Maha M. Abdelrahman

Simultaneous determination of Cinnarizine and Domperidone by area under curve and dual wavelength spectrophotometric methods

Accurate, selective and sensitive spectrophotometric methods have been developed and validated for simultaneous determination of Cinnarizine and Domperidone, a binary mixture with overlapping spectra, without preliminary separation. These methods include area under the curve (AUC) and dual wavelength spectrophotometry. For the AUC method, the area under curve of mixture solutions in the wavelength ranges 241-258 nm and 280-292 nm were selected for determination of Cinnarizine and Domperidone and by applying Cramers rule, concentration of each drug was obtained. In dual wavelength method, two wavelengths were selected for each drug in a way so that the difference in absorbance is zero for another drug. Domperidone shows equal absorbance at 240.2 nm and 273.2 nm, where the differences in absorbance were measured for the determination of Cinnarizine. Similarly, differences in absorbance at 230.8 nm and 259.2 nm were measured for determination of Domperidone. The proposed methods were applied for determination of Cinnarizine and Domperidone over the concentration ranges of 2-20 and 2-22 μg mL(-1), respectively. The suggested methods were validated as per USP guidelines and the results revealed that they are reliable, reproducible and precise for routine use with short analysis time. The results obtained by the proposed methods were statistically compared to the reported method, and there was no significant difference between them regarding both accuracy and precision.

Spectrophotometric and spectrodensitometric determination of Clopidogrel Bisulfate with kinetic study of its alkaline degradation

Four sensitive, selective and precise stability-indicating methods for the determination of Clopidogrel Bisulfate (CLP) in presence of its alkaline degradate and in pharmaceutical formulations were developed and validated. Method A is a second derivative (D(2)) spectrophotometric one, which allows the determination of CLP in presence of its alkaline degradate at 219.6, 270.6, 274.2 and 278.4 nm (corresponding to zero-crossing of the degradate) over a concentration range of 4-37 microg mL(-1) with mean percentage recoveries 99.81+/-0.893, 99.72+/-0.668, 99.88+/-0.526 and 100.46+/-0.646, respectively. CLP can be determined in the presence of up to 65% of its degradate. D(2) method was used to study the kinetic of CLP alkaline degradation that was found to follow a first-order reaction. The t(1/2) was 6.42 h while K (reaction rate constant) was 0.1080 mol/h. Method B is the first derivative of the ratio spectra (DD(1)) spectrophotometric method, by measuring the peak amplitude at 217.6 and 229.4 nm using acetonitrile and CLP can be determined in the presence of up to 70% of its degradate. The linearity range was 5-38 microg mL(-1) with mean percentage recoveries 99.88+/-0.909 and 99.70+/-0.952, respectively. Method C based on the determination of CLP by the bivariate calibration depending on simple mathematic algorithm which provides simplicity and rapidity. The method depends on quantitative evaluation of the absorbance at 210 and 225 nm over a concentration range 5-38 microg mL(-1) with mean percentage recovery 99.27+/-1.115. CLP can be determined in the presence of up to 70% of its degradate. Method D is a TLC-densitometric one, where CLP was separated from its degradate on silica gel plates using hexane:methanol:ethyl acetate (8.7:1:0.3, v/v/v) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of CLP at 248 nm over a concentration range of 0.6-3 microg/band with mean percentage recovery 99.97+/-1.161. CLP can be determined in the presence of up to 90% of its alkaline degradate. The selectivity of the proposed methods was checked using laboratory prepared mixtures. The proposed methods have been successfully applied to the analysis of CLP in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with the official method.

In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients

Abstract Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients.

Modelling of in-vitro and in-vivo performance of aerosol emitted from different vibrating mesh nebulisers in non-invasive ventilation circuit

&NA; Substituting nebulisers by another in non‐invasive ventilation circuit (NIV) involves many process variables which must be adjusted to ensure patient optimum therapy. However, there is a doubt when nebulisers use the same technology. Data mining technology based on artificial neural networks and genetic algorithms were used here to model in‐vitro inhalation process and predict bioavailability from inhaled doses delivered by three different vibrating mesh nebulisers (VMNs) in NIV. Modelling of data indicated that in‐vitro performance of VMNs was dependent mainly on fine particle fraction, mass median aerodynamic diameter (MMAD), total emitted dose (TED) and to lesser extent on nebuliser type. Ex‐vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by TED. In‐vivo model showed that amount of salbutamol deposited into the lung (0.5 hQ) and amount absorbed systemically (24 hQ) were dependent directly on MMAD and TED. Female patients showed higher 24 hQ values than males. Nebuliser type affected TED, 0.5 hQ but not 24 hQ values. Results indicate suitability of VMNs in achieving appropriate in‐vitro inhalation performance model. The results also, indicate that the three VMNs are comparable and can be interchanged with no fear of any additional toxicity. Graphical abstract Figure. No caption available.

In vitro aerodynamic characteristics of aerosol delivered from different inhalation methods in mechanical ventilation

Abstract Aerodynamic characteristics of aerosol delivery during invasive mechanical ventilation (IMV) are mostly determined by inserting cascade impactor in the circuit. Impactor might have some effect on airflow within IMV. Hence, the aim of the present study was to develop and evaluate new in vitro aerodynamic characterization methodology without affecting airflow in IMV. Breathing simulator was set in standard adult IMV circuit with inspiratory and expiratory pressures of 20 and 5 cm H2O, 1:3 inspiratory–expiratory ratio, 15 breaths min−1, and tidal volume of 500 ml. Two ml of salbutamol solution containing 10,000 μg was nebulized using three different vibrating mesh nebulizers (VMNs) and Sidestream jet nebulizer (JET). Sixteen-metered doses, containing 100 μg salbutamol each, were delivered using three different spacers. Each device was placed in inspiration limb of Y-piece of ventilator tubing. Aerodynamic characteristics of aerosol delivered were measured using cooled Andersen cascade impactor, with mixing inlet connected to it. VMNs used had significantly more total mass in the impactor (p < .001) and fine particle dose (p < .001) compared to JET. Spacers used had higher total mass in the impactor percent (p < .001) and fine particle fraction compared to nebulizers. The in vitro IMV methodology setting suggested here showed encouraging results in comparison of different aerosol delivery systems in intubated patient.

In-vitro/in-vivo comparison of inhaled salbutamol dose delivered by jet nebulizer, vibrating mesh nebulizer and metered dose inhaler with spacer during non-invasive ventilation

ABSTRACT Background: Patients receiving noninvasive ventilation (NIV) may benefit from medical aerosol, but most guidance on dosing with different aerosol devices is limited to in-vitro studies. The study was designed to in-vitro, ex-vivo, and in-vivo compare aerosol delivery during bilevel NIV with three types of aerosol generators: metered dose inhaler with AeroChamber-MV spacer (AC), Aerogen Pro vibrating mesh nebulizer (PRO), and Sidestream jet nebulizer (SIDE). Materials and Method: A bilevel ventilator with dry single limb circuit and fixed expiratory port was set in spontaneous mode with initial inspiratory and expiratory pressures of 20 and 5 cmH20, 1:3 inspiratory-expiratory ratio, and 15 breaths.min−1. Aerosol generators were placed proximal to facial mask of NIV chronic obstructive pulmonary disease (COPD) patients. 1 mL salbutamol nebulizer solution (5 mg/mL) was nebulized using PRO and SIDE. 12MDI doses, containing 100μg salbutamol each, were delivered using AC. In-vitro aerosol fate and aerodynamic droplet characteristics, in-vivo amount of salbutamol excreted 30 mins and pooled up to 24 h post inhalation in urine from 12 COPD patients (as indices of pulmonary deposition and systemic absorption, respectively) and amount of salbutamol deposited on ex-vivo filters (expected inhalable amount) was determined. Results: The in-vitro, in-vivo and ex-vivo testing showed that PRO had better aerosol delivery compared to SIDE (p < 0.01). However, with smaller nominal dose MDI with AC resulted in similar aerosol delivery to PRO suggesting better aerosol delivery stress on careful attention and proper delivery by health care provider. Conclusions: These similarities and differences between the three aerosol generators tested suggest that aerosol delivery methods should be carefully chosen or substituted in non-invasive ventilated patients.

Validated stability indicating methods for determination of nitazoxanide in presence of its degradation products

Three sensitive, selective and reproducible stability-indicating methods are presented for determination of nitazoxanide (NTZ), a new anti-protozoal drug, in presence of its degradation products. Method A utilizes the first derivative of ratio spectra spectrophotometry by measurement of the amplitude at 364.4 nm using one of the degradation products as a divisor. Method B is a chemometric-assisted spectrophotometry, where principal component regression (PCR) and partial least squares (PLS) were applied. These two approaches were successfully applied to quantify NTZ in presence of degradation products using the information included in the absorption spectra in the range 260–360 nm. Method C is based on the separation of NTZ from its degradation products followed by densitometric measurement of the bands at 254 nm. The separation was carried out on silica gel 60F254, using chloroform–methanol–ammonia solution–glacial acetic acid (95:5:1:1 by volume, pH=5.80) as a developing system. These methods are suitable as stability-indicating methods for the determination of NTZ in presence of its degradation products either in bulk powder or in pharmaceutical formulations. Statistical analysis of the results has been carried out revealing high accuracy and good precision.

Spectrophotometric and spectrodensitometric determination of triamterene and xipamide in pure form and in pharmaceutical formulation.

Sensitive and validated UV-spectrophotometric, chemometric and TLC-densitometric methods were developed for determination of triamterene (TRM) and xipamide (XIP) in their binary mixture, formulated for use as a diuretic, without previous separation. Method A is the isoabsorptive point spectrophotometry, in which TRM concentration alone can be determined at its λ(max) while XIP concentration can be determined by measuring total concentration of TRM and XIP at their isoabsorptive point followed by subtraction. Method B is the ratio subtraction spectrophotometry, where XIP can be determined by dividing the spectrum of the mixture by the spectrum of TRM (as a divisor) followed by subtracting the constant absorbance value of the plateau region, then finally multiplying the produced spectrum by the spectrum of the divisor, while TRM concentration can be determined at its λ(max). Method C is a chemometric-assisted spectrophotometry where classical least squares, principal component regression, and partial least squares were applied. Method D is a TLC-densitometry; this method depends on quantitative densitometric separation of thin layer chromatogram of TRM and XIP using silica gel plates at 254 nm. The proposed methods were successfully applied for the analysis of TRM and XIP in their pharmaceutical formulation and the results were statistically compared with the established HPLC method.

Spectrophotometric determination of isopropamide Iodide and trifluoperazine hydrochloride in presence of trifluoperazine oxidative degradate

Four sensitive, selective and precise stability indicating methods for the determination of isopropamide iodide (ISO) and trifluoperazine hydrochloride (TPZ) in their binary mixture and in presence of trifluoperazine oxidative degradate (OXD). Method A is a derivative spectrophotometric one, where ISO was determined by first derivative (D(1)) at 226.4 nm while TPZ was determined by second derivative (D(2)) at 270.2 nm. Method B is the first derivative of the ratio spectra (DD(1)) spectrophotometric method, ISO can be determined by measuring the peak amplitude at 227.4 nm using 5 microg mL(-1) of OXD as a divisor, while TPZ can be determined by measuring the peak amplitude at 249.2 and 261.4 nm using 15 microg mL(-1) of ISO as a divisor. Method C is the isoabsorptive spectrophotometric method. This method allows determination of ISO and TPZ in their binary mixture by measuring total concentration of ISO and TPZ at their isoabsorptive point at lambda(229.8) nm (Aiso1) while TPZ concentration alone can be determined at lambda(max) 311.2 nm, then ISO concentration can be determined by subtraction. On the same basis TPZ can be determined in presence of ISO and OXD, where OXD concentration alone was determined by measuring the peak amplitude at lambda(281.6) and lambda(309.4) nm while total concentration of TPZ and OXD was determined at their isoabsorptive points at (Aiso2 = 270.2 nm), (Aiso3 = 310.6 nm) and (Aiso4 = 331.8 nm) then TPZ concentration was determined by subtraction. Method D is the multivariate calibration techniques [the classical least squares (CLS), principal component regression (PCR) and partial least squares (PLS)], using the information contained in the absorption spectra of ISO, TPZ and OXD mixtures. The selectivity of the proposed methods was checked using laboratory prepared mixtures. The proposed methods have been successfully applied to the analysis of ISO and TPZ in pharmaceutical dosage form without interference from other dosage form additives and the results were statistically compared with the reported method.

Superior spectrophotometric method for determination of a ternary mixture with overlapping spectra

Ambroxol hydrochloride (AMB), guaifenesin (GUF) and theophylline (THP) are co-formulated together for treatment of common cold and influenza. A newly developed spectrophotometric method; namely; ratio isoabsorptive point and ratio difference in subtracted spectra (RIDSS) spectrophotometric method was applied for resolving this ternary mixture with overlapping spectra in two steps. The proposed method is based on dividing the ternary mixture of the studied drugs by the spectrum of AMB to get the division spectrum, from which concentration of AMB can be obtained by measuring the amplitude values in the plateau region at 310 nm. Then the amplitude value of the plateau region at 310 nm was subtracted from the division spectrum and THP concentration was obtained by measuring the difference in amplitude values at 235 and 268 nm (corresponding to zero difference of GUF) while the total concentration of THP and GUF in the mixture was measured at their isoabsorptive point in the division spectrum at 235 nm (Aiso). GUF concentration is then obtained by subtraction. Validity of the method was tested by application to laboratory prepared mixtures and pharmaceutical formulations containing the studied drugs. Statistical comparison between the results of the proposed method and those of the reported HPLC method showed no significant difference.