Outcome of Early Hemostatic Intervention in Children With Sepsis and Nonovert Disseminated Intravascular Coagulation Admitted to PICU: A Randomized Controlled Trial.

OBJECTIVES: Evaluation of the outcome of early hemostatic management of disseminated intravascular coagulopathy in patients with severe sepsis/septic shock admitted to PICU, before the development of clinically overt disseminated intravascular coagulopathy. DESIGN: Prospective interventional, open label randomized controlled clinical trial. SETTING: PICU at Alexandria University Children's Hospital. PATIENTS: The study included 80 patients with proven severe sepsis/septic shock in nonovert disseminated intravascular coagulopathy stage. They were randomly assigned into two groups (group 1 and group 2). INTERVENTIONS: Specific intervention was applied for group 1 (plasma transfusion, low-dose unfractionated heparin, and tranexamic acid). MEASUREMENTS: All patients had assessment of Pediatric Index of Mortality 2 score, Pediatric Logistic Organ Dysfunction score, inotropic score, routine laboratory, and hemostatic tests including fibrin degradation products and d-dimers. Disseminated intravascular coagulopathy risk assessment scores were calculated on daily basis. RESULTS: Mortality rate was significantly higher in group 2. Progression to overt disseminated intravascular coagulopathy was significantly more common among group 2 patients than group 1 (45% and 10%, respectively) (p < 0.0001). Disseminated intravascular coagulopathyRisk Assessment Scores were significantly higher on the second and fifth days among group 2 patients. The initial specific hemostatic intervention was the only significant predictor of survival and prevention of progression to overt disseminated intravascular coagulopathy. CONCLUSIONS: Our results suggest that early use of a combination of fresh frozen plasma transfusion, low-dose heparin, and tranexamic acid in children with severe sepsis/septic shock in the "window of opportunity" before the development of overt disseminated intravascular coagulopathy stage was associated with better outcome for survival and prevention of progression to overt disseminated intravascular coagulopathy, with no increase in bleeding risk. Larger multicenter studies are needed to further prove this practice.

Optimization of localized surface plasmon resonance hot spots in surface-enhanced infrared absorption spectroscopy aluminum substrate as an optical sensor coupled to chemometric tools for the purity assay of quinary mixtures.

Surface-enhanced infrared absorption spectroscopy offers an alternative to conventional IR spectroscopy and utilizes the signal enhancement exerted by the plasmon resonance of nanostructured metal thin films. Citrate-capped silver nanoparticles were prepared in a single-step method, and their morphology was identified using transmission electron microscopy, scanning electron microscopy, ultraviolet/visible spectrophotometry, and Zetasizer. The nanoparticles generated were deposited on the surface of cheap aluminum slides for different durations aiming for the selection of the best time producing a thin film, suitable to act as a lab-on-a-chip SEIRA substrate. These substrates were coupled to partial least squares regression tools for simultaneous resolving of the quinary mixture in commercial dosage forms of bisoprolol, perindopril, bisoprolol acid degradation product, bisoprolol alkali degradation product, and perindoprilat in concentration ranges of 15-75, 60-300, 15-55, 12-60, and 20-80 µg/mL with limits of detection values of 0.69, 3.43, 0.97, 1.25, and 1.09 µg/mL, respectively. Overall, we could demostrate that the localized surface plasmon resonance sensor coupled to chemometrics provides cheap, simple, selective, multiplex, rapid, and molecular specific procedures for impurity detection, which would be beneficial in many applications for quality control and quality accuracy of active pharmaceutical ingredients.

Point-of-care diagnostics for drugs of abuse in biological fluids: application of a microfabricated disposable copper potentiometric sensor.

The major objective of this work was to develop a portable, disposable, cost-effective, and reliable POC solid-state electrochemical sensor based on potentiometric transduction to detect benzodiazepine abuse, mainly diazepam (DZP), in biological fluids. To achieve that, microfabricated Cu electrodes on a printed circuit board modified with the conducting polymer poly(3-octylthiophene) (POT) have been employed as a substrate. This polymer was introduced to enhance the stability of the potential drift (0.9 mV/h) and improve the limit of detection (0.126 nmol mL-1). Nernstian potentiometric response was achieved for DZP over the concentration range 1.0 × 10-2 to 5.0 × 10-7 mol L-1 with a slope of 55.0 ± 0.4 mV/decade and E0 ~ 478.9 ± 0.9. Intrinsic merits of the proposed sensor include rapid response time (11 ± 2 s) and long life time (3 months). In order to enhance the selectivity of the potentiometric sensor towards the target drug and minimize any false positive results, calix[4]arene (CX4) was impregnated as an ionophore within the PVC plastic ion-sensing membrane. The performance of the POC sensors was assessed using electrochemical methods of analysis and electrochemical impedance spectroscopy as a surface characterization tool. The studied sensors were applied to the potentiometric determination of DZP in different biological fluids (plasma, urine, saliva, and human milk) in the presence of its metabolite with an average recovery of 100.9 ± 1.3%, 99.4 ± 1.0%, 101.8 ± 1.2%, and 99.0 ± 2.0%, respectively. Graphical abstract.

Clinical Outcomes Associated with Fluid Overload in Critically Ill Pediatric Patients.

BACKGROUND: Fluid overload (FO) has been accused as being one of the ICU problems affecting morbidity and mortality. The aim of the study was to assess the effect and critical threshold of FO that is related to mortality. METHODS: This prospective observational study was conducted in a pediatric ICU. All patients admitted (n = 203) during 12 months with a length of stay more than 48 h were recruited. RESULTS: FO was found to be related to mortality (p = 0.025) but was not proved to be an independent risk factor of fatal outcome by the logistic regression model. This raises the suspicion about any cause-effect relationship between FO and mortality. Even though, FO was statistically a fair discriminator of death (AUC = 0.655, p = 0.0008) and a cutoff level of FO was set at 7%. Kaplan-Meier curve showed that cumulative of survival differed significantly between groups of patients with FO more and less than 7% (p = 0.002). CONCLUSION: Frequent and accurate monitoring of FO is crucial among critically ill patients. The present study suggested a threshold of 7% FO beyond which a more conservative regimen of fluid administration might improve patients' outcome.

Different techniques for the determination of tofisopam.

Five simple and sensitive methods were developed for the determination of tofisopam (TF). The first four are stability-indicating depending on the determination of TF in the presence of its degradation product, while the fifth depended on the determination of TF via its degradation product. Method A was based on first and second derivative spectrophotometry, D and 2D, measuring the amplitude at 298 and 332 nm in the case of 1D and at 312 and 344 nm in the case of 2D. Method B depended on measuring the peak amplitude of the first derivative of the ratio spectra 1DD at 336 nm. Method C was based on difference spectrophotometry by measuring deltaA at 366 nm. Method D was a TLC method using silica gel 60 F254 plates, the optimized mobile phase ethyl acetate-methanol-ammonium hydroxide 10% (8.5 + 1.0 + 0.5, v/v/v), and quantification by densitometric scanning at 315 nm. In method E, spectrofluorometry was applied for the determination of TF via its degradation product; maximum emission was 383 nm when excitation was 295 nm. Linearities were obtained in the concentration range 2-20 microg/mL for methods A, B, and C and 2-20 microg/band and 0.2-1.6 microg/mL for D and E, respectively. In method A, the mean recoveries were 99.45 +/- 0.287 and 100.28 +/- 0.277% at 298 and 332 nm, respectively, in the case of 1D and 99.40 +/- 0.245% and 99.50 +/- 0.292% at 312 and 344 nm, respectively in the case of 2D. The mean recovery was 100.03 +/- 0.523% at 366 nm in method B. Method C showed mean recovery of 100.20 +/- 0.642%. Recoveries for methods D and E were 98.98 +/- 0.721 and 100.25 +/- 0.282%, respectively. The degradation product was obtained in acidic stress condition, separated, and identified by IR and mass spectral analysis, from which the degradation product was confirmed and the degradation pathway was suggested. The first four methods were specific for TF in the presence of different concentrations of its degradation product. The five proposed methods were successfully applied for the determination of TF in Nodeprine tablets. Statistical comparison among the results obtained by these methods and that obtained by the official method for the determination of the drug was made, and no significant differences were found.

Evaluation of colonization index and (1,3)- ß- D glucan as diagnostic tools of invasive candidiasis in a pediatric Intensive Care Unit.

PURPOSE: The study aimed to evaluate the corrected colonization index (CCI) and (1, 3)-ß-D Glucan (BDG) in diagnosis of Invasive Candidiasis (IC) in critically ill pediatric patients. METHODS: A prospective observational study in a tertiary care (PICU) were surveyed for Candida colonization and CCI was calculated. For cases with suspicious clinical presentation, samples were cultured, and double(1,3) ß-D- glucan (BDG) performed. RESULTS: According to the European Organization for Research and Treatment of Cancer EORTC case definition for critically ill non-neutropenic patients, only 7.14 % (9/188) were diagnosed as IC (4 proven and 5 probable cases). The combined use of CCI with BDG proved to have excellent discriminative power AUC= 0.946, improved sensitivity 87.5 % and specificity 85.71 %. CONCLUSION: The key in diagnosis of IC relies in compiling proofs from the clinical context, high CCI (≥ 0.4) and BDG.

Greenness assessment of two chromatographic methods developed for the determination of Mupirocin in two binary mixtures along with its impurity.

Two simple, accurate and precise chromatographic methods have been developed and validated for estimating Mupirocin (MUP) in two binary mixtures. Mixture (1); with Fluticasone propionate (FLU) together with two of their impurities, namely; Pseudomonic acid-D (Pseud-D) and Fluticasone impurity C (FIC). Mixture (2); with Mometasone furoate (MF) along with Pseud-D impurity. High performance thin layer chromatography (HPTLC-densitometry) and high performance liquid chromatography (RP-HPLC) were the two proposed methods. In the HPTLC method, good separation of both mixtures was achieved by using HPTLC plates pre-coated with silica gel 60 F254 as stationary phase and the mobile phase consisted of toluene: chloroform: ethanol at a ratio of (5: 4: 2, by volume). The detection was carried out at 220 nm for MUP and 254 nm for FLU, MF, Pseud-D and FIC. In the HPLC method, chromatographic separation was carried out using Agilent Eclipse XDB (250 mm×4.6 mm, 5 µm) C18 column. For mixture (1), a mobile phase of methanol: sodium di-hydrogen phosphate (pH 3.0) was applied in stepwise gradient elution starting at ratios of (50: 50, v/v) and then switching to (80: 20, v/v) after 7 min at a flow rate of 1 mL.min- 1. Detection was performed using diode array detector at 220 nm for MUP and Pseud-D and 240 nm for FLU and FIC. For mixture (2), the same mobile phase was used, but in isocratic elution in the ratio (80: 20, v/v) at flow rate of 1 mL.min- 1 and detection at 220 nm for MUP and Pseud-D and 248 nm for MF. The two methods successfully separated the cited drugs and were used to determine the drugs in pure form as well as pharmaceutical dosage forms. Validation was done as per International Council on Harmonization guidelines. Furthermore, the greenness of the proposed methods compared to the reported method, was evaluated as per the National Environmental Method Index, analytical Eco scale, Green Analytical Procedure Index and Analytical Greenness metric approaches.

Can Lactate Clearance Predict Mortality in Critically Ill Children?

Serial evaluation of blood lactate, including lactate clearance, may have greater value over single measurement at the time of presentation. The rationale of the current study was to evaluate the use of lactate clearance after 6 hours of admission to pediatric intensive care unit (PICU) as a predictor of mortality in critically ill children. A prospective observational study was conducted in a nine-bed PICU of a tertiary care teaching hospital over a period of 6 months. Lactate levels were measured in arterial blood samples of 76 patients at the time of admission and 6 hours later. According to calculated lactate clearance, patients were divided into group A (lactate clearance more than 0) which included 71% of patients and group B (lactate clearance ≤0) which included 29% of patients. Lactate level at admission was a poor predictor of mortality (area under receiver operating characteristic curve [AUC] = 0.519, p = 0.789). Lactate clearance after 6 hours of admission was a significant predictor of mortality (AUC = 0.766, p < 0.001). Using Kaplan-Meier survival curve, overall survival was significantly better among group A ( p < 0.001). Using multivariate logistic regression model, lactate clearance after 6 hours (odds ratio = 0.98, 95% confidence interval [CI]: 0.96-0.99) and The Pediatric Index of Mortality 2 (PIM2) score (odds ratio = 4.7, 95% CI: 1.85-12.28) had independent prognostic significance with regard to mortality ( p = 0.030, 0.001 respectively). We conclude that lactate clearance after 6 hours of admission can predict mortality in critically ill children.

Advanced chemometric methods as powerful tools for impurity profiling of drug substances and drug products: Application on bisoprolol and perindopril binary mixture.

Impurity profiling has a rising importance nowadays due to the increased health problems associated with impurities and degradation products found in several drug substances and formulations. Three advanced, accurate and precise chemometric methods were developed as impurity profiling methods for a mixture of bisoprolol fumarate (BIS) and perindopril arginine (PER) with their degradation products which represent drug impurity or a precursor to such impurity. The methods applied were Partial Least Squares (PLS-1), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Artificial Neural Networks (ANN). Genetic Algorithm (GA) was used as a variable selection tool to select the most significant wavelengths for the three chemometric models. For proper analysis, a 5-factor 5-level experimental design was used to establish a calibration set of 25 mixtures containing different ratios of the drugs and their degradation products (impurities). The validity of the proposed methods was assessed using an independent validation set. The designed models were able to predict the concentrations of the drugs and the degradation products/impurities in the validation set and pharmaceutical formulation. The proposed methods presented a powerful alternative to traditional and expensive chromatographic methods as impurity profiling tools.

Microfabricated potentiometric sensor for personalized methacholine challenge tests during the COVID-19 pandemic.

The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary function labs or doctors' offices. Methacholine (MCH) acts by inducing airway tightening/bronchoconstriction, and more importantly, MCH is hydrolyzed by cholinesterase enzyme (ChE). Recently, the American Thoracic Society raised concerns about pulmonary function testing during the COVID-19 pandemic due to recently reported correlation between cholinesterase and COVID-19 pneumonia severity/mortality, and it was shown that cholinesterase levels are reduced in the acute phase of severe COVID-19 pneumonia. This work describes the microfabrication of potentiometric sensors using copper as the substrate and chemically polymerized graphene nanocomposites as the transducing layer for tracking the kinetics of MCH enzymatic degradation in real blood samples. The in-vitro estimation of the characteristic parameters of the MCH metabolism [Michaelis-Menten constant (Km) and reaction velocity (Vmax)] were found to be 241.041 µM and 56.8 µM/min, respectively. The proposed sensor is designed to be used as a companion diagnostic device that can (i) answer questions about patient eligibility to perform methacholine challenge tests, (ii) individualize/personalize medical dosing of methacholine, (iii) provide portable and inexpensive devices allowing automated readouts without the need for operator intervention (iv) recommend therapeutic interventions including intensive care during early stages and reflecting the disease state of COVID-19 pneumonia. We hope that this methacholine electrochemical sensor will help in assaying ChE activity in a "timely" manner and predict the severity and prognosis of COVID-19 to improve treatment outcomes and decrease mortality.

Green spectrophotometric methods for the determination of a binary mixture of lidocaine hydrochloride and cetylpyridinium chloride in the presence of dimethylaniline.

Three green, simple, precise, accurate and sensitive spectrophotometric methods were developed for the determination of a binary mixture of lidocaine hydrochloride (LDC) and cetylpyridinium chloride (CPC) in the presence of dimethylaniline (DMA). In the three methods, the interference of DMA spectrum is eliminated using the ratio subtraction method. Method (A) depended on determining LDC and CPC by measuring the first derivative of the ratio spectra (1DD) at 271.0 and 268.4 nm, respectively. Method (B) was the ratio difference (RD), based on dividing the absorption spectrum of the binary mixture by a standard spectrum of CPC or LDC, then measuring the amplitude difference of the ratio spectra (∆P) between 231.2 and 240.0 nm for LDC and between 242.8 and 258.0 nm for CPC. Method (C) based on the application of dual wavelength coupled with the isoabsorptive point method. This was achieved by measuring the absorbance difference (∆A) between 243.0 and 268.6 nm for the determination of LDC, followed by application of isoabsorptive point method comprised of measurement the total content of the mixture of LDC and CPC at their isoabsorptive point at 240.0 nm. The content of CPC was obtained by subtraction. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures containing different ratios of LDC and CPC in presence of DMA. The proposed methods displayed useful analytical characteristics for the determination of LDC and CPC in bulk powder and their combined dosage form. The obtained results were statistically compared with those obtained by the official methods, showing no significant difference with respect to accuracy and precision.

Stability-Indicating RP-HPLC and CE Methods for Simultaneous Determination of Bisoprolol and Perindopril in Pharmaceutical Formulation: A Comparative Study.

Two fast, accurate and selective stability-indicating methods were developed and validated for the simultaneous determination of bisoprolol, perindopril and three of their possible degradation products. The first proposed method was a gradient reversed phase-high-performance liquid chromatography (HPLC) method, whereas the second was a capillary electrophoresis method. The structures of the obtained degradation products were elucidated using infrared and mass spectrometry. They were also confirmed to be either a drug impurity in the British Pharmacopoeia or a precursor to such impurity. The linearity for bisoprolol and perindopril was achieved in the range of 1-20 µg mL-1 and 5-30 µg mL-1 for HPLC and capillary electrophoresis methods, respectively. The proposed methods were validated according to the International Conference on Harmonisation guidelines. The HPLC method proved to be more sensitive and succeeded in the quantitative determination of the obtained degradation products. Also, it was able to quantify perindopril impurity up to three times lower than the desired limit set by the British Pharmacopoeia. They were successfully employed in the determination of bisoprolol and perindopril in their combined pharmaceutical formulation.

A comparative study of two analytical techniques for the simultaneous determination of amprolium HCl and ethopabate from combined dosage form and in presence of their alkaline degradation.

Chemometric and separation-based techniques (HPLC) are the most applicable and versatile analytical techniques for the analysis of multicomponent mixtures, in the present contribution, a comparison was highlighted between the two analytical techniques of utmost importance as stability indicating assays: UV-spectrophotometry and HPLC-UV focusing on the greenness of each for the simultaneous determination of amprolium HCl (AMP) and ethopabate (ETHOP) in the presence of their alkaline degradation products. The first method was chemometric methods applied were PLS-1, GA-PLS and GA-ANN. To compare the prediction ability of the models, a 4-factor 5-level experimental design was used to establish a calibration set of 25 mixtures containing different ratios of the drugs and their degradation products. The validity of the proposed methods was assessed using an independent validation set of 5 mixtures. The comparison between the different models showed the superiority of ANN model in solving the highly overlapped spectra of the quaternary mixture, yet using inexpensive and easy to handle instruments like the UV-VIS spectrophotometer. The ANN method was used for the quantitative analysis of the drugs in pharmaceutical dosage form via handling the UV spectral data. The second method was based on liquid chromatographic HPLC determination of AMP and ETHOP using C18 column (250 × 4.6 mm2)-PRONTOSIL 5 µm, a mobile phase consisting of methanol: Hexane sulphonic acid sodium salt at (pH = 3.4 ± 0.2) adjusted by orthophosphoric acid (55: 45 v/v). Quantitation was achieved with UV detection at 270 nm at temperature 24 °C. Linearity, accuracy and precision were found to be acceptable over the concentration range of 10.0-70.0 and 1.0-25.0 µg·mL-1 for AMP and ETHOP, respectively. The proposed methods could be successfully applied for the routine analysis of the studied drugs either in their pure bulk powders or in their pharmaceutical preparations without any preliminary separation step. The results obtained were statistically compared with those obtained by applying the reported method.

Functionalized Fe3O4 Magnetic Nanoparticle Potentiometric Detection Strategy versus Classical Potentiometric Strategy for Determination of Chlorpheniramine Maleate and Pseudoephedrine HCl.

Nanosized adsorbents when used in potentiometric methods of analysis usually show better performance rather than the traditional potentiometric approach; this is attributed to the high specific surface area of the nanomaterial used in addition to the lack of internal diffusion resistance, thus improving their adsorption capacity. In the presented work, a rapid and sensitive potentiometric determination of chlorpheniramine maleate (CPM) and pseudoephedrine hydrochloride (PSE) in pure form, in pharmaceutical preparation, and in biological fluid was developed based on functionalized magnetic nanoparticles (Fe3O4). This strategy was compared with the classical potentiometric strategy. Three types of sensors were constructed using phosphotungstic acid (PTA), ß-cyclodextrin (ß-CD), and ß-cyclodextrin-conjugated Fe3O4 magnetic nanoparticles for the potentiometric determination of each of CPM and PSE. The prepared sensors were characterized in regards to their composition, life duration, working pH range, and response time. The sensors have demonstrated promising selectivity to CPM and PSE in the presence of pharmaceutical formulation excipients, plasma matrix, and a diversity of both organic and inorganic interfering materials. The developed sensors have displayed good responses. Statistical comparison of the achieved results with a reported method has revealed no significant difference regarding both accuracy and precision.

Association of lactate/albumin ratio level to organ failure and mortality in severe sepsis in a pediatric intensive care unit in Egypt.

Moustafa AA, Antonios MAM, Abdellatif EM, Hussain AH. Association of lactate/albumin ratio level to organ failure and mortality in severe sepsis in a pediatric intensive care unit in Egypt. Turk J Pediatr 2018; 60: 691-701. This study aimed at investigating the lactate to albumin ratio, as a newly introduced biomarker of multiple organ dysfunction syndrome (MODS) and mortality compared to the classic lactate clearance in pediatric patients. We designed a prospective cohort study and 155 patients with severe sepsis or septic shock admitted to a Pediatric Intensive Care Unit were included, starting from January 2016 to March 2017. The data of 119 patients who completed the study, were analyzed. Results revealed that lactate clearance (6h, 24h) was significantly lower and lactate/albumin ratio (0h, 6h, 24h) was significantly higher in patients who developed MODS and in those who passed away. The univariate logistic regression showed that both lactate clearance and lactate/albumin ratio were significant prognostic factors of MODS and mortality. According to the AUC, lactate/albumin ratio (0h, 6h, 24h) showed better discrimination of MODS development (with AUC of 0.729, 0.814, and 0.819, respectively) compared to lactate clearance (6h, 24h; AUC of 0.738, and 0.672, respectively). Again the lactate/albumin ratio (0h, 6h, 24h) showed better discriminatory power of mortality (0.681, 0.741, and 0.856, respectively) compared to the lactate clearance (6h, 24h; 0.638 and 0.77, respectively). The Youden Index specified a lactate/albumin ratio (0h, 6h, 24h) of 1.17, 1.07, and 1.1 to be the cut-off discriminating values, respectively. The Kaplan-Meier curves revealed that the cumulative of survival is significantly better for the group of patients with a lactate/albumin ratio less than the cut-off values. It was concluded that lactate/albumin ratio is a better discriminator of MODS development and mortality than lactate clearance in pediatric patients with severe sepsis or septic shock.

Novel Approach for the Simultaneous Determination of Carbinoxamine Maleate, Pholcodine, and Ephedrine Hydrochloride Without Interference from Coloring Matter in an Antitussive Preparation Using Smart Spectrophotometric Methods.

The presence of coloring matters in syrups usually interferes with the spectrophotometric determination of active pharmaceutical ingredients. A novel approach was introduced to eliminate the interference of sunset yellow (coloring matter) in Cyrinol syrup. Smart, simple, accurate, and selective spectrophotometric methods were developed and validated for the simultaneous determination of a ternary mixture of carbinoxamine maleate, pholcodine, and ephedrine hydrochloride in syrup. Four of the applied methods used ratio spectra: successive derivative subtraction coupled with constant multiplication, successive derivative of ratio spectra, ratio subtraction coupled with ratio difference, and ratio spectra continuous wavelet transforms zero-crossing. In addition, a method that was based on the presence of an isosbestic point, the amplitude summation method, was also established. A major advantage of the proposed methods is the simultaneous determination of the mentioned drugs without prior separation steps. These methods were successfully applied for the determination of laboratory-prepared mixtures and a commercial pharmaceutical preparation without interference from additives, thus proving the selectivity of the methods. No significant difference regarding both accuracy and precision was observed upon statistical comparison of the results obtained by the proposed methods with each other and with those of official or reported ones.

Stability-indicating methods for the determination of disopyramide phosphate.

Four methods were developed for the determination of intact disopyramide phosphate in the presence of its degradation product. In the first and second methods, third-derivative spectrophotometry and first derivative of the ratio spectra were used. For the third-derivative spectrophotometric method, the peak amplitude was measured at 272 nm, while for the derivative ratio spectrophotometric method, disopyramide phosphate was determined by measuring the peak amplitude at 248 and 273 nm. Both methods were used for the determination of disopyramide phosphate in the concentration range 12.5-87.5 microg/mL, with corresponding mean recovery 100.8 +/- 0.7% for the first method and 99.9 +/- 0.7% and 99.6 +/- 0.7% for the second method at 248 and 273 nm, respectively. In the third method, an ion selective electrode (ISE) was fabricated using phosphotungstic acid as an anionic exchanger, PVC as the polymer matrix, and dibutylsebacate as a plasticizer. The ISE was used for the determination of disopyramide phosphate in pure powder form in the concentration range 10(-2)-10(-5) M. The slope was found to be 58.5 (mV/decade), and the average recovery was 99.9 +/- 1.6%. The fourth method depended on the quantitative densitometric determination of the drug in concentration range of 0.25-2.5 microg/spot using silica gel 60 F245 plates and ethyl acetate-chloroform-ammonium hydroxide (85 + 10 + 5, v/v/v) as the mobile phase, with corresponding mean accuracy of 100.3 +/- 1.1%. The 4 proposed methods were found to be specific for disopyramide phosphate in presence of up to 80% of its degradation product for the spectrophotometric methods, 90% of its degradation for the densitometric method, and 40% for the ISE method. The 4 proposed procedures were successfully applied for the determination of disopyramide phosphate in Norpace capsules. Statistical comparison between the results obtained by these methods and the official method of the drug was done, and no significant differences were found.

Evaluation of multivariate calibration models with different pre-processing and processing algorithms for a novel resolution and quantitation of spectrally overlapped quaternary mixture in syrup.

A novel approach for the resolution and quantitation of severely overlapped quaternary mixture of carbinoxamine maleate (CAR), pholcodine (PHL), ephedrine hydrochloride (EPH) and sunset yellow (SUN) in syrup was demonstrated utilizing different spectrophotometric assisted multivariate calibration methods. The applied methods have used different processing and pre-processing algorithms. The proposed methods were partial least squares (PLS), concentration residuals augmented classical least squares (CRACLS), and a novel method; continuous wavelet transforms coupled with partial least squares (CWT-PLS). These methods were applied to a training set in the concentration ranges of 40-100 µg/mL, 40-160 µg/mL, 100-500 µg/mL and 8-24 µg/mL for the four components, respectively. The utilized methods have not required any preliminary separation step or chemical pretreatment. The validity of the methods was evaluated by an external validation set. The selectivity of the developed methods was demonstrated by analyzing the drugs in their combined pharmaceutical formulation without any interference from additives. The obtained results were statistically compared with the official and reported methods where no significant difference was observed regarding both accuracy and precision.

Novel strategy for online monitoring of the degradation kinetics of propantheline bromide via a calixarene-based ion-selective electrode.

Propantheline bromide (PB) is a hydrolysable anti-cholinergic drug. A novel strategy for the online monitoring of PB degradation kinetics catalysed by hydroxyl ions is presented. This is achieved by the incorporation of an on-site PB-selective electrode constructed using as an ionophore. This sensor was used to track the hydrolysis of PB by continuous measurement of the decrease in the produced emf over time. The use of this new technique provides real-time observation and yields a continuous profile of the hydrolysis behaviour of PB under various pH conditions as well as the temperature dependency of each reaction. Moreover, a great advantage of this proposed on-line system is its higher accuracy for rate constant estimation relative to other off-line methods. This kinetic data analysis permitted the determination of the hydrolysis activation energy and prediction of the drug shelf life. The estimated activation energy from Arrhenius plot was 20.77 kcal mol(-1).

Spectrophotometric methods for simultaneous determination of ternary mixture of amlodipine besylate, olmesartan medoxomil and hydrochlorothiazide.

Four, accurate, precise, and sensitive spectrophotometric methods are developed for the simultaneous determination of a ternary mixture containing amlodipine besylate (AM), olmesartan medoxomil (OL) and hydrochlorothiazide (HZ), where AM is determined at its λ(max) 364.6 nm ((0)D), while (OL) and (HZ) are determined by different methods. Method (A) depends on determining OL and HZ by measuring the second derivative of the ratio spectra ((2)DD) at 254.4 and 338.6 nm, respectively. Method (B) is first derivative of the double divisor ratio spectra (D-(1)DD) at 260.4 and 273.0 nm for OL and HZ, respectively. Method (C) based on successive spectrophotometric resolution technique (SSRT). The technique starts with the ratio subtraction method then measuring OL and HZ at their isoabsorptive point at 260.0 nm, while HZ is measured using the amplitude of first derivative at 335.2 nm. Method (D) is mean centering of the ratio spectra (MCR) at 252.0 nm and 220.0 nm for OL and HZ, respectively. The specificity of the developed methods is investigated by analyzing laboratory prepared mixtures containing different ratios of the three drugs and their combined dosage form. The obtained results are statistically compared with those obtained by the official or reported methods, showing no significant difference with respect to accuracy and precision at p=0.05.