Analysis of unknown (unlabeled/mislabeled) drug products for active pharmaceutical ingredients and related substances by an international mail facility satellite laboratory equipped with rapid screening devices.

Two chemists employed a three-device rapid screening "toolkit" consisting of a handheld Raman spectrometer, transportable mass spectrometer, and portable Fourier transform infrared (FT-IR) spectrometer at an international mail facility (IMF) satellite laboratory to examine unknown (unlabeled/mislabeled) products for the presence of active pharmaceutical ingredients (APIs). Phase I of this project previously demonstrated that this toolkit was the most effective collection of instruments for identifying APIs in product types collected at IMFs during a nationwide mail blitz and Phase II of this project previously demonstrated that results generated using the toolkit during a satellite laboratory pilot program were as reliable as those generated by a full-service library when two or more of these instruments identify an API. This study (Phase III) described the results of the satellite laboratory toolkit during production mode and encompassed the period ranging from June 2021 through December 2022. During this study, a total of 858 products were examined on-site at the IMF. The satellite laboratory yielded conclusive results for 726 (84.6%) products, which were used to support regulatory action, and identified 132 (15.4%) products that required additional full-service laboratory analyses due to inconclusive results. The satellite and full-service laboratory verified/confirmed at least one API/related substance in 617 (71.9%) products. A total of 709 APIs/related substances were found in the 617 products, and 202 of these 709 compounds were unique/different. Overall, during Phases I through III of this program, 350 different substances have been identified in products collected at IMFs.

Comparison of direct analysis in real-time mass spectrometry, atmospheric solids analysis probe-mass spectrometry, and ion mobility spectrometry for ensuring food safety by rapid screening of poppy seeds.

The opium poppy (Papaver somniferum) is a global commercial crop that has been historically valued for both medicinal and culinary purposes. Naturally occurring opium alkaloids including morphine, codeine, thebaine, noscapine, and papaverine are found primarily in the latex produced by the plant. If the plant is allowed to fully mature, poppy seeds that do not contain the opium alkaloids will form within the pods and may be used in the food industry. It is possible for the seeds to become contaminated with alkaloids by the latex during harvesting, posing a potential health risk for consumers. In the USA, there have been more than 600 reported adverse events including 19 fatalities that may be linked to the consumption of a contaminated poppy-containing product such as home-brewed poppy seed tea. Unwashed poppy seeds and pods may be purchased over the Internet and shipped worldwide. The Forensic Chemistry Center, US Food and Drug Administration (FDA) has evaluated several mass spectrometers (MS) capable of rapid screening to be used for high-throughput analysis of samples such as poppy seeds. These include a direct analysis in real-time (DART) ambient ionization source coupled to a single-quadrupole MS, an atmospheric solids analysis probe (ASAP) ionization source coupled to the same MS, and ion mobility spectrometers (IMS). These instruments have been used to analyze 17 poppy seed samples for the presence of alkaloids, and the results were compared to data obtained using liquid chromatography with mass spectral detection (LC-MS/MS). Results from the 17 poppy seed samples indicate that the DART-MS, ASAP-MS, and IMS devices detect many of the same alkaloids confirmed during the LC-MS/MS analyses, although both the false-positive and false-negative rates are higher, possibly due to the non-homogeneity of the samples and the lack of chromatographic separation.

Rapid screening of 2-benzylbenzimidazole nitazene analogs in suspect counterfeit tablets using Raman, SERS, DART-TD-MS, and FT-IR.

Developing methods to rapidly screen for novel synthetic 2-benzylbenzimidazole opioids, also known as nitazenes, has become increasingly important due to their high potency. These compounds have potency comparable or exceeding that of fentanyl by up to 10 times and have been implicated in approximately 5% of all drug overdose deaths in the United States in 2021. This paper details the authenticity determination of suspect tablets and the identification of three nitazene analogs (N-pyrrolidino etonitazene, isotonitazene, and etodesnitazene) in suspect tablets seized at a mail facility using Raman and surface-enhanced Raman scattering (SERS) with handheld devices, portable Fourier transform infrared spectrometer (FT-IR), and a direct analysis in real-time ambient ionization coupled to a thermal desorption unit and a mass spectrometer (DART-TD-MS). These methods are rapid and excellent for screening opioids in suspect tablets but could not fully determine the exact structure of some of the nitazene analogs present due to spectral similarities or similar fragmentation patterns. Liquid chromatography-mass spectrometry (LC-MS) confirmed the presence of these nitazene compounds in addition to other opioids/drugs that were in trace quantities. The quantitative high-performance liquid chromatography coupled with ultraviolet (HPLC-UV) detection experiments determined that the suspect tablets contained an average of 0.817 mg of N-pyrrolidino etonitazene per tablet. The results obtained reveal that the simultaneous deployment of these complementary and orthogonal portable analytical techniques as part of a workflow allows suspect tablets to be screened and nitazene-type drugs to be identified in suspect counterfeit tablets at remote sampling sites.

Rapid detection of active pharmaceutical ingredients in drug products collected at an international mail facility by a satellite laboratory using a "toolkit" consisting of a handheld Raman spectrometer, portable mass spectrometer and portable FT-IR spectrometer.

A satellite laboratory "toolkit" consisting of a handheld Raman spectrometer, portable direct analysis in real-time mass spectrometer (DART-MS) and portable Fourier transform infrared (FT-IR) spectrometer was employed to examine 926 pharmaceutical, unknown and dietary supplement products collected at an international mail facility (IMF) for the presence of declared and undeclared active pharmaceutical ingredients (APIs) over the course of 68 working days. The toolkit successfully identified over 650 APIs, including over 200 unique APIs, using two or more devices. The performance of each individual device, and toolkit as a whole, were evaluated on all products and a subset of the products was forwarded to full-service laboratories for confirmatory analysis to determine false positive and false negative rates of the toolkit. The subset consisted of seven negative items (those not found to contain APIs using the toolkit) and 124 positive items (those found to contain at least one API using the toolkit). Overall, no false positives were detected in the negative items and only four false negatives and five false positives were detected in the positive items. Regarding the positive items, 119 of the 124 items were found to contain at least one API using at least two toolkit devices; each of these APIs were confirmed by a full-service laboratory. Furthermore, 90.2% of the APIs found by confirmatory laboratory analysis were detected by at least two toolkit devices. Based on these metrics and the fact that no false positives were detected by more than one device, it was concluded that when the toolkit detects and subsequently verifies/confirms an API using two or more devices, the results are as reliable as those generated by a full-service laboratory.

Psychological Symptoms Associated with Sexual Victimization Experiences: Differences as a Function of the Type and Number of Sexual Acts and Aggressive Tactics.

Different types of sexual victimization are associated with different outcomes; for example, on average, physically forced sex is associated with worse psychological outcomes than verbally coerced sex. This study evaluated outcomes associated with sexual victimization as a function of sexual act and aggressive tactic, expanding upon the acts and tactics examined in prior studies. Participants who had experienced sexual victimization (N = 402) completed a survey about their most upsetting victimization experience, identifying the sexual act(s) and aggressive tactic(s) that occurred. They completed measures of PTSD, depression, anger, and trauma-related cognitions. Relationships between symptom severity and most upsetting act and tactic, as well as the number of acts and tactics, were analyzed. Related to the sexual act, non-penetrative sexual acts were associated with the lowest symptom severity on several measures. Related to the aggressive tactic, sex obtained through anger/criticism and physical force were associated with the greatest symptom severity on some measures. A larger number of tactics were associated with more severe symptoms on all measures, whereas number of acts only explained unique variance in PTSD symptom severity. The pattern of severity for outcomes differed from previous conceptualizations, suggesting that current hierarchies of victimization severity may require revision.

Evaluation of "Toolkit" consisting of handheld and portable analytical devices for detecting active pharmaceutical ingredients in drug products collected during a simultaneous nation-wide mail blitz.

A "toolkit" consisting of a handheld Raman spectrometer equipped with a 1064 nm laser, a portable Fourier transform infrared (FT-IR) spectrometer and a portable direct analysis in real-time mass spectrometer (DART-MS) was employed in a laboratory setting to examine 82 representative products collected during a nationwide mail blitz for the presence of APIs. These results were compared to those obtained using laboratory-based methods; 8 of the products were not found to contain APIs and 74 of the products were found to contain a total of 88 APIs (65 of the 88 APIs were unique). The individual performance of each device and combined performance of the three-device toolkit were evaluated with regard to true positives, true negatives, false positives and false negatives. Using this toolkit, 81 (92.0 %) of the APIs were detected by at least one technique and 47 (64.8 %) of the APIs were detected by at least two techniques. Seven false negatives (8.0 %) were encountered and while the toolkit yielded 12 false positives, no false positives were detected by more than one technique. Overall, this study demonstrated that when the toolkit detects an API using two or more devices, the results are as reliable as those generated by a full-service laboratory.

Evaluation of four field portable devices for the rapid detection of mitragynine in suspected kratom products.

The development of a method for the rapid screening of food and drug products for constituents such as mitragynine, the most abundant alkaloid found in Mitragyna speciosa (kratom) plant leaves, has become increasingly important. The use of kratom is said to produce stimulant or narcotic effects and poses risks of addiction, abuse, and dependence, much like other opioids. Direct Analysis in Real Time with thermal desorption mass spectrometry (DART-TD-MS), hand-held mass spectrometry, portable ion mobility spectrometry (IMS), and portable Fourier-transform infrared spectroscopy (FT-IR) were each evaluated as field-deployable screening techniques for the detection of mitragynine in food and drug products. These devices offer the potential for rapid, early detection of mitragynine in suspect products entering the United States through international mail facilities and other ports of entry. Ninety-six kratom products, including capsules, bulk powder, and bulk plant material, were analyzed by either direct sampling of the solid material or by solvent extraction. True and false positive and negative results are reported, based on comparison to results from qualitative screening using gas chromatography with mass spectral detection (GC-MS), liquid chromatography with mass spectral detection (LC-MS), and/or quantitative screening using high-performance liquid chromatography with ultraviolet detection (HPLC-UV), with a discussion of the assessment of each technique for use in the field. Each device demonstrated attributes that would be favorable for use in screening of suspected mitragynine-containing products at places like ports of entry, and simultaneous deployment of two or more of these devices as part of a workflow would be the most effective for rapid screening of these products. This combination of rapid screening orthogonal techniques suited to a non-laboratory environment will allow onsite destruction of products found to contain mitragynine.

Negative Cognitions Following Distressing Unwanted Sex: The Role of Coercion Severity and Perceived Consent.

Findings from past research suggest that unwanted sex (i.e., sex that is not fully desired) can result in a variety of outcomes, ranging from positive to negative. Some research has demonstrated that more severe coercion within unwanted sex is associated with more negative cognitions (particularly self-blame) following the unwanted sex, but findings are inconsistent. Previous research also has demonstrated that individuals' perceptions of how much they consented to sex-regardless of the level of coercion-are associated with negative cognitions. In this study, we aimed to explore the potential moderating role of perceived consent in the relationship between sexual coercion severity and negative cognitions following unwanted sex. Participants (N = 196) who had had a distressing unwanted sexual experience provided descriptions of their most distressing experience, rated their perceptions of how much they consented to this experience, and completed a questionnaire measuring the amount and content of negative cognitions they experienced following this experience. Two independent raters coded descriptions to determine coercion severity. Results demonstrated that perceived consent significantly moderated the relationship between coercion severity and two types of negative cognitions: characterological self-blame and negative thoughts about the world. This suggests that individuals' perceptions of their consent are often as important as the level of coercion involved in predicting cognitive outcomes of unwanted sex.

From Freewill to Force: Examining Types of Coercion and Psychological Outcomes in Unwanted Sex.

Unwanted sex is sex that is not fully desired, whether an individual agrees to it or not. It can be coerced-when one person compels another unwilling person-or not coerced-when a person willing agrees to participate. Experiencing unwanted sex, especially when coerced, has been associated with negative psychological outcomes. Researchers have created severity continua of coerced sex based on type of coercion used, but relative severity of outcomes across the range of unwanted sex has not been fully evaluated. This study aimed to identify types of coercion experienced in unwanted sex and evaluate differences in psychological outcomes as a function of type of coercion experienced. Participants (N = 276) provided narrative descriptions of an unwanted sexual experience. Three categories of coercive tactics and two categories of unwanted but non-coerced sex were identified. Differences across categories emerged for the following outcomes: PTSD symptoms, perpetrator blame, situational blame, societal blame, negative thoughts about the self, negative thoughts about the world. Individuals who experienced actively forced sex reported significantly more symptoms than individuals who experienced other types of unwanted sex on most measures. These results are a first step in better understanding the psychological influence of the entire range of unwanted sexual experiences.

Forensic Analysis of Stains on Fabric Using Direct Analysis in Real-time Ionization with High-Resolution Accurate Mass-Mass Spectrometry.

A rapid technique using direct analysis in real-time (DART) ambient ionization coupled to a high-resolution accurate mass-mass spectrometer (HRAM-MS) was employed to analyze stains on an individual's pants suspected to have been involved in a violent crime. The victim was consuming chocolate ice cream at the time of the attack, and investigators recovered the suspect's pants exhibiting splatter stains. Liquid chromatography with mass spectral detection (LC-MS) and stereoscopic light microscopy (SLM) were also utilized in this analysis. It was determined that the stains on the pants contained theobromine and caffeine, known components of chocolate. A shard from the ceramic bowl that contained the victim's ice cream and a control chocolate ice cream sample were also found to contain caffeine and theobromine. The use of DART-HRAM-MS was useful in this case due to its rapid analysis capability and because of the limited amount of sample present as a stain.

Description of a Mass Poisoning in a Rural District in Mozambique: The First Documented Bongkrekic Acid Poisoning in Africa.

Background: On 9 January 2015, in a rural town in Mozambique, >230 persons became sick and 75 died of an illness linked to drinking pombe, a traditional alcoholic beverage. Methods: An investigation was conducted to identify case patients and determine the cause of the outbreak. A case patient was defined as any resident of Chitima who developed any new or unexplained neurologic, gastrointestinal, or cardiovascular symptom from 9 January at 6:00 am through 12 January at 11:59 pm. We conducted medical record reviews, healthcare worker and community surveys, anthropologic and toxicologic investigations of local medicinal plants and commercial pesticides, and laboratory testing of the suspect and control pombe. Results: We identified 234 case patients; 75 (32%) died and 159 recovered. Overall, 61% of case patients were female (n = 142), and ages ranged from 1 to 87 years (median, 30 years). Signs and symptoms included abdominal pain, diarrhea, vomiting, and generalized malaise. Death was preceded by psychomotor agitation and abnormal posturing. The median interval from pombe consumption to symptom onset was 16 hours. Toxic levels of bongkrekic acid (BA) were detected in the suspect pombe but not the control pombe. Burkholderia gladioli pathovar cocovenenans, the bacteria that produces BA, was detected in the flour used to make the pombe. Conclusions: We report for the first time an outbreak of a highly lethal illness linked to BA, a deadly food-borne toxin in Africa. Given that no previous outbreaks have been recognized outside Asia, our investigation suggests that BA might be an unrecognized cause of toxic outbreaks globally.

Identification of the potent toxin bongkrekic acid in a traditional African beverage linked to a fatal outbreak.

In January 2015, 75 people died and 177 were hospitalized in the Mozambique village of Chitima after attending a funeral. The deaths were linked to the consumption of a traditional African beverage called pombe. Samples of the suspect pombe were subjected to myriad analyses and compared to a control sample. Ultimately, non-targeted liquid chromatography-mass spectrometry screening revealed the presence of the potent toxin bongkrekic acid, and its structural isomer, isobongkrekic acid. Quantitative analysis found potentially fatal levels of these toxins in the suspect pombe samples. Bongkrekic acid is known to be produced by the bacterium Burkholderia gladioli pv. cocovenenans. This bacterium could not be isolated from the suspect pombe, but bacteria identified as B. gladioli were isolated from corn flour, a starting ingredient in the production of pombe, obtained from the brewer's home. When the bacteria were co-plated with the fungus Rhizopus oryzae, which was also isolated from the corn flour, synergistic production of bongkrekic acid was observed. The results suggest a mechanism for bongkrekic acid intoxication, a phenomenon previously thought to be restricted to specific regions of Indonesia and China.

Isolation and structural characterization of a new tadalafil analog (chloropropanoylpretadalafil) found in a dietary supplement.

A screen for known PDE-5 inhibitors in a dietary supplement product marketed for "enhanced sexual performance" detected a compound that structurally resembled chloropretadalafil, a known analog of tadalafil. The compound was isolated from the supplement matrix using high performance liquid chromatography with ultraviolet detection (HPLC-UV) and a fraction collector, and was further characterized using gas chromatography with Fourier Transform infrared detection and mass spectral detection (GC/FT-IR/MS), as well as high resolution mass spectrometry (HRMS). The analog had an accurate mass of m/z 441.1216 (error is 0.8706ppm) for the protonated species [M+H](+), corresponding to a molecular formula of C23H22ClN2O5. HRAM and GC/FT-IR/MS mass spectral fragmentation data suggested that the modification is a chloropropanoyl moiety extending from the nitrogen on the piperidine ring of chloropretadalafil. The proposed new analog has been named chloropropanoylpretadalafil.

Isolation and structural characterization of a new tadalafil analog (2-hydroxyethylnortadalafil) found in a dietary supplement.

A screen for known PDE-5 inhibitors in a dietary supplement product marketed for "enhanced sexual performance" detected a compound that structurally resembled tadalafil. The compound was isolated from the supplement matrix using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) and a fraction collector, and was further characterized using nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), as well as high-resolution accurate mass mass spectrometry (HRAM-MS). The analog had an accurate mass of m/z 420.15614 (error is 1.77235ppm) for the protonated species [M+H](+), corresponding to a molecular formula of C23H22N3O5. Mass spectral fragmentation data suggested that the modification occurred in place of the CH3 located on the pyrazinopyridoindole-1,4-dione of tadalafil. NMR was utilized to further elucidate the configuration of the substitution. The analysis indicated that the moiety is a CH2CH2OH, hydroxyethyl group. The new analog has been named 2-hydroxyethylnortadalafil.

Accurate mass fragment library for rapid analysis of pesticides on produce using ambient pressure desorption ionization with high-resolution mass spectrometry.

U.S. food imports have been increasing steadily for decades, intensifying the need for a rapid and sensitive screening technique. A method has been developed that uses foam disks to sample the surface of incoming produce. This work provides complimentary information to the extensive amount of published pesticide fragmentation data collected using LCMS systems (Sack et al. Journal of Agricultural and Food Chemistry, 59, 6383-6411, 2011; Mol et al. Analytical and Bioanalytical Chemistry, 403, 2891-2908, 2012). The disks are directly analyzed using transmission-mode direct analysis in real time (DART) ambient pressure desorption ionization coupled to a high resolution accurate mass-mass spectrometer (HRAM-MS). In order to provide more certainty in the identification of the pesticides detected, a library of accurate mass fragments and isotopes of the protonated parent molecular ion (the [M+H]⁺) has been developed. The HRAM-MS is equipped with a quadrupole mass filter, providing the capability of "data-dependent" fragmentation, as opposed to "all -ion" fragmentation (where all of the ions enter a collision chamber and are fragmented at once). A temperature gradient for the DART helium stream and multiple collision energies were employed to detect and fragment 164 pesticides of varying chemical classes, sizes, and polarities. The accurate mass information of precursor ([M+H]⁺ ion) and fragment ions is essential in correctly identifying chemical contaminants on the surface of imported produce. Additionally, the inclusion of isotopes of the [M+H]⁺ in the database adds another metric to the confirmation process. The fragmentation data were collected using a Q-Exactive mass spectrometer and were added to a database used to process data collected with an Exactive mass spectrometer, an instrument that is more readily available for this screening application. The commodities investigated range from smooth-skinned produce such as apples to rougher surfaces like broccoli. The minimal sample preparation and absence of chromatography has shortened the analysis time to about 15 min per sample, and the simplicity and robustness of the technique make it ideal for rapid screening.