Karl-Fisher titration

Ethyl lactate was purchased from Aldrich Chemical Company, Inc., and used without further purification. The water content was 0.8 mg/mL by Karl Fisher titration (Metrohm model 684 KF coulometer). 

Tetrahydrofuran was purchased from Fisher Scientific Company and dried over 4 A molecular sieves for 18 hr prior to use. The water content was less than 0.05 mg/mL by Karl Fisher titration. 

Karl Fisher titrations for H2O on both alcohols prior to usage gave values of <0.01% H2O. Bis (2-ethylhexyl) sodium sulfosuccinate was purum grade obtained from Fluka and received no further... 

Small amounts of moisture (up to about 0.5%) in crystalline sugars can be determined chemically by titration with Kad Fisher reagent. A volumetric Karl Fisher titration procedure for moisture in molasses is accepted by AO AC. Automatic Karl Fisher titrators are available, and as acceptance of pyridine-free reagents increases, their use may increase. 

There are three ways to obtain the total solid (1) determine the water content by Karl Fisher titration, (2) weigh an evaporate portion of product, or (3) sum up all the ingredients, including mometasone furoate and phenylethyl alcohol, which are stated (claimed) on the label. The combination of all three measurements generally gives quite an accurate estimation of the total solid and total cellulose ... 

The Karl Fisher titration is one of the most common and most sensitive methods used in the analytical laboratory. The titrimetric determination of water is based on the quantitative reaction of water with an anhydrous solution of sulfur dioxide and iodine in the presence of a buffer that reacts with hydrogen ions. This titration is a two-stage process ... 

There are two types of Karl Fisher titrations volumetric and coulometric. Volumetric titration is used to determine relatively large amounts of water (1 to 100. ig) and can be performed using the single- or two-component system. Most commercially available titrators make use of the one-component titrant, which can be purchased in two strengths 2 mg of water per milliliter of titrant and the 5 mg of water per milliliter of titrant. The choice of concentration is dependent on the amount of water in the sample and any sample size limitations. In both cases, the sample is typically dissolved in a methanol solution. The iodine/SCVpyridine (imidazole) required for the reaction is titrated into the sample solution either manually or automatically. The reaction endpoint is generally detected bivoltametrically. 

The effects of moisture content in drug substances iancthed dosage form have been widely studied. Static moisture content can be determined by many methods like Karl Fisher titration, loss on drying (LOD), and TGA. Dynamic hygroscopicity of a drug substance has beerLcWaato four... 

The analytical method for moisture determination must be validated before use during process validation studies. There are numerous techniques for moisture analysis that range from physical methods, such as loss on drying, to chemical methods, such as Karl Fisher titration. A comparative review of the conventional techniques are presented in an overview [32], The measurement of residual moisture is lyophilized pharmaceuticals by near-infrared (NIR) spectroscopy has recently been expanded [33]. 

Water concentrations in liquid and solid phases were measured by the Karl Fisher method using the Karl Fisher Titrator (Mettler DL 18). Butanol and butyl butyrate were determined by gas chromatography using a 6-ft, 5% DEGS on a Chromosorb WHP, 80/10 mesh column (Hewlett Packard, Palo Alto, CA) and hexanol as internal standard. Acid consumption was monitored by volumetric titration of samples diluted in ethanol employing 0.02 M KOH alcoholic solution and phenolphthalein as pH indicator. Esterification was expressed as molar percent of consumed reactant, according to Eq. 1 ... 

The submitters used reagent grade tetrahydrofuran (EM Science) dried over 4 A or 5 A molecular sieves (Aldrich Chemical Company, Inc.), and determined the water content in the solvents by Karl Fisher titration (KF). The submitters report that the tetrahydrofuran should be dry (KF < 50 pg/mL) and MUST NOT contain any DMF (< 1 ppm). Also, the KF of the tetrahydrofuran/proline suspension should be < 50 pg/mL. The submitters used (S)-proline obtained from Ajinomoto while the checkers used (S)-proline from Aldrich Chemical Company, Inc. The proline should be milled and/or delumped prior to use, if necessary, to insure complete reaction. The enantiomeric purity of the (S)-proline should be > 99.5%, and can be assayed via the procedure of Marfey.2 The checkers used HPLC grade THF (Fisher Scientific Company) that was dried over 4 A molecular sieves. 

The xylenes (EM Science) were dried over 4 A molecular sieves. Residual water content < 20 pg/mL by Karl Fisher titration. The checkers dried hexanes (Fisher Scientific Company), tetrahydrofuran, and xylenes over 4 A molecular sieves. The checkers did not measure the residual waler content of the solvents. 

Materials. Sulfolane (99%purity) (Aldrich) was treated with calcium hydride and distilled under reduced pressure. The freshly prepared solvent had a specific conductivity of 1.0 X 10 7 O"1 cm"1 and a residual water content of 8 X 10"3M as determined by Karl Fisher titration. Conductivity water and reagent grade ether (Baker) were used. Glacial acetic acid (CIL), trifluoroacetic acid (Baker), and trifluoro-methanesulfonic acid (3M) were used as received. All these acids had a minimum purity of 99.5% as determined by titration with standard sodium hydroxide. Methanesulfonic acid (Eastman), distilled under reduced pressure, had a purity of 99.6%. Sulfolane solutions of these acids were prepared by weight, and the acid concentrations were checked by acidimetry after the samples were flooded with water. The solutions... 

Analytical Procedures. Standard methods for analysis of food-grade adipic acid are described in the Food Chemicals Codex (see Refs, in Table 8). Classical methods are used for assay (titration), trace metals (As, heavy metals as Pb), and total ash. Water is determined by Karl-Fisher titration of a methanol solution of the acid. Determination of color in methanol solution (APHA, Hazen equivalent, max. 10), as well as iron and other metals, are also described elsewhere (175). Other analyses frequently are required for resin-grade acid. For example, hydrolyzable nitrogen (NH3, amides, nitriles, etc) is determined by distillation of ammonia from an alkaline solution. Reducible nitrogen (nitrates and nitroorganics) may then be determined by adding DeVarda s alloy and continuing the distillation. Hydrocarbon oil contaminants may be determined by ir analysis of halocarbon extracts of alkaline solutions of the acid. 

For over 60 years, the specific titration of water has used a reagent developed by Karl Fisher, which consists of iodine, sulfur dioxide, and pyridine in methanol. The Karl Fisher titration of water is addressed in most analytical chemistry texts and is not presented here. A brief review with a pharmaceutical perspective has recently been published. However, the advantages and disadvantages of this method for the characterization of water associated with solids are discussed later. 

In its simplest form, the Karl Fisher titration is a one-point determination of moisture content. The principal advantage is specificity for water. It is also a non-thermal method, which is very sensitive and can be easily automated. The main disadvantage is that the solid must dissolve in the titration medium to be sure that the total amount of moisture is released. If the analysis is carefully designed in such a way that moisture is extracted from the solid to the same degree each time, accurate and reproducible results can be obtained for solids that do not dissolve. 

With automation, the Karl Fisher titration provides a titration kinetics profile (e.g., milliliters of titrant vs. time). If the rate of water release from the solid is the rate-limiting step, the kinetics of the Karl Fisher titration profile can provide indirect information about the state of water associated with the solid. Fig. 14 shows the titrations of two different samples of dicaldum phosphate dihydrate. Here, and in the titration profiles in Fig. 15, the data have been normalized in such a way that each titration ultimately consumes 25 mL of reagent. This normalization is... 

Fig. 14 Normalized Karl Fisher titrations of dicalcium phosphate dihydrate (A) unmilled form (B) milled form.

In Fig. 15, Karl Fisher titration of anhydrous dicalcium phosphate, which had been exposed to 100% RH for 3 months (curve B), is compared to with that of milled dicalcium phosphate dihydrate (curve A). The adsorbed water, which was not incorporated into the crystal lattice, was released from the solid very rapidly. 

Results of normalized Karl Fisher titrations for lactose monohydrate and microcrystalline cellulose both... 

Fig. 15 Normalized Karl Fisher titration for dicalcium phosphate (A) milled sample (B) anhydrous sample with adsorbed moisture.

The influence of sorbed moisture on chemical stability and the flow and compaction of powders and granulations is well established. The moisture content and hygroscopicity of excipients is particularly important as total product processing as well as finished product stability can be affected. Hygroscopicity, moisture-sorption isotherms, and equilibrium moisture content can be determined by thermogravimetric analysis and Karl Fisher titration methods. 

The characterization of the total mass thus obtained, performed on representative samples taken during the vial filling procedure, gave additional information on the properties of the material. The average moisture content, measured by Karl-Fisher titration, was lower than 3%. The particle size distribution of the whole mass, measured using the Sympatec analyzer with Helos measuring device, was to peak at 80-90 pm with an upper limit of 435 pm. 

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