Detection Of Active Pharmaceutical Ingredients Research Articles

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.

Morphological evaluation of low-dose midazolam granules by laser Raman microscopy.

Raman analysis has higher sensitivity for the detection of active pharmaceutical ingredients (APIs) than additives; thus, it is expected to be used for the evaluation of low-content preparations. The purpose of this study was to clarify the usefulness of granule morphology assessment using Raman analysis in the development of low-content formulations. In this study, midazolam was used as a model drug to prepare granules as a low-content formulation. Raman images were used to visualize the distribution of ingredients on the surface of the granules, determine the particle size of midazolam bound to the granules, and investigate the types of excipient components to which midazolam is bound. It was suggested that midazolam particles of a certain size were difficult to bind to excipients and had particularly low adhesion to mannitol. It was revealed that this phenomenon caused the segregation of the content of midazolam particles in the granules. Therefore, to obtain granules with good content uniformity, it was considered necessary to control the particle size of the API and select an additive that does not differ in adhesiveness to the main drug. Additionally, the findings obtained by morphological observation could be clarified by the quantitative evaluation of additives using Raman.

Paper-Based Electrochemical Devices for the Pharmaceutical Field: State of the Art and Perspectives.

The current international pharmaceutical scenario encompasses several steps in drug production, with complex and extremely long procedures. In the last few decades, scientific research has been trying to offer valid and reliable solutions to replace or support conventional techniques, in order to facilitate drug development procedures. These innovative approaches may have extremely positive effects in the production chain, supplying fast, and cost-effective quality as well as safety tests on active pharmaceutical ingredients (APIs) and their excipients. In this context, the exploitation of electrochemical paper-based analytical devices (ePADs) is still in its infancy, but is particularly promising in the detection of APIs and excipients in tablets, capsules, suppositories, and injections, as well as for pharmacokinetic bioanalysis in real samples.

Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy

Atomic-level characterization of active pharmaceutical ingredients (API) is crucial in pharmaceutical industry because APIs play an important role in physicochemical properties of drug formulations. However, the analysis of targeted APIs in intact tablet formulations is less straightforward due to the coexistence of excipients as major components and different APIs at dilute concentrations (often below 10 ​wt% loading). Although solid-state (ss) NMR spectroscopy is widely used to investigate short-range order, polymorphism, and pseudo-polymorphism in neat pharmaceutical compounds, the analysis of complex drug formulations is often limited by overlapped signals that originate from structurally different APIs and excipients. In particular, such examples are frequently encountered in the analysis of 1H ssNMR spectra of pharmaceutical formulations. While the high-resolution in 1H ssNMR spectra can be attained by, for example, high magnetic fields accompanied by fast magic-angle spinning (MAS) approaches, the spectral complexity associated with the mixtures of compounds hinders the accurate determination of chemical shifts and through-space proximities. Here we propose a fast MAS (70 ​kHz) NMR experiment for the selective detection of 1H signals associated with an API from a severely overlapped NMR spectrum of a tablet formulation. Spectral simplification is achieved by combining (i) symmetry-based dipolar recoupling (SR412) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses, (ii) radio frequency-driven recoupling (RFDR), and (iii) double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements. First, 1H sites in close proximities to 14N nuclei of an API are excited using a PM-S-RESPDOR sequence, and simultaneously, the other unwanted 1H signals of excipients are suppressed. Then, 1H magnetization transfer to adjacent 1H sites in the API is achieved by spin diffusion process using a RFDR sequence, which polarizes to 1H sites within the crystalline API regions of the drug formulation. Next, a PM-S-RESPDOR-RFDR sequence is combined with a Back-to-Back (BaBa) sequence to elucidate local-structures and 1H–1H proximities of the API in a dosage form. The PM-S-RESPDOR-RFDR-BaBa experiment is employed in one- (1D) and two-dimensional (2D) versions to selectively detect the 1H ssNMR spectrum of l-cysteine (10.6 ​wt% or 0.11 ​mg) in a commercial formulation, and compared with the spectra of neat l-cysteine recorded using a standard BaBa experiment. The 2D 1H double-quantum−single-quantum (DQ-SQ) spectrum of the API (l-cysteine)-detected pharmaceutical tablet is in good agreement with the 2D 1H DQ-SQ spectrum obtained from the pure API molecule. Furthermore, the sensitivity and robustness of the experiment is examined by selectively detecting 1H{14N} signals in an amino acid salt, l-histidine.H2O.HCl.

Modeling pharmaceutical emissions and their toxicity-related effects in life cycle assessment (LCA): A review.

Over the last few decades, worldwide detection of active pharmaceutical ingredients (APIs) in aquatic environments and the associated toxicological effects on wildlife and human health have become a matter of public and scientific debate. While life cycle assessment (LCA) and life cycle impact assessment (LCIA) models are increasingly used to assess the potential eco- and human-toxicological effects of chemical emissions, few studies have looked into the issue of modeling pharmaceutical emissions specifically and their toxicity-related effects in an LCA context. This paper reviews the state of the art to inventory and characterize API emissions in LCA with the goal to identify relevant gaps and challenges. A search for 208 environmentally relevant APIs in 2 life cycle inventory (LCI) databases revealed a meager representation of this group of chemicals. Similarly, the LCIA model USEtox was found to include characterization factors (CFs) for less than 60 APIs. First approaches to model API emissions in LCA were identified on the basis of an examination of 40 LCA case studies in the pharmaceutical sector and in the field of wastewater treatment. Moreover, CFs for 79 additional APIs, expressing their ecotoxicity and/or human toxicity potential, were gathered from literature. An analysis of the variability of API-CFs in different LCIA models showed a variation of about 2-3 orders of magnitude. Based on the review results, 3 main gaps in the modeling and characterization of API emissions in an LCA context were identified: (1) incomplete modeling of API flows and API emissions along the life cycle of human pharmaceuticals, especially during their use and end-of-life phase, (2) limited API coverage in existing LCIA toxicity models, and (3) missing pharma-specific impact pathways (e.g., endocrine disruption and antibiotic resistance) in existing LCIA models. Recommendations to tackle these gaps are provided, and priority action steps are discussed. Integr Environ Assess Manag 2019;15:6-18. © 2018 SETAC.

Bioaccumulation, uptake, and toxicity of carbamazepine in soil-plant systems.

Since the detection of active pharmaceutical ingredients (APIs) in various environmental media, research has explored the potential uptake and toxicity of these chemicals to species inhabiting these matrices. Specifically, pharmaceuticals, including the antiepileptic API carbamazepine (CBZ), are taken up from soil by a range of plants. Many short-term studies have also suggested that certain APIs induce toxicity in plants. However, the effects of APIs on fruiting plants remain relatively unexplored. The present study investigated the uptake, bioaccumulation, and toxicity of CBZ in Cucurbita pepo (zucchini) from seed to full maturity across a range of CBZ exposure concentrations in soil (0.1-20 mg/kg). Results of biomass, chlorophyll, starch and total nitrogen (N) concentration in C. pepo indicated toxicity at soil concentrations of ≥10 mg/kg. There were clear visual indications of increasing toxicity on leaves, including chlorosis and necrosis, from soil concentrations of 1 up to 20 mg/kg. The present study also revealed novel insights into the effect of CBZ accumulation on C. pepo fruiting: female C. pepo flowers were unable to set fruit when leaf concentrations were ≥14 mg/kg. These findings may have implications for future agricultural productivity in areas where reclaimed wastewater containing APIs is a source of irrigation. Detectable CBZ concentrations were found in edible C. pepo fruit, indicating the possibility of trophic transfer. Environ Toxicol Chem 2018;37:1122-1130. © 2017 SETAC.

Analytical perspectives of chemical adulterants in herbal sexual enhancer drugs

Context: Detection of active pharmaceutical ingredients in herbal drugs has been described in numerous studies. However, few reports have been published in relation to the analysis of counterfeit herbal supplements for the detection of synthetic drugs in Iran. Aims: To analyze herbal drugs used as sexual performance enhancer from forensic and analytical toxicology point of view. Methods: Eighty herbal drugs gathered from herbal shops in Bushehr city, Iran were analyzed. High-performance liquid chromatography and gas chromatography/mass spectrometry were used for detecting and identifying the chemical structures of probable active pharmaceutical ingredients as adulterants. Results: Among 80 samples, 23% contained only sildenafil. Three samples contained sildenafil, tramadol, and diazepam in combination with each other reported for the first time. Conclusions: This study substantiates regular analysis of purported herbal drugs is needed for more effective quality control and health promotion.

Analysis of low molecular weight compounds using MALDI- and LDI-TOF-MS: Direct detection of active pharmaceutical ingredients in different formulations.

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a high throughput, easy to use analytical technique. The simple sample preparation of this technique and its tolerance to the presence of contaminants are among its advantages. In contrast, depending on the matrix used, MALDI can ionize and generates ions in the low m/z range that complicate the interpretation of the spectra of low molecular weight compounds. To address this issue, one can envisage the use of tunable ionic matrices that can reduce the low m/z interferents. In this work, the ionic matrices triethylammonium α-cyano-4-hydroxycinnamate and diisopropylammonium α-cyano-4-hydroxycinnamate were used to directly analyze 14 pharmaceutical drugs in different formulations (coated tablets, noncoated tablets, capsules, and solutions). This methodology enabled the detection of their active compounds with minimum sample preparation, thus providing a straightforward approach for the forensic analysis of pharmaceutical drugs in the quest for detecting counterfeits. LDI-MS experiments were also performed, and the active ingredient in all of the medicines analyzed were detected. However, MALDI-MS spectra for the medicines analyzed herein showed less or no fragmentation than LDI-MS, which makes the analysis easier.

Raman chemical imaging for spectroscopic screening and direct quantification of falsified drugs

Falsified drugs are a threat to the health of patients. The analytical control of such products contributes to the fight against this global issue. Raman chemical imaging is a method that relies on consecutive measurements at the surface of a sample, combining spectroscopy, microscopy and chemometrics. This article explores the capabilities of this analytical technique proposing an innovative methodology with spectroscopic screening for the identification of chemical compounds and the direct quantification of the active substance (without prior calibration). Two chemometric methods were used: Multivariate Curve Analysis − Alternate Least Squares for the qualitative analysis and Direct Classical Least Squares for the quantitative analysis. The methodology was optimized with samples prepared in the laboratory and validation parameters were studied. The methodology was then applied to real (authentic and falsified) samples of Viagra® and Plavix®. Despite the presence of fluorescence emission in some samples, the methodology succeeded in the detection of active pharmaceutical ingredients, and in the discrimination of three salts of clopidogrel (in generic formulations of Plavix®). The quantitative deviation from the reference method ranged from −15% to +24% of the active substance content. This deviation may be considered to be acceptable since it is sufficient for assessing the risk to the health of patients and for quickly alerting the health authorities.

Coupling laser ablation/desorption electrospray ionization to atmospheric pressure drift tube ion mobility spectrometry for the screening of antimalarial drug quality

Significant developments in the field of ambient desorption/ionization mass spectrometry (MS) have led to high-throughput direct analysis and imaging capabilities. However, advances in coupling ambient ionization techniques with standalone drift tube ion mobility spectrometry (DTIMS) have been comparatively slower, despite the attractive ruggedness and simplicity of IMS. In this study, we have developed and characterized a laser ablation/desorption electrospray ionization (LADESI) DTIMS platform, and applied it to the detection of active pharmaceutical ingredients (APIs) in antimalarial tablets collected in developing countries. The overarching goal of this work was to perform an initial evaluation of LADESI DTIMS as a technique with the potential for constituting the core of a portable drug quality-testing platform. The set-up consisted of an IR laser for desorption and an electrospray ionizer for capturing the ablated plume coupled to a high-resolution monolithic resistive glass drift tube ion mobility spectrometer. For more confident API identification, tablet extracts were also investigated via electrospray IM MS to correlate LADESI DTIMS reduced mobility (K(0)) values to m/z values. Overall, it was found that the IR LADESI DTIMS platform provided distinct ion mobility spectral fingerprints that could be used to detect the presence of the expected APIs, helping to distinguish counterfeit drugs from their genuine counterparts.