Karl Fischer Reagent Research Articles

Diclofenac Salts, Part 7: Are the Pharmaceutical Salts with Aliphatic Amines Stable?

Eight cyclic aliphatic amines, pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz), and the N-hydroxyethyl (HE) analogues, were employed to prepare a salt with acidic diclofenac (D). These salts were examined by thermal [differential scanning calorimetry (DSC), thermogravimetric analysis, and hot-stage microscopy (HSM)] and spectroscopic [Fourier transform infrared (FTIR), Raman, (1) H NMR, and ultraviolet] analysis. The results show the thermal instability of these salts: the thermal dissociation leaves the starting acidic D, evidenced by the FTIR and Raman spectra inside the molten mass of the salts with M and HEM. The nature of the salt with Pz (1:1 or 1:2) and HEPy (anhydrous or hydrate polymorph), but not for the salt with HEPz and Py, depends on the polarity of the solvent used for the preparation of the salt. Incomplete dehydration of the hydrate Py and Pz salts progressively modifies the thermogram profiles and originates false information. Melting of the salts with Pp, M, and HEM could be demonstrated by HSM, but not with DSC. The difficulty of providing a description of these salts in a simple way originates doubts on the utility of a wide application of aliphatic amines to prepare pharmaceutical salts with D, whose solubility in water does not significantly differ from that of the common sodium D.

Investigation of amine-buffered amide reagents for coulometric Karl Fischer titration

Formamide (FA), N-methylformamide (NMF), and dimethylformamide (DMF), were evaluated as solvents for coulometric Karl Fischer (KF) reagents in combination with several amine bases. Except for the effect of the iodine species (iodine or triiodide), the pH of the reagent and the position of the sulfur dioxide/hydrogen sulfite equilibrium were found to be the main factors explaining the large difference in the observed reaction rates between water and the KF reagent in these solvents. Acid–base titrations showed that hydrogen sulfite is the main sulfur reactant in these media. The results will be of great importance in finding suitable combinations of base and solvent with respect to stoichiometry, side reactions caused by active carbonyl compounds, and reagent stability.

Measurement of water by oven evaporation using a novel oven design. 2. Water in motor oils and motor oil additives

The measurement of water in lubricating oils is important because water accelerates the corrosion of metal parts and bearings in motors. Some of the additives added to lubricating oils to improve their performance react with the Karl Fischer reagent (KFR) causing a positive bias in the water measurement. A new oven evaporation technique for measuring water in oils has been developed that is automated, requires less sample handling, is easily calibrated, and is capable of measuring relatively small mass fractions of water (> or =50 mg/kg sample). A series of motor oils was analyzed with the standard KFR, a reagent that detects interfering substances that reduce iodine, and the aldehyde-ketone reagent that does not detect substances that react with methanol and form water. The oil samples were heated to 107 degrees C and then reheated to 160 degrees C. At both temperatures, material was measured by both KFRs, but only zinc dithiophosphate released sulfur compounds that would react with the reagent that detects interfering substances. Mass fractions of between 20 and 70% of the volatile material released at either temperature were measured with the standard KFR but not with the aldehyde-ketone reagent. These results demonstrate that there are a number of sources of positive bias in the measurement of water in motor oils and that the standard KFR cannot be used to measure water in motor oils and motor oil additives. These results also indicate that some of the material reacts with methanol to form water. Finally, these results suggest that some of the material that is volatile at 160 degrees C and not at 107 degrees C may be water that is physically occluded or may be substances that react with diethyleneglycol monomethylether to produce water.

Measurement of water by oven evaporation using a novel oven design. 1. Water in water-saturated 1-octanol, coal, cement, and refined oils.

Using an automated oven evaporation technique combined with the coulometric Karl Fischer method, the mass fraction of water has been measured in cement, coal, and refined oil samples. The accuracy of this method was established by using SRM 2890, water-saturated 1-octanol that was added to white oil. The samples were analyzed for total reactive Karl Fischer reagent (KFR) material, for interfering materials, and for material that does not react with the aldehyde-ketone KFR. All of the samples yielded volatile material that reacted with the standard KFR. None of the samples contained significant masses of material that reacted with iodine. The cement and coal SRMs contained no material that reacted with methanol and very little material that did not volatilize at 107 degrees C. The refined oils contained some material that was volatile at 107 degrees C and some at 160 degrees C. However, none of this material reacted with the aldehyde-ketone reagent. These results show that the material in the solid samples is water and that the material in the refined oils is a material other than water which reacts with methanol to form water.

Stoichiometry and chemical metrology: Karl Fischer reaction

Stoichiometry of analytical reactions is discussed as an important element of many primary methods (gravimetry, volumetry, spectrophotometry, etc.) and therefore, of chemical metrology as a whole. Variations in stoichiometry caused by non-equilibrium conditions, by changes in the reaction medium or by other factors can be a source of the dominant uncertainty component in the analytical measurement. Such a situation is illustrated with the Karl Fischer (KF) reaction which is widely used in aquametry. Two kinds of solvents used as a part of the reaction medium – alcohols and amides – are compared. The influence of the media on the stoichiometry of the reaction and, correspondingly, on the titre of the KF reagent is evaluated.

Water Determination in Drugs Containing Ascorbic Acid

A new rapid analytical method was applied for water determination in tablets of vitamin C, Ce De Calcium Veterinary, and C-Tamin-500 containing ascorbic acid and therefore is not amenable for direct Karl Fischer (KF) titration. The method is based on the consecutive titration first of ascorbic acid by a novel reagent and then of water by a conventional KF reagent (KFR) in the same sample and cell with the electrometric “dead-stop” location of the end point in both titrations. The new reagent consists of iodine, potassium iodide, and sodium acetate in nonaqueous medium. Estimated repeatability and accuracy of both water and ascorbic acid determination are satisfactory.

Coulometric Study of Recovery Rates for Karl Fischer Titration of Water in Aldehydes and Ketones Using Rapidly Reacting Methanolic and 2-Methoxyethanolic Reagents

Factors itch influence the recovery of water with use of rapidly reaching imidazole-based methanolic or 2-methoxyethanolic Karl Fischer (KF) reagents were investigated coulometrically. Using cyclohexanone and benzaldehyde as model substances, it was found that, in addition to the well-known problems associated with low recoveries of water due to the bissulfite addition reaction, errors may also be caused by side reactions involving iodine. Such interferences are largest at the end point of a titration, where an excess of iodine is present, and will lead to an overcompensation when correcting the results for the endpoint drift. The extent of the sum of all the side reactions was found to decrease with the concentration of ioxide for all types of KF reagent investigated. The high reaction rates for the imidazole-based KF reagents, despite the high concentration of iodide, make it possible to use a very low end-point concentration of iodine. In this way, side reactions involving iodine can be further suppressed. However, for titrations carried out in 2-methoxyethanolic reagents, a relatively high concentration of iodine must be present at the end point in order to decrease the time needed for the reversal of the bisulfite addition reaction. For small amounts of water, i.e., less than 30 μg, a reagent based on metanol can be recommended, since the titrations are rapid and the recovery was found to be 100% for both cyclohexanone and benzaldehyde. For large amounts of water or slow titrations, the recoveries tend to decrease for all reagent mixtures investigated. One reason for this seems to be related to a change in stoichiometry for the KF reaction involved in the reversal of the bisulfite addition reaction

Determination of water content of hygroscopic lithium salts

Determination of the water content in hygroscopic lithium chloride, lithium bromide, lithium nitrate and lithium sulfate by Karl Fischer reagent (KFR), Hydranal (Eugen Scholz reagent) and by thermal-vacuum drying is discussed. Agreement between the results of the KFR titrations and drying methods is satisfactory whereas the Hydranal titrations gave high values. Only the drying method was suitable for lithium sulfate.

Determination of water by flow injection analysis with the karl fischer reagent: Minization of effects caused by differences in physical properties of the samples

In the previously described flow-injection method for the spectrophotometric determination of water with the Karl Fischer reagent, problems can arise from the rather large variation between the calibration curves for different types of samples. Different combinations of flow-injection arrangements and detector types are described here, to establish a system which levels out this undesirable spreading between the calibration curves. One necessary condition for attaining a low spread is shown to be the use of a spectrophotometric detector especially constructed to minimize refractive index effects. The best results, including samples with large differences in refractive indices and viscosities, were obtained by a combination of peak area measurements and the use of this detector. For example, the relative mean deviation for a sample containing 0.1% water was about 2%.

Minimization of interference effects from iodine-consuming samples in the determination of water with the karl fischer reagent in a flow-injection system

A principal feature of the flow-injection approach for determination of water with the Karl Fischer reagent is the small influence of side reactions. This is confirmed by the determination of water in an iodine-consuming sample, penicillin (fugacillin).

Determination of water by flow-injection analysis with the karl fischer reagent

A method for the determination of water in organic solvents by flow-injection analysis (f.i.a.) is described. The method, which is based on the reaction between water and the Karl Fischer reagent, is capable of 120 determinations per hour. The concentration range 0.01–5% (v/v) of water can be covered by using a single Karl Fischer reagent solution. The results obtained with a specially constructed potentiometric detector showed a relative standard deviation of less than 0.5% (v/v). This value was about 3 times less than that obtained with a spectrophotometric detector. The f.i.a. technique is shown to offer some unique possibilities in minimizing interferences associated with the standard Karl Fischer batch titration method.

Measurement of the strongly held water of myoglobin by drying

AbstractThe karl Fischer reagent method has been used to study the drying of whale skeletal muscle myoglobin. Drying curves for metmyglobin were obtained by mechanical pumping (moderate vacuum) and diffusion pumping (high vacum) at 20, 10, 0, −10, and −20°C. Strongly held water is present in about the same amounts as were previously observed with lysozyme. Nearly all of this strongly held water is still present during the drying of acid denatured metmyoglobin. This suggest that a core structure containing strongly held water is still present at pH 4.0. Comparison of the drying of metmyoglobin, deoxymyoglobin, and oxymyoglobin indicates that the iron‐coordinated water of methyoglobin is the second most strongly held water of the molocule.

Mechanism and reaction rate of the Karl-Fisher titration reaction Part II. Rotating ring-disk electrode measurements

Abstract A platinum disk-platinum ring electrode was used to investigate the kinetics of the oxidation of the monomethyl sulfite ion (which is the oxidizable species in the Karl-Fischer reagent) by triiodide and iodine, generated with controlled current at the disk electrode. The experimental conditions were such, that the technique for measurement of homogeneous pseudo-first order reactions could be used. The results are in reasonable agreement with those of the potentiometric investigations as described in part I. The reaction rate constant of triiodide is approximately 600 1 2 mol −2 s −1 ; for iodine the rate constant is approximately 7×10 6 .

Mechanism and reaction rate of the Karl-Fischer titration reaction: Part II. Rotating ring-disk electrode measurements

A platinum disk-platinum ring electrode was used to investigate the kinetics of the oxidation of the monomethyl sulfite ion (which is the oxidizable species in the Karl-Fischer reagent) by triiodide and iodine, generated with controlled current at the disk electrode. The experimental conditions were such, that the technique for measurement of homogeneous pseudo-first order reactions could be used. The results are in reasonable agreement with those of the potentiometric investigations as described in part I. The reaction rate constant of triiodide is approximately 600 1 2 mol −2 s −1; for iodine the rate constant is approximately 7×10 6.