicability of these methods to metabolite analysis of airway samples for CF and CFRD research.

An Effective Approach for Coupling Direct Analysis in Real Time with Atmospheric Pressure Drift Tube Ion Mobility Spectrometry

AbstractDrift tube ion mobility spectrometry (DTIMS) has evolved as a robust analytical platform routinely used for screening small molecules across a broad suite of chemistries ranging from food and pharmaceuticals to explosives and environmental toxins. Most modern atmospheric pressure IM detectors employ corona discharge, photoionization, radioactive, or electrospray ion sources for efficient ion production. Coupling standalone DTIMS with ambient plasma-based techniques, however, has proven to be an exceptional challenge. Device sensitivity with near-ground ambient plasma sources is hindered by poor ion transmission at the source–instrument interface, where ion repulsion is caused by the strong electric field barrier of the high potential ion mobility spectrometry (IMS) inlet. To overcome this shortfall, we introduce a new ion source design incorporating a repeller point electrode used to shape the electric field profile and enable ion transmission from a direct analysis in real time (DART) plasma ion source. Parameter space characterization studies of the DART DTIMS setup were performed to ascertain the optimal configuration for the source assembly favoring ion transport. Preliminary system capabilities for the direct screening of solid pharmaceuticals are briefly demonstrated. Figureᅟ

A tiered analytical approach for investigating poor quality emergency contraceptives.

Reproductive health has been deleteriously affected by poor quality medicines. Emergency contraceptive pills (ECPs) are an important birth control method that women can use after unprotected coitus for reducing the risk of pregnancy. In response to the detection of poor quality ECPs commercially available in the Peruvian market we developed a tiered multi-platform analytical strategy. In a survey to assess ECP medicine quality in Peru, 7 out of 25 different batches showed inadequate release of levonorgestrel by dissolution testing or improper amounts of active ingredient. One batch was found to contain a wrong active ingredient, with no detectable levonorgestrel. By combining ultrahigh performance liquid chromatography-ion mobility spectrometry-mass spectrometry (UHPLC-IMS-MS) and direct analysis in real time MS (DART-MS) the unknown compound was identified as the antibiotic sulfamethoxazole. Quantitation by UHPLC-triple quadrupole tandem MS (QqQ-MS/MS) indicated that the wrong ingredient was present in the ECP sample at levels which could have significant physiological effects. Further chemical characterization of the poor quality ECP samples included the identification of the excipients by 2D Diffusion-Ordered Nuclear Magnetic Resonance Spectroscopy (DOSY 1H NMR) indicating the presence of lactose and magnesium stearate.