Mohamed K. Abd El-Rahman

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).

Comparative study of 2-hydroxy propyl beta cyclodextrin and calixarene as ionophores in potentiometric ion-selective electrodes for neostigmine bromide

Three novel neostigmine bromide (NEO) selective electrodes were investigated with 2-nitrophenyl octyl ether as a plasticiser in a polymeric matrix of polyvinyl chloride (PVC). Sensor 1 was fabricated using tetrakis(4-chlorophenyl)borate (TpClPB) as an anionic exchanger without incorporation of an ionophore. Sensor 2 used 2-hydroxy propyl β-cyclodextrin as an ionophore while sensor 3 was constructed using 4-sulfocalix-8-arene as an ionophore. Linear responses of NEO within the concentration ranges of 10(-5) to 10(-2), 10(-6) to 10(-2) and 10(-7) to 10(-2) mol L(-1) were obtained using sensors 1, 2 and 3, respectively. Nernstian slopes of 51.6 ± 0.8, 52.9 ± 0.6 and 58.6 ± 0.4 mV/decade over the pH range of 4-9 were observed. The selectivity coefficients of the developed sensors indicated excellent selectivity for NEO. The utility of 2-hydroxy propyl β-cyclodextrin and 4-sulfocalix[8]arene as ionophores had a significant influence on increasing the membrane sensitivity and selectivity of sensors 2 and 3 compared to sensor 1. The proposed sensors displayed useful analytical characteristics for the determination of NEO in bulk powder, different pharmaceutical formulations, and biological fluids (plasma and cerebrospinal fluid (CSF)) and in the presence of its degradation product (3-hydroxyphenyltrimethyl ammonium bromide) and thus could be used for stability-indicating methods.

Novel potentiometric application for the determination of pantoprazole sodium and itopride hydrochloride in their pure and combined dosage form

Three sensitive and selective polyvinyl chloride (PVC) matrix membrane electrodes were developed and investigated. Sensor I was developed using tetraheptylammonium bromide (THB) as an anion exchanger with 2-nitrophenyl octyl ether (2-NPOE) as a plasticizer for the determination of the anionic drug pantoprazole sodium sesquihydrate (PAN). To determine the cationic drug itopride hydrochloride (ITH), two electrodes (sensors II and III) were developed using potassium tetrakis(4-chlorophenyl) borate (KTCPB) as a cation exchanger with dioctyl phthalate (DOP) as a plasticizer. Selective molecular recognition components, 2-hydroxypropyl-β-cyclodextrin (2-HP βCD) and 4-tert-butylcalix[8]arene (tBC8), were used as ionophores to improve the selectivity of sensors II and III, respectively. The proposed sensors had a linear dynamic range of 1×10(-5) to 1×10(-2) mol L(-1) with Nernstian slopes of -54.83±0.451, 56.90±0.300, and 51.03±1.909 mV/decade for sensors I, II and III, respectively. The Nernstian slopes were also estimated over the pH ranges of 11-13, 3.5-8 and 4-7 for the three sensors, respectively. The proposed sensors displayed useful analytical characteristics for the determination of PAN and ITH in bulk powder, in laboratory prepared mixtures and in combined dosage forms with clear discrimination from several ions, sugars and some common drug excipients. The method was validated according to ICH guidelines. Statistical comparison between the results from the proposed method and the results from the reference methods showed no significant difference regarding accuracy and precision.

Spectrophotometric and spectrodensitometric methods for the determination of rivastigmine hydrogen tartrate in presence of its degradation product.

Three sensitive, selective and precise stability-indicating methods for the determination of the anti-Alzheimers drug, rivastigmine hydrogen tartrate (RIV) in the presence of its alkaline degradation product (major metabolite, NAP 226-90) and in pharmaceutical formulation were developed and validated. The first method is a second derivative (D(2)) spectrophotometric one, which allows the determination of RIV in the presence of its degradate at 262 nm (corresponding to zero crossing of the degradate) over a concentration range of 50-500 microg/ml with mean percentage recovery 100.18 +/- 0.628. The second method is the first derivative of the ratio spectra (DD(1)) by measuring the peak amplitude at 272 nm over the same concentration range as (D(2)) spectrophotometric method, with mean percentage recovery 99.97 +/- 0.641. The third method is a TLC-densitometric one, where RIV was separated from its degradate on silica gel plates using methanol:butanol:H(2)O:ammonia (5:4:1:0.01 v:v:v) as a developing system. This method depends on the quantitative densitometric evaluation of thin layer chromatogram of RIV at 263 nm over a concentration range of 20-160 microg/spot, with mean percentage recovery 100.19 +/- 1.344. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The proposed methods have been successfully applied to the analysis of RIV in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with reference method.

Stability-indicating spectrophotometric and spectrodensitometric methods for the determination of diacerein in the presence of its degradation product.

Three sensitive, selective, and precise stability-indicating methods for the determination of the novel osteoarthritis drug, diacerein (DIA) in the presence of its alkaline degradation product (active metabolite, rhein) and in pharmaceutical formulation were developed and validated. The first method is a first derivative (D(1) ) spectrophotometric one, which allows the determination of DIA in the presence of its degradate at 322 nm (corresponding to zero crossing of the degradate) over a concentration range of 4-40 µg/mL with mean percentage recovery 100.21 ± 0.833. The second method is the first derivative of the ratio spectra (DD(1) ) by measuring the peak amplitude at 352 nm over the same concentration range as (D(1) ) spectrophotometric method, with mean percentage recovery 100.09 ± 0.912. The third method is a TLC-densitometric one, where DIA was separated from its degradate on silica gel plates using ethyl acetate:methanol:chloroform (8:1.5:0.5 v:v:v) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of DIA at 340 nm over a concentration range of 1-10 µg/spot, with mean percentage recovery 100.24 ± 1.412. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The proposed methods have been successfully applied to the analysis of DIA in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with reference method.

A novel approach for spectrophotometric determination of succinylcholine in pharmaceutical formulation via host-guest complexation with water-soluble p-sulfonatocalixarene

Succinylcholine (SUC) is a quaternary ammonium neuromuscular blocking agent. Direct determination of SUC in bulk drugs and formulations is a challenging analytical task due to the lack of a detectable chromophore and sensitive detection techniques. We have exploited both the strong UV absorbance of p-sulfonatocalix[4]arene (SCX4) and its outstanding complexation properties towards quaternary ammonium compounds to determine SUC. The characteristics of a host–guest complexation between SCX4 and SUC were investigated using UV and 1H NMR spectroscopy. The Jobs plot analysis reveals a 1 : 1 stoichiometry of the host–guest complex with a binding affinity Ka of 7.8 × 104 L mol−1. This novel method is based on spectrophotometric measurement of the formed complex peak after resolving the overlap from the host SCX4 spectrum and was used for the quantitation of SUC. The linear range was found to be from 1.0 × 10−5 to 18.0 × 10−5 mol L−1 with a detection limit of 7.3 × 10−6 mol L−1 (2.88 μg mL−1). This method is straightforward and shows high sensitivity. Moreover, it was successfully employed to determine SUC in pharmaceutical formulation. Subsequent statistical analysis of the obtained results and comparison with the official US pharmacopeial benchmark yielded favorable results.

Stability indicating spectrophotometric and spectrodensitometric methods for the determination of diatrizoate sodium in presence of its degradation product.

Three sensitive, selective, and precise stability indicating methods for the determination of the X-ray contrast agent, diatrizoate sodium (DTA), in the presence of its acidic degradation product (highly cytotoxic 3,5 diamino metabolite) and in pharmaceutical formulation were developed and validated. The first method is a first derivative (D1) spectrophotometric one, which allows the determination of DTA in the presence of its degradate at 231.2 nm (corresponding to zero crossing of the degradate) over a concentration range of 2-24 μg/mL with mean percentage recovery 99.95±0.97%. The second method is the first derivative of the ratio spectra (DD1) by measuring the peak amplitude at 227 nm over the same concentration range as D1 spectrophotometric method, with mean percentage recovery 99.99±1.15%. The third method is a TLC-densitometric one, where DTA was separated from its degradate on silica gel plates using chloroform:methanol:ammonium hydroxide (20:10:2 by volume) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of DTA at 238 nm over a concentration range of 4-20 μg/spot, with mean percentage recovery 99.88±0.89%. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The proposed methods have been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives. The results were statistically compared with the official US pharmacopeial method. No significant difference for either accuracy or precision was observed.

A comparative study between three stability indicating spectrophotometric methods for the determination of diatrizoate sodium in presence of its cytotoxic degradation product based on two-wavelength selection

Three sensitive, selective, and precise stability indicating spectrophotometric methods for the determination of the X-ray contrast agent, diatrizoate sodium (DTA) in the presence of its acidic degradation product (highly cytotoxic 3,5-diamino metabolite) and in pharmaceutical formulation, were developed and validated. The first method is ratio difference, the second one is the bivariate method, and the third one is the dual wavelength method. The calibration curves for the three proposed methods are linear over a concentration range of 2-24 μg/mL. The selectivity of the proposed methods was tested using laboratory prepared mixtures. The proposed methods have been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives. The results were statistically compared with the official US pharmacopeial method. No significant difference for either accuracy or precision was observed.

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.

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride

HIGHLIGHTSNovel use of ISEs for simultaneous acquisition of dissolution profiles of binary co‐formulated tablets.ISEs exceptionally provide straight forward way for dissolution testing.No preliminary separation in reference to UV spectrophotometry and HPLC.Promising approach to the ICH and FDA regulatory requirements to perform dissolution tests.Faster, more sensitive, greener with respect to spectroscopic and chromatographic methods. ABSTRACT Acquisition of the dissolution profiles of more than single active ingredient in a multi‐analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off‐line separation‐based chromatographic methods. This contribution adopts a new “Double‐Track” approach with the ultimate goal of advancing the in‐line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real‐time measurements is the key driver for adoption of “green analytical chemistry” (GAC) principles aiming to expand the application of eco‐friendly analytical methods With the aim of performing a side‐by‐side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first “Double‐Track” in‐line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4‐chlorophenyl) borate as a cation exchanger. The second off‐line strategy utilizes a separation‐based HPLC method via off‐line tracking the increase of peak area by UV detection at 220 nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced “Double‐Track” approach regarding GAC principles are highlighted, and the merits of these benign real‐time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described.