Occurrence, ecological risk assessment and prioritization of pharmaceuticals and abuse drugs in estuarine waters along the São Paulo coast, Brazil.

The pollution of the surface waters by pharmaceuticals and personal care products (PPCPs) has attracted worldwide attention, but data regarding their occurrence and potential risks for the aquatic biota on tropical coastal rivers of South America are still scarce. In this context, the occurrence and the preliminary ecological risk assessment of eleven pharmaceuticals of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine) were investigated, for the first time, in five rivers of São Paulo, southeast Brazil, covering a coastline of about 140 km, namely Perequê River, Itinga River, Mongaguá River, Itanhaém River and Guaraú River. Although these five rivers are born in well-preserved areas of the Atlantic rainforest biome, on its way to sea and when they cross the urban perimeter, they receive untreated sewage discharges containing a complex mixture of contaminants. In addition, a "persistence, bioaccumulation and toxicity" (PBT) approach allowed to pre-select the priority PPCPs to be monitored in this coastline. Identification of several PPCPs in the samples was done using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Ten PPCPs were successfully quantified in all five rivers, namely caffeine (9.00-560.00 ng/L), acetaminophen (

First report on the occurrence of pharmaceuticals and cocaine in the coastal waters of Santa Catarina, Brazil, and its related ecological risk assessment.

The worldwide occurrence of pharmaceuticals and personal care products (PPCPs) in aquatic ecosystems is reason for public concern. These emerging micropollutants include a large and diverse group of organic compounds, with continuous input, high environmental persistence and potential threat to biota and human health. The aim of this study was to evaluate, for the first time, the occurrence of twenty-seven PPCPs of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine), in the coastal waters of Santa Catarina, southern Brazil. Water samples were taken in November 2020, during the low tide periods, at eight sampling points located along the coast of Santa Catarina, covering its entire geographical extension. Sampling was carried out in triplicate and at different depths of the water column. Nine compounds were detected through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS): caffeine (12.58-119.80 ng/L), diclofenac (1.34-7.92 ng/L), atenolol (1.13-2.50 ng/L), losartan (0.43-3.20 ng/L), acetaminophen (0.21-10.04 ng/L), orphenadrine (0.07-0.09 ng/L), cocaine (0.02-0.17 ng/L), benzoylecgonine (0.01-1.1 ng/L) and carbamazepine (0.02-0.27 ng/L). The highest occurrence of these compounds was detected in the northern and central coastal region of Santa Catarina, namely in Penha and Palhoça cities. Moreover, the risk assessment showed that almost compounds (atenolol, benzoylecgonine, carbamazepine, cocaine and orphenadrine) presented no ecological risk in the recorded concentrations. However, a few compounds suggest low (caffeine and diclofenac) to moderate (acetaminophen and losartan) risk taking into consideration the acute and chronic effects for the three trophic levels (algae, crustacean and fish) tested. These compounds are usually found in areas with high population density, aggravated by tourism, because of the sanitary sewage and solid waste. Although in low concentrations, the occurrence of these chemical compounds can imply deleterious effects on the environmental health of Santa Catarina coastal zone, and therefore deserve more attention by the public authorities and environmental agencies.

Different techniques for overlapped UV spectra resolution of some co-administered drugs with paracetamol in their combined pharmaceutical dosage forms.

Six simple, specific, accurate and precise spectrophotometric methods were developed for the first time analysis of some co-administered drugs with paracetamol in their mixture form without prior separation. Paracetamol & orphenadrine citrate were determined by using dual wavelength, bivariate, ratio difference, ratio derivative and mean centering of ratio spectra methods. Paracetamol & caffeine were determined by using ratio difference, ratio derivative and mean centering of ratio spectra methods. Paracetamol & diclofenac sodium were determined by using advanced absorption subtraction, ratio difference, ratio derivative and mean centering of ratio spectra methods. All of these methods were validated according to ICH guidelines where accuracy, precision, repeatability and robustness were found to be within the accepted limits. Advantages and limitations of each method are demonstrated and statistical comparison between the proposed methods was performed.

Development and Validation of Chromatographic Methods for Simultaneous Determination of Paracetamol, Orphenadrine Citrate and Caffeine in Presence of P-aminophenol; Quantification of P-aminophenol Nephrotoxic Impurity Using LC-MS/MS.

Three chromatographic methods were developed, optimized and validated for Paracetamol (PAR), Orphenadrine citrate (Or.cit) and Caffeine (CAF) determination in their mixture and in presence of PAR toxic impurity; P-aminophenol (PAP) in tablets. The first method is based on a thin layer chromatography combined with densitometry. Separation was achieved using silica gel 60 F254 TLC plates and dichloromethane:methanol:acetone:glacial acetic acid (9:1:0.5:0.3, v/v/v) as a developing system at 230 nm. The second method is based on high-performance liquid chromatography with diode array detection. The proposed compounds are separated on a reversed phase C18 analytical column using phosphate buffer (pH 9; 0.05 M) and methanol (80:20, v/v) at 1.2 mL/min. Linear regressions are obtained in the range of 1-500 µg/mL, 25-1000 µg/mL and 1-400 µg/mL for PAR, Or.cit and CAF, respectively. Quantification of the toxic PAP is carried out using LC-MS-MS by electrospray ionization in the positive mode using triple quadrupole mass spectrometry. The limit of quantification for PAP is 1 ng/mL. All methods are validated according to the ICH guidelines and successfully applied to determine PAR, Or.cit, CAF and PAP in pure powder and in combined tablets dosage form without interference from excipients.

Fast determination of codeine, orphenadrine, promethazine, scopolamine, tramadol, and paracetamol in pharmaceutical formulations by capillary electrophoresis.

Paracetamol is an active ingredient commonly found in pharmaceutical formulations in combination with one of the following compounds: codeine, orphenadrine, promethazine, scopolamine, and tramadol. In this work, we propose a unique analytical method for determination of these active ingredients in pharmaceutical samples. The method is based on capillary electrophoresis with capacitively coupled contactless conductivity detection. The separation was achieved on a fused silica capillary (50 cm total length, 40 cm effective length, and 50 µm id) using an optimized background electrolyte composed of 20 mmol/L ß-alanine/4 mmol/L sodium chloride/4 µmol/L sodium hydroxide (pH 9.6). Each sample can be analyzed in a single run (≤2 min) and the limits of detection were 2.5, 0.62, 0.63, 2.5, 15, and 1.6 µmol/L for scopolamine, tramadol, orphenadrine, promethazine, codeine, and paracetamol, respectively. Recovery values for spiked samples were between 94 and 104%.

A tentative component analysis of Norjizak: A new abused drug in Iran.

Norjizak is a new drug abused in the past few years in Iran with symptoms and complications distinct from other common forms of drug and characterized by higher rate of mortality. The present study aims to analyze the chemical components of this substance. Five samples were obtained from abusers referring from different areas of Tehran to a treatment clinic. All samples were 2 ml vials with yellowish fluid. Thin Layer Chromatography (TLC) was performed first to analyze the samples semi-quantitatively and the quantitative levels of components were then explored using high-performance liquid chromatography (HPLC). TLC revealed steroid (in form of betamethasone), heroin, codeine, morphine and thebaine in all five samples. Four samples contained acetaminophen and two samples contained caffeine. None of them contained amphetamine, benzodiazepine, tricyclic antidepressant, aspirin, barbiturates, tramadol and buprenorphine. HPLC revealed that heroin, codeine, morphine and thebaine constituted the narcotic foundation in all samples. In addition, the heroin to acetylcodeine ratio was significantly lower in three samples, which indicates their higher toxicity. The results of the present study on the chemical components of Norjizak showed that this substance is an opiate one similar to heroin and the heroin-based crack prevalent in Iran which contains betamethasone.

Application of normalized spectra in resolving a challenging Orphenadrine and Paracetamol binary mixture.

Normalized spectra have a great power in resolving spectral overlap of challenging Orphenadrine (ORP) and Paracetamol (PAR) binary mixture, four smart techniques utilizing the normalized spectra were used in this work, namely, amplitude modulation (AM), simultaneous area ratio subtraction (SARS), simultaneous derivative spectrophotometry (S(1)DD) and ratio H-point standard addition method (RHPSAM). In AM, peak amplitude at 221.6nm of the division spectra was measured for both ORP and PAR determination, while in SARS, concentration of ORP was determined using the area under the curve from 215nm to 222nm of the regenerated ORP zero order absorption spectra, in S(1)DD, concentration of ORP was determined using the peak amplitude at 224nm of the first derivative ratio spectra. PAR concentration was determined directly at 288nm in the division spectra obtained during the manipulation steps in the previous three methods. The last RHPSAM is a dual wavelength method in which two calibrations were plotted at 216nm and 226nm. RH point is the intersection of the two calibration lines, where ORP and PAR concentrations were directly determined from coordinates of RH point. The proposed methods were applied successfully for the determination of ORP and PAR in their dosage form.

Selective spectrophotometric methods for determination of ternary mixture with overlapping spectra: a comparative study.

Comparable double divisor ratio spectra derivative, area under curve of derivative ratio and mean centering of ratio spectra spectrophotometric methods were introduced for determination of orphenadrine citrate (ORPH), caffeine (CAF) and aspirin (ASP); a combination for symptomatic relief of mild to moderate pain of acute musculoskeletal disorders; with evident accuracy and precision. The suggested methods have the advantage over the previously published spectrophotometric method for determination of the same combination in that they did not require a preliminary separation step and able to resolve the ternary mixture, with severe overlapping spectra, with competent sensitivity and selectivity. The recommended methods allow the determination of ORPH, CAF and ASP in the range of 2-32, 2-28 and 3-28 µg mL(-1), respectively. The validity of the proposed methods was examined by analysis of different laboratory prepared mixtures of ORPH, CAF and ASP and assay of their tablet formulation where reliable results were obtained. Statistical analysis between the suggested spectrophotometric methods and the reported HPLC method using student's-t and F-ratio tests reveals that the suggested methods are as accurate and precise as the reported one.

Validated stability-indicating reversed-phase-HPLC method for simultaneous determination of orphenadrine citrate, caffeine and aspirin.

New, simple, rapid and precise reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of orphenadrine citrate, caffeine and aspirin in presence of aspirin degradation products, orphenadrine citrate and caffeine process related impurities, and excipients. Good resolution and quantization were achieved on reversed-phase column [Phenomenex™ Luna ODS C(18) (25 cm×4.6 mm, 5 µm particles)]. Gradient elution based on; eluant [A]: 0.1% triethylamine in aqueous potassium dihydrogen phosphate buffer (50 mM; pH 3.0), while as, eluant [B]: acetonitrile, at a flow rate of 1.5 mL min(-1). UV quantitation was set at 215 nm. Linearity was exhibited for orphenadrine citrate, caffeine and aspirin within 0.5-150, 0.5-360 or 0.7-301 µg mL(-1) ranges, respectively. Satisfactory validation results were ascertained in terms of low limits of quantiation (6.33×10(-2)-7.94×10(-2)), mean percentage recovery (98.9-101.4%), precision (<2%) and robustness. The proposed method was proved to be specific, robust and accurate for the determination of cited drugs in pharmaceutical preparations in presence of their degradation products.

Spectrophotometric determination of phenylephrine HCl and orphenadrine citrate in pure and in dosage forms.

A simple and rapid spectrophotometric methods have been estimated for the microdetermination of phenylephrine HCl (I) and orphenadrine citrate (II). The proposed methods are based on the formation of ion-pair complexes between the examined drugs with alizarine (Aliz), alizarine red S (ARS), alizarine yellow G (AYG) or quinalizarine (Qaliz), which can be measured at the optimum lambda(max). The optimization of the reaction conditions is investigated. Beer's law is obeyed in the concentration ranges 2-36 microgram ml(-1), whereas optimum concentration as adopted from Ringbom plots was 3.5-33 microgram ml(-1). The molar absorptivity, Sandell sensitivity, and detection limit are also calculated. The correlation coefficient was >/=0.9988 (n=6) with a relative standard deviation of

Analysis of hospital-formulated oral liquid preparations by second derivative ultraviolet spectroscopy.

Second derivative ultraviolet spectrophotometric methods have been devised for the analysis of hospital-formulated oral liquid preparations. These rapid techniques are useful in the routine quality control of oral liquid formulations where direct spectrophotometric determination of the drug analyte is precluded by interference from formulation excipients and colouring agents. This report describes examples in which the active principles of a dipipanone mixture, a methadone mixture and an orphenadrine syrup were determined by derivative spectroscopy. In each case spectral interference from formulation excipients was abolished. The accuracy, precision and specificity of each method has been established.

Isothermal gas chromatographic analysis of diphenhydramine after direct injection onto a fused-silica capillary column.

The packed column injector of a gas chromatograph was modified to accommodate direct injection by syringe onto a wide-bore fused-silica capillary column. No changes were made to the nitrogen-phosphorus detector. The resultant configuration combines fast separations with precise quantitations. The analysis of diphenhydramine in serum is presented as an application. Chromatographic separation of diphenhydramine and orphenadrine (internal standard) from caffeine and other endogenous material takes 2 min. Serum diphenhydramine concentrations are presented for six volunteers following a 50-mg oral dose.

Sensitive and specific gas chromatographic and extraction method for the determination of orphenadrine in human body fluids.

A gas chromatographic and extraction method for the assay of orphenadrine in plasma and urine has been developed, in which diphenhydramine is used as the internal standard. The procedure involves extraction with isopentane and alkali flame ionization (nitrogen) detection. Orphenadrine N-oxide and N-dealkylated orphenadrine did not interfere with the analysis. Orphenadrine concentrations down to 1 ng/ml can be determined. Application in a pharmacokinetic/bioavailability study is reported.

Forensic toxicology of some orphenadrine-related deaths.

Toxicological data for orphenadrine in ten cases of fatal poisoning are presented together with results for a further eight cases in which orphenadrine was present in combination with alcohol or another drug. Collapse and convulsions occur within an hour of ingestion of an overdose and death supervenes soon after. Autopsy blood concentrations of orphenadrine in such acute fatal poisonings range from 5.5-37 mug/ml. The unchanged drug was found in the bile and urine and the concentrations in the liver, lung and kidney, though differing between cases, were of the same order in any one case.