Fentanyl is now the primary driver of the current opioid crisis. Fentanyl and its analogues are subject to the Controlled Substances Act of 1970, the Controlled Substances Analogue Enforcement Act of ...1986 (Federal Analogue Act), state laws, international treaties, and the laws of foreign countries. The appearance of novel psychoactive substances led to further legislative developments in scheduling. New fentanyl analogues proliferated in a manner previously unseen since about 2016. Overdose deaths of these fentanyl analogues prompted the Drug Enforcement Administration to reactively emergency schedule each new fentanyl analogue as it appeared. The international community also acted. Finally, on February 6, 2018, a proactive temporary (emergency) class‐wide scheduling of fentanyl‐related substances was implemented based upon the fentanyl core structure to save lives. This action spurred a similar action in China. Fentanyl analogues fell dramatically in the marketplace, despite further increases in fentanyl itself. Congress temporarily extended this scheduling, but it will soon expire. Opposition to permanent class‐wide was lodged due to concerns over law enforcement overreach, inadequate Health and Human Services input, and hindrance of research. This paper reaffirms the importance of a class‐based scheduling strategy while also arguing for increased research of schedule I controlled substances.
Favipiravir finished dosage was approved for emergency use in many countries to treat SARS‐CoV‐2 patients. A specific, accurate, linear, robust, simple, and stability‐indicating HPLC method was ...developed and validated for the determination of degradation impurities present in favipiravir film‐coated tablets. The separation of all impurities was achieved from the stationary phase (Inert sustain AQ‐C18, 250 × 4.6 mm, 5‐μm particle) and mobile phase. Mobile phase A contained KH2PO4 buffer (pH 2.5 ± 0.05) and acetonitrile in the ratio of 98:2 (v/v), and mobile phase B contained water and acetonitrile in the ratio of 50:50 (v/v). The chromatographic conditions were optimized as follows: flow rate, 0.7 mL/min; UV detection, 210 nm; injection volume, 20 μL; and column temperature, 33°C. The proposed method was validated per the current International Conference on Harmonization Q2 (R1) guidelines. The recovery study and linearity ranges were established from the limit of quantification to 150% optimal concentrations. The method validation results were found to be between 98.6 and 106.2% for recovery and r2 = 0.9995–0.9999 for linearity of all identified impurities. The method precision results were achieved below 5% of relative standard deviation. Forced degradation studies were performed in chemical and physical stress conditions. The compound was sensitive to chemical stress conditions. During the study, the analyte degraded and converted to unknown degradation impurities, and its molecular mass was found using the LC–MS technique and established degradation pathways supported by reaction of mechanism. The developed method was found to be suitable for routine analysis of research and development and quality control.
A method for separation and determination of 32 fentanyl‐related substances, including seven sets of isomeric fentanyl analogues, was developed using ultra‐high‐performance liquid chromatography ...coupled with quadrupole‐orbitrap high‐resolution mass spectrometry. The collision energy, chromatographic column, and mobile phase were optimized. All compounds were efficiently flushed out of a universal C18 column with a soft gradient consisting of solvent A (2 mM ammonium formate and 0.1% formic acid in water) and solvent B (2 mM ammonium formate and 0.1% formic acid in methanol) in only 20 min, achieving excellent resolution. Detection and analysis were carried out simultaneously in the positive ion mode using the full scan and data‐dependent tandem mass spectrometry modes with a normalized collision energy of 40. The method was validated in terms of limit of detection, limit of quantification, linearity, accuracy, and precision. For all fentanyl‐related substances, the limit of detection (0.5 ng/mL) and limit of quantification (1 ng/mL) were adequate for screening and quantification in daily drug control. Calibration curves for all compounds were established in the range of 1–500 ng/mL. The intra‐ and interday precision (RSD%) were within 0.4–2.3 and 0.7‐2.7%, respectively. The accuracy ranged from 99 to 106%. The method was applied to analyze seized drug samples.
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•Spray drying enables production of s-SMEDDS with high SMEDDS loading (up to 67% w/w).•Mixing time of dispersion before spray drying has impact on process yield.•Carrier type has ...impact on process yield, drug content and s-SMEDDS characteristics.•Carvedilol forms amides with fatty acids from the oily components of SMEDDS.
In this study, various formulations of solidified carvedilol-loaded SMEDDS with high SMEDDS loading (up to 67% w/w) were produced with the spray drying process using various porous silica-based carriers. The process yield was improved with higher atomization gas flow rate during the spray drying process and with prolonged mixing time of dispersion of liquid SMEDDS and solid porous carriers prior to the spray drying process. Depending on the choice of the carrier and the SMEDDS:carrier ratio in solid SMEDDS, different drug loading, self-microemulsifying properties, drug release rates, and released drug fractions were obtained. The products exhibited fast drug release due to preserved self-microemulsifying properties and the absence of crystalline carvedilol, which was confirmed with XRD and Raman mapping. A decrease in drug content during the stability study was observed and investigated. This was at least partially attributed to the chemical degradation of the drug. Key degradation products determined by the LC-MS method were amides formed by in situ reaction of carvedilol with fatty acids present in the oily phase of SMEDDS.
Pharmaceutical drug analysis (PDA), besides quantifying drugs and related substances (RS), can enrich drug discovery (DD) by suggesting new leads. PDA may be extended towards comparative in-silico ...predictions for drugs and RS. This may lead to the assessment of drug likeliness of nontoxic RS as an incentive to study them further. This review overviews the in-silico profiling of drugs and RS as an innovative scope. It may help extending classical PDA with in-silico determinations to widen horizon from regulatory toxicology evaluation towards drug discovery. The virtual screening of selected RS may indicate them as potential DD leads. The extension of impurity profiling, after toxicity evaluation, to ADME estimation, QSAR studies, molecular docking, and bioactivity prediction, has widened the purposes of drug analysis. The RS which are predicted to have low toxicity may be in-silico exploited for their therapeutic potential prior to entering into the DD path.
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•A recent trend, evolving pharmaceutical analysis since a decade, is explored.•Extension of impurity profiling to in-silico studies is discussed.•Impurities/related substances, less toxic than the drug, are particularly focused.•Bridging pharmaceutical drug analysis to modern drug discovery is reviewed.•Fate of drug impurities beyond analysis to use them in drug discovery is discussed.
This article provides recommendations for documenting an analytical procedure for the determination of related substances by high-performance liquid chromatography in a product specification file ...(PSF). The article contains a description of specific aspects and a template for the typical contents and layout of the PSF section dedicated to related substances. A unified approach to the PSF content and layout will ensure error-free testing, reliable results, and streamlined regulatory assessments.
In the present study, a reliable LC-QTOF-MS method was developed and employed for the separation and characterization of process-related substances and forced degradation products of Lurasidone ...hydrochloride. The chromatographic separation was carried out using an Agilent Poroshell 120 Bonus-RP C18 column (100 mm × 4.6 mm, 2.7 µm) and a mobile phase consisting of a gradient elution of 10 mM ammonium formate solution and methanol. The degradation studies followed the guidelines outlined in ICH Q1A (R2). It was observed that Lurasidone hydrochloride exhibited instability under photolytic, alkaline, and oxidative stress conditions, while remaining relatively stable under acidic and thermal stresses. Through positive ESI-QTOF mass spectrometric analysis, fourteen related compounds in total, including both process-related and stress degradation products, were identified based on the accurate masses of parent and product ions and calculated elemental compositions. Amongst these substances, nine had not been previously reported, and their formation mechanisms were speculated. The process-related substances were further confirmed by NMR spectra determination, and suggestions were proposed to eliminate them. This study highlights the potential for monitoring and controlling related substances during the manufacturing processes, providing valuable insights for process optimization and quality control of Lurasidone hydrochloride.
•LC/QTOF/MS analysis was utilized to characterize both process-related substances and the degradants of Lurasidone.•A total of fourteen, including nine previously unreported lurasidone-related substances, were successfully identified.•The mass fragmentation pathways for Lurasidone and its related substances were accurately elucidated.•Strategies for monitoring and controlling manufacturing-related substances were suggested.
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