Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector

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Isotachophoretic separation of alkylsulfonates and determination of methanesulfonic acid as main component and as trace component in pharmaceutical drug substances

Alkylsulfonates from methanesulfonic acid to decanesulfonic acid were separated by isotachophoresis with conductivity detection in a common electrolyte system at pH 4.8. The electrolyte system consisted of 10 mM HCl buffered with epsilon-aminocaproic acid (pH 4.8) and 0.1% methylhydroxyethylcellulose (MHEC) acting as the leading electrolyte. The terminating electrolyte was 20 mM caproic acid also containing 0.05% MHEC. Current settings of 250 microA for the first and 50 microA for the second capillary were applied. On one hand, the method was applied to the determination of the content of methanesulfonate as the salt forming agent (mesilate) in a recently registered drug substance. The results obtained by ITP were compared with an orthogonal titration method. On the other hand, due to the column-coupling configuration of the electrophoretic instrument, the method could be extended to the trace determination in the ppm range in order to monitor methanesulfonic acid as an impurity in a drug substance. The validation confirmed the linearity of the method between 1 and 10 mg/l, limits of detection and quantification below 1 mg/l, recovery rates from 92.4 to 95.4%, and repeatability with a R.S.D. of 3.8% (six runs with a 4 mg/l spiked sample). Finally, three batches of a newly produced drug substance could be checked for methanesulfonic acid giving results of below 0.0014% (concentration related to the drug substance).     

Flow-injection chemiluminescent determination of metoclopramide hydrochloride in pharmaceutical formulations and biological fluids using the [Ru(dipy)(3)(2+)]-permanganate system

A flow-injection (FI) methodology using (2,2′-dipyridyl) ruthenium(II) [Ru(dipy)₃²⁺] chemiluminescence (CL) was developed for the rapid and sensitive determination of metoclopramide hydrochloride. The method is based on the CL reaction of metoclopramide with Ru(dipy)₃²⁺ and KMnO₄ in a sulfuric acid medium. Under the optimum conditions, a calibration graph was obtained over the concentration range 0.005-3.5 μg ml⁻¹ with a limit of detection (S/N=2) of 1 ng ml⁻¹. The correlation coefficient was 0.99993 (n=8) with a relative standard deviation of 0.48% for 10 determinations of 1 μg ml⁻¹ of drug. The method was successfully applied to the determination of metoclopramide in pharmaceutical preparations and biological fluids after IP administration of 25 mg kg⁻¹ dose to rats. The elimination half-life was 2.5±0.4 h.     

Voltammetric determination of L-dopa using an electrode modified with trinuclear ruthenium ammine complex (Ru-red) supported on Y-type zeolite

The L-dopa is the immediate precursor of the neurotransmitter dopamine. Unlike dopamine, L-dopa easily enters the central nervous system and is used in the treatment of Parkinson’s disease. A sensitive and selective method is presented for the voltammetric determination of L-dopa in pharmaceutical formulations using a carbon paste electrode modified with trinuclear ruthenium ammine complex [(NH₃)₅Ru^IIIORu^IV(NH₃)₄ORu^III(NH₃)₅]⁶⁺ (Ru-red) incorporated in NaY zeolite. The parameters which influence on the electrode response (paste composition, potential scan rate, pH and interference) were also investigated. The optimum conditions were found to an electrode composition (m/m) of 25% zeolite containing 6.7% Ru, 50% graphite and 25% mineral oil in acetate buffer at pH 4.8. Voltammetric peak currents showed a linear response for L-dopa concentration in the range between 1.2×10⁻⁴ and 1.0×10⁻² mol l⁻¹ (r=0.9988) with a detection limit of 8.5×10⁻⁵ mol l⁻¹. The variation coefficient for a 1.0×10⁻³ mol l⁻¹ L-dopa (n=10) was 5.5%. The results obtained for L-dopa in pharmaceutical formulations (tablet) was in agreement with compared official method. In conclusion, this study has illustrated that the proposed electrode modified with Ru-red incorporated zeolite is suitable valuable for selective measurements of L-dopa.     

Simultaneous Determination of Four Active Components in a Compound Formulation by Liquid Chromatography

Summary A rapid and accurate LC method is described for simultaneous determination of pseudoephedrine hydrochloride (PSE), acetaminophen (AMP), dextromethorphen hydrobromide (DEX), and diphenhydramine hydrochloride (DPH) in a compound formulation. Chromatographic separation of the four drugs was achieved on a Hypersil CN column (150 mm × 4.6 mm, 5 m particle) by use of a mobile phase comprising a mixture of 3 mM ion-pairing solution, 2% aqueous triethylamine solution, and 2 M phosphoric acid, 68:48:88 (v/v), pH 3.0, delivered at 1.0 mL min^–1. Compounds were detected at 215 nm and the run time was less than 10 min. The linearity, accuracy, and precision of the method were found to be acceptable over the concentration ranges 6.1–36.4 g mL^–1 for PSE, 65.0–390.0 g mL^–1 for AMP, 3.1–18.6 g mL^–1 for DEX, and 5.0–30.0 g mL^–1 for DPH.     

Electrochemical studies and square-wave voltammetric determination of fenofibrate in pharmaceutical formulations

The electrochemical reduction of fenofibrate at a hanging mercury drop electrode (HMDE) was investigated by cyclic voltammetry, square-wave voltammetry, and chronoamperometry. Different buffer solutions were used over a wide pH range (3.0–10.0). The best definition of the analytical signals was found in borate buffer (pH 9.0)–tetrabutylammonium iodide mixture containing 12.5% (v/v) methanol at –1.2 V (versus Ag/AgCl). According to cyclic voltammetric studies, the reduction was irreversible and diffusion controlled. The diffusion coefficient was 2.38×10^–6 cm² s^–1 as determined by chronoamperometry. Under optimized conditions of square-wave voltammetry, a linear relationship was obtained between 0.146–4.96 g mL^–1 of fenofibrate with a limit of detection of 0.025 g mL^–1. Validation parameters such as sensitivity, accuracy, precision, and recovery were evaluated. The proposed method was applied to the determination of fenofibrate in pharmaceutical formulations. The results were compared with those obtained by a published high-performance liquid chromatography method. No difference was found statistically.     

A multicommuted fluorescence-based sensing system for simultaneous determination of Vitamins B2 and B6

A multicommuted flow-through optosensor based on the direct fluorescence measurements of Vitamins B₂ and B₆ using a non-polar sorbent (C₁₈ silica gel) as solid sensing zone (to accomplish the separation and subsequent preconcentration/detection of the target analytes) have been developed. The proposed flow system was controlled by Java-written home-made software and designed using three-way solenoid valves for independent automated manipulation of sample and carrier solutions. The native fluorescence signal was simultaneously monitored at two pairs of excitation/emission wavelengths (450/519 and 294/395 for B₂ and B₆, respectively). The separation of the analytes was performed in the detection flow cell, using the differences in the sorption/elution process on the solid support between the two vitamins, due to their different polarity. Using an optimised sampling time, the analytical signal showed linearity in the range 0.01-0.4 and 0.15-3 μg ml⁻¹ with detection limits of 0.003 and 0.045 μg ml⁻¹ for B₂ and B₆, respectively, obtaining R.S.D. (%) values better than 2% for both analytes. The proposed methodology was applied to different pharmaceutical preparations, obtaining remarkably good results with recoveries ranging from 96 to 107.5%.     

Determination of impurities in clodronic acid by anion-exchange chromatography

A validated ion chromatographic method for the determination of anionic impurities in clodronic acid or disodium clodronate is described. Separations are performed by using an anion-exchange column (IonPac AS5) and a sodium hydroxide gradient. Impurities are detected by suppressed conductivity without the need for derivatisation. The most important variable affecting the separation was shown to be the column temperature.     

A finite volume cell‐centered Lagrangian hydrodynamics approach for solids in general unstructured grids

A finite volume cell‐centered Lagrangian hydrodynamics approach, formulated in Cartesian frame, is presented for solving elasto‐plastic response of solids in general unstructured grids. Because solid materials can sustain significant shear deformation, evolution equations for stress and strain fields are solved in addition to mass, momentum, and energy conservation laws. The total stress is split into deviatoric shear stress and dilatational components. The dilatational response of the material is modeled using the Mie‐Grüneisen equation of state. A predicted trial elastic deviatoric stress state is evolved assuming a pure elastic deformation in accordance with the hypo‐elastic stress‐strain relation. The evolution equations are advanced in time by constructing vertex velocity and corner traction force vectors using multi‐dimensional Riemann solutions erected at mesh vertices. Conservation of momentum and total energy along with the increase in entropy principle are invoked for computing these quantities at the vertices. Final state of deviatoric stress is effected via radial return algorithm based on the J‐2 von Mises yield condition. The scheme presented in this work is second‐order accurate both in space and time. The suitability of the scheme is evinced by solving one‐ and two‐dimensional benchmark problems both in structured grids and in unstructured grids with polygonal cells. Copyright © 2013 John Wiley & Sons, Ltd.     

Ethylenically unsaturated polycarbosiloxanes for novel silicone hydrogels: synthesis,end‐group analysis,contact lens formulations,and structure–property correlations

A series of novel mono‐ethylenically unsaturated polycarbosiloxanes macromonomers as compatibilizer materials for soft silicon hydrogels were prepared from the anionic ring‐opening polymerization (AROP) of 2,2,5,5‐tetramethyl‐2,5‐disila‐1‐oxacyclopentane followed by methacrylation. The characterization was performed by end‐group analysis and included the determination of molecular weight, molecular weight distributions, end‐group functionality, and impurity profiles using gas chromatography‐mass spectrometry, gel permeation chromatography, nuclear magnetic resonance, and matrix‐assisted laser desorption/ionization time of flight mass spectrometry. The synthetic procedure was optimized to minimize the formation of any dimer that would have the potential to act as a low molecular weight cross linker. In addition, the novel di‐ethylenically unsaturated polycarbosiloxanes were synthesized by cationic polymerization. Use of these silicone derivatives was explored in the formulation of contact lenses, and the structure–property relationship was examined. When copoymerized with hydrophilic monomers, these were able to give transparent and wettable films with desired properties, particularly a low moduli for contact lenses. Contact lens with high modulus is often shown to impart a higher degree discomfort when worn upon the eye. It was clear from the structure–property relationship that the modulus and the tensile strength of the formulated material depend on the nature and length of the polycarbosiloxane used and may be tuned for the purpose as needed. Copyright © 2013 John Wiley & Sons, Ltd.