Analytical Quality-by-Design principles were used to develop and validate a reverse-phase high-performance liquid chromatography method for the simultaneous quantification of butamirate citrate and chlorpheniramine maleate in pharmaceutical formulations. Box- Behnken Design systematically optimized three critical variables mobile phase pH, flow rate, and column temperature with response surface plots confirming robust chromatographic performance. Using an isocratic mobile phase of ethanol: water (40:60 v/v) containing 0.33% triethylamine and adjusted to pH 6.0 using 1% orthophosphoric acid, separation was accomplished on a Waters Spherisorb cyano column (250 mm × 4.6 mm, 5 μm) at 1.2 mL/min with photodiode array detection at 225 nm. Validation per ICH Q2(R2) demonstrated excellent linearity (r²=0.999) across 112-337 μg/mL and 10-30 μg/mL for both analytes, with percentage recoveries of 99% and 98%, respectively. Environmental sustainability was confirmed through Analytical Eco-scale (score: 80), Analytical Greenness metric (0.69), and Complex Modified Green Analytical Procedure Index (83). Analytical performance was evaluated using the Red Analytical Performance Index (70) and Multi-Color Assessment Tool (72.6%), collectively reflecting strong scope, sensitivity, accuracy, and precision. Reliable quantification of both compounds in pharmaceutical dosage forms is offered by a validated, environmentally friendly approach, supporting routine quality control and research applications.

We report a case of a previously healthy 3-year-old girl who developed acute altered consciousness, agitation, and visual hallucinations consistent with an anticholinergic toxidrome. Initial examinations were unremarkable, and urine immunoassay screening (SIGNIFY™ ER) was negative. Serum analysis by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) identified chlorpheniramine and scopolamine, while excluding other agents. Concentrations were 370 ng/mL for chlorpheniramine and 1 ng/mL for scopolamine, both near reported toxic ranges. An empty blister pack of 22 pediatric motion sickness tablets was found at the patient's home, confirming accidental overdose of an over-the-counter (OTC) anti-motion sickness medication. This case demonstrates the diagnostic utility of high-resolution mass spectrometry in pediatric poisoning, particularly for drugs not detected by routine screening. It represents a rare report documenting quantitative confirmation of both chlorpheniramine and scopolamine in a child, with correlation between serum concentrations and clinical presentation. Scopolamine is highly toxic even at low concentrations, and pediatric cases with measured blood levels are exceedingly rare. Our findings highlight the need to consider additive or synergistic toxicity in OTC formulations containing multiple anticholinergic agents and emphasize the importance of caregiver education regarding the potential risks of OTC medications often perceived as safe.

Hierarchical liposome-in-liposome (LIL) structures enable sophisticated multi-stage drug delivery, their application is however often limited by complex, time-consuming fabrication and the use of organic solvents. Here we report a simple two-step hydration (TSH) method for fabricating stable LIL architectures in aqueous media within 2 h. This process employs ultrasonication for the formation of structurally robust inner liposomes (IL) and gentle hydration for their subsequent encapsulation within outer liposomes (OL), achieving high-quality dual-spacing configurations. Optical microscopy and differential staining verified the structural integrity and physical encapsulation, demonstrating distinct spatial segregation. The functional efficacy and temperature-sensitive release kinetics of the LIL system were validated through the release theory, confirming that the hierarchical membranes confine encapsulated agents and prevent premature leakage below the phase transition temperature (Tphase) of the OL. The programmable stepwise release was demonstrated through a macroscopic hydrogelation model, where crosslinking was triggered only upon the sequential thermal release of the initiator and accelerator. This was further validated by the independent release of commercial drugs, chlorpheniramine maleate and riboflavin sodium phosphate, as confirmed via HPLC analysis. These results validate the TSH-based LIL platform as a versatile and scalable strategy for developing smart, multi-stage delivery vehicles with environment-responsive release profiles.

Many drugs that block voltage-gated K[+] channels encoded by the human Ether-à-go-go-Related Gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically-approved hERG blockers including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism undergirds facilitation. We focus on nifekalant, a Class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblock of these open-yet-blocked channels results in supranormal hERG current. We develop rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generate atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements reveal that agonism-while-blocking undergirds nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

The emergence of novel pharmaceutical formulations requires the establishment of a reliable analytical method that can accurately quantify active ingredients for use in diverse quality control applications. An over-the-counter pharmaceutical combination of phenylephrine hydrochloride (PHE), chlorpheniramine maleate (CPM), and ibuprofen (IBU) is formulated to treat allergy, lessen fever, and relieve congestion. Two efficient and applicable liquid chromatographic methodologies were established, with an emphasis on ecological sustainability while preserving analytical precision and accuracy, in addition system suitability parameters were successfully determined for each method. The first approach involved high-performance thin-layer chromatography (HPTLC) combined with densitometric quantification, employing silica gel HPTLC 60 F254 aluminum sheets as the stationary phase. The developing system comprised ethyl acetate-methanol-aqueous ammonium hydroxide (8.0:2.0:0.1, by volume), and scanning was carried out at 265.0 nm. The respective resolutions (Rs) were 8.44 and 4.57 for PHE, IBU, and CPM, respectively. The second one is high-performance liquid chromatographic methodology (HPLC), whereas, efficient separation was achieved on a Kromasil 60-5-CN column using isocratic elution of 10.0 mM ammonium acetate buffer and ethanol (50: 50, v/v), adjusted with acetic acid to pH 2.5 at a flow rate of 1.3 mL/min, with DAD quantification at 265.0 nm, with overall run time about 6 min to achieve sufficient separation among the target analytes. The resolutions (Rs) were determined to be 7.62 and 3.21 for PHE, CPM, and IBU, respectively. The investigated approaches' performance was validated in adherence to the guidelines established by the International Conference on Harmonization guidelines, confirming its reliability for analytical application. Limit of detection (LOD) values were determined to be 0.02, 0.01, and 0.22 µg/band for PHE, CPM, and IBU, respectively in HPTLC method, whilst in HPLC-DAD method, LOD values were 0.03, 0.01, and 0.24 µg/mL for PHE, CPM, and IBU, respectively. These approaches can concurrently estimate the cited drugs in their raw forms, as well as their pharmaceutical combination. In addition, HPLC can monitor their dissolution profiles. Moreover, the applicability profile and ecological sustainability of the studied approaches were verified via employing up-to-date evaluation tools, along with comparisons against official and reported methodologies.

Background: H1-antihistamines are widely used for allergic and upper respiratory conditions; however, several agents included in this class have been associated with cardiac electrophysiological adverse effects, including QT interval prolongation and torsades de pointes (TdP). These effects are largely exposure-dependent and mechanistically linked to inhibition of cardiac ion channels. Chlorpheniramine maleate (CPM), a first-generation H1-antihistamine, has been implicated in arrhythmic events primarily under conditions of increased systemic exposure, prompting interest in whether alternative routes of administration may lower cardiac risk. Methods: This narrative review integrates mechanistic, preclinical, clinical, pharmacokinetic, and regulatory evidence. Information was extracted from PubMed, Google Scholar, and Scielo using search terms such as cardiotoxicity, chlorpheniramine, QT prolongation, intranasal administration, and cardiac arrhythmias, with no language restriction. Results: Comparative pharmacokinetic evidence shows that, on a dose-normalized basis, intranasal and oral chlorpheniramine exhibit comparable bioavailability; however, in a clinical context, intranasal doses (1.12-2.24 mg) are lower than oral daily doses (4-12 mg/day), resulting in a lower systemic exposure (Cmax and AUC) with intranasal administration. Available pharmacovigilance or epidemiological data have not specifically evaluated intranasal chlorpheniramine, and the number of dedicated safety trials remains limited. Conclusions: Preclinical, in vitro, mechanistic studies suggest that intranasal administration of chlorpheniramine should confer superior cardiac safety compared to the oral route. However, clinical data from human studies directly comparing the cardiac safety of intranasal chlorpheniramine versus systemic chlorpheniramine is extremely limited. More data from clinical trials, case-control studies, and regulatory databases are needed to validate these theoretical claims.

Small (2 to 4 mg), occasional doses of chlorpheniramine are acceptable during breastfeeding. Larger doses or more prolonged use might cause effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug. The nonsedating antihistamines are preferred alternatives, though.

Upper respiratory tract disorders are seriously prevalent disorders that impact people daily all over the world. Antipyretics, analgesics, bronchodilators, antitussives, expectorants, mucolytics, antihistamines, and antibiotics are among the pharmacological classes that are often administered either alone or in combination to treat and manage the symptoms attributed to upper respiratory tract disorders. In the rising era of green analytical chemistry, the development of broad, multi-analyte analytical techniques that can separate and quantify numerous pharmacologically related substances simultaneously is becoming of increasing significance. This work introduces a new, concise, accurate, and robust high performance liquid chromatography method with diode array detection approach for the simultaneous assay of eight substances, namely; Albuterol, Erdosteine, Paracetamol, Amoxicillin, Chlorpheniramine, Guaifenesin and two of the most frequently encountered preservatives that are incorporated in upper respiratory tract medications; Methyl and Propyl Parabens in their bulk and pharmaceutical formulations. An Inertsil octadecyl silane-3 (4.6 × 250 mm, 5 μm) column and a gradient mobile phase system consisting of methanol and 0.025 M potassium dihydrogen orthophosphate buffer (pH 4) were employed to achieve the separation. Chromatograms were detected at 225 nm for Albuterol and Chlorpheniramine, 230 nm for Guaifenesin and Amoxicillin, 236 nm for Erdosteine, 250 nm for Paracetamol, and 256 nm for Methyl and Propyl Parabens using the diode array detector. The suggested approach was successfully verified in compliance with the International Council for Harmonization guidelines with low values of percentage relative error and percentage relative standard deviation (< 2%) and strong correlation coefficients (> 0.9991), demonstrating its good accuracy, precision and linearity. Additionally, an in-depth five-sided examination was conducted to demonstrate the suggested method’s greenness, blueness, violet innovation and sustainability profiles using the analytical GREEnness metric, analytical eco-scale, blue applicability grade index, click analytical chemistry index, violet innovation grade index and white analytical chemistry assessment metrics. This work represents the establishment of a broad spectrum, multianalyte, versatile methodology that would provide an indispensable asset for quality control laboratories in terms of its affordability, speed, sensitivity, and sustainability.

A 66-year-old Japanese man received loxoprofen twice for pain in his right first toe. Systemic pruritus and flushing subsequently appeared, and his body movements became difficult with drowsy consciousness. He was admitted to the intensive care unit, where he was administered epinephrine, prednisolone, and d-chlorpheniramine maleate for hypotension, systemic pruritus, and flushing. Severe hypofibrinogenemia, APTT, PT-INR prolongation, and markedly increased FDP were observed. He was diagnosed with anaphylaxis and disseminated intravascular coagulation (DIC). After a transfusion of FFP and antithrombin concentrates, the coagulopathy rapidly improved. Subsequently, the patient was discharged without any bleeding or thrombotic episodes six days after admission.

Chlorpheniramine maleate is a commonly used antiallergic drug; excessive ingestion can cause adverse effects such as hallucinations, tachycardia, central nervous system depression, and organ dysfunction. However, rhabdomyolysis induced by this drug is rarely reported. This study presents a case of rhabdomyolysis secondary to chlorpheniramine maleate poisoning.

Photo-thermal stability is a key factor in pharmaceutical development, as light and heat can compromise drug safety and efficacy. Conventional methods such as HPLC, DSC, and GC-MS are slow, require complex pretreatment, and often treat photolysis and thermolysis separately. Here, we demonstrate microwave plasma torch mass spectrometry (MPT-MS) as a rapid, pretreatment-free approach for simultaneous analysis of photo-thermal stability and degradation pathways. Using direct desorption/ionization of intact tablets, six pharmaceuticals: chlorpheniramine, ornidazole, metronidazole, tinidazole, acetaminophen, and theophylline, were analyzed on average in 2 min with milligram-level sample consumption. Their stability order matched reported thermal decomposition data, validating the method. MPT-MS revealed unique photo-thermal fragmentation patterns, including nitroimidazole-specific [M + H-29][+] ions not accessible by electrospray ionization. The more MPT power the pharmaceutical molecules require to reach 80% abundance of the precursor ion, the more stable the pharmaceuticals are. The technique also resolved stability differences among isomers such as xylenes and nitrobenzenes. These results highlight MPT-MS as a powerful high-throughput tool for rapid screening of drug candidates, providing both stability ranking and mechanistic insight.