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Raman spectroscopy is used for material characterization by analyzing molecular or crystal symmetrical vibrations and rotations that are excited by a laser, and exhibit vibrations specific to the molecular bonds and crystal arrangements in the molecules. Raman technology is a valuable tool in distinguishing different polymorphs. Examples of portable Raman spectroscopy for identification of polymorphs and in monitoring the polymorphic transiton of citric acid and its hydrated form are presented.

Raman spectroscopy is an advantageous analytical tool that allows for the measurement of molecular structure and identifying chemical composition of materials based on the rotational and vibrational modes of a molecule. With advanced technology and an optimized optical design, the B&W Tek BAC102 series E-grade probe can access lower frequency modes down to 65 cm-1, providing key information for applications in protein characterization, polymorph detection, and identification, along with material phase and structure determination.

This article demonstrates the utility of portable Raman spectroscopy as a versatile tool for process analytical technology (PAT) for raw material identification, in-situ monitoring of reactions in developing active pharmaceutical ingredients (APIs), and for real-time process monitoring. Raw material identification is done for verification of starting materials as required by PIC/S and cGMP, and can be readily done with handheld Raman. Portable Raman systems allow users to make measurements to bring process understanding and also provide proof of concept for the Raman measurements to be implemented in pilot plants or large-scale production sites. For known reactions which are repetitively performed or for continuous online process monitoring of reactions, Raman provides a convenient solution for process understanding and the basis for process control.

Although the process of building, validating and using a method is well-defined through software, the robustness of the method is dependent on proper practice of sampling, validation, and method maintenance. In this document, we will detail the recommended practices for using the multivariate method with NanoRam-1064. These practices are recommended for end users who are in the pharmaceutical environment, and can expand to other industries as well. This document aims to serve as a general reference for NanoRam-1064 users who would like to build an SOP for method development, validation and implementation.

This poster describes a method for automated and precise dosing of liquid samples into the Karl Fischer titration cell using Metrohm Dosino liquid handling technology. First, the titer was automatically determined with ultrapure water. The same dosing procedure proved valuable for the automated water determination in highly viscous water-glycol fluids and low-boiling organic solvents such as n-pentane. Lastly, the method copes with the labor-intensive and human error-prone suitability test stipulated in chapter 2.5.12 in the European Pharmacopoeia.

If chloride and bromide are present in approximately equal molar concentrations they can be titrated directly with silver nitrate solution after addition of barium acetate. If, however, the molar ratio n(Br-) : n(Cl-) changes from 1 : 1 to 1 : 5, 1 : 10, 5 : 1 or 10 : 1 then greater relative errors must be expected with this method. The Bulletin describes an additional titration method that allows bromide to be determined in the presence of a large excess of chloride. The determination of small chloride concentrations in the presence of a large excess of bromide is not possible by titration.

A potentiometric, nonaqueous method is described for analyzing nitrating acid using cyclohexylamine as titrant. Both sulfuric and nitric acid can be determined quantitatively.

This Bulletin describes fluoride determination in various matrices with the help of the ion-selective fluoride electrode (F-ISE). The F-ISE is comprised of a lanthanum fluoride crystal and exhibits a response in accordance with the Nernst equation across a wide range of fluoride concentrations.The first part of this Bulletin contains notes regarding the handling and care of the electrode and the actual fluoride determination itself. The second part demonstrates the direct determination of fluoride with the standard addition technique in table salt, toothpaste and mouthwash.

Bromide is removed from the sample as BrCN by distillation. The BrCN is absorbed in sodium hydroxide solution and decomposed with concentrated sulfuric acid, then the released bromide ions are determined by potentiometric titration with silver nitrate solution. Iodide does not interfere with the determination.Iodide is oxidized to iodate by hypobromite. After destruction of the excess hypobromite, the potentiometric titration (of the iodine released from iodate) is carried out with sodium thiosulfate solution. Bromide does not interfere, even in great excess.The described methods allow the determination of bromide and iodide in the presence of a large excess of chloride (e.g., in brine, seawater, sodium chloride, etc.).

After acid digestion, the sample solution is neutralized with sodium hydroxide to form sodium dihydrogen phosphate. An excess of lanthanum nitrate is added and the released nitric acid is then titrated with sodium hydroxide solution.NaH2PO4 + La(NO3)3 → LaPO4 + 2 HNO3 + NaNO3This determination method is suitable for higher phosphate concentrations.

This Application Bulletin gives an overview of the coulometric water content determination according to Karl Fischer.Amongst others, it describes the handling of electrodes, samples, and water standards. The described procedures and parameters comply with the ASTM E1064.

This Bulletin describes three potentiometric, one photometric, one thermometric and one conductometric titration method for sulfate determination. The question of which indication method is the most suitable depends primarily on the sample matrix.Method 1: Precipitation as barium sulfate and back titration of the Ba2+ surplus with EGTA. Use of the ion-selective calcium electrode as indicator electrode.Method 2: As with Method 1, although with the electrode combination tungsten/platinum.Method 3: Precipitation titration in semi-aqueous solution with lead nitrate in accordance with the European Pharmacopoeia using the ion-selective lead electrode as indicator electrode.Method 4: Photometric titration with lead nitrate, dithizone indicator and the Optrode 610 nm, particularly suitable for low concentrations (up to 5 mg SO42- in the sample solution).Method 5: Thermometric precipitation titration with Ba2+ in aqueous solution, particularly suitable for fertilizers.Method 6: Conductometric titration with barium acetate in accordance with DIN 53127

4-Carboxybenzaldehyde, in the following referred to as 4-CBA, can be reduced directly at the dropping mercury electrode (DME) in an ammoniacal solution. After a very simple sample preparation it is now possible to determine the concentration of 4-CBA in terephthalic acid quickly and precisely by polarography down to the lower ppm range.

Sulfate can be rapidly and easily titrated thermometrically using a standard solution of Ba2+ as titrant. In industry, the widespread procedure is applied to the determination of sulfate in wet-process phosphoric acid.

Phosphate can be rapidly and easily titrated thermometrically using a standard solution of Mg2+ as titrant. The phosphate-containing solution is basified and buffered with NH3/NH4Cl solution before titration. The formation of insoluble MgNH4PO4 is exothermic. The method is a titrimetric adaptation of a classical gravimetric procedure. This bulletin deals with the determination of phosphate in phosphoric acid and granular fertilizers such as MAP (monoammonium phosphate), DAP (diammonium phosphate) and TSP (triple superphosphate). Results are reported as percentage of P and P2O5.

The present Application Bulletin contains NIR applications and feasibility studies for NIRSystems devices in the chemical industry. Qualitative and quantitative analyses of a wide variety of samples are part of this bulletin. Each application describes the instrument that was originally used for the analysis, as well as the system recommended for the analysis and the results that were achieved thereby.

MATi 4 (Metrohm Automated Titration) is a configured system for automated water content determination in liquid samples using coulometric Karl Fischer titration. The maximum sample volume is 5 mL. Up to 160 samples are filled in glass vials and sealed with lids. This ensures that the water content in the samples remains constant. The samples are aspirated and transferred into the coulometric cell through a needle. The tiamo™ software controls the system.

This method is applicable to all samples containing glycerin in the absence of other triols or other compounds that react with periodate to produce acidic products. Glycerin may be determined in the presence of glycols. A periodate solution reacts slowly with diols and triols in acidic aqueous media at room temperature. A quantitative amount of formic acid is generated from the reaction with glycerin (a triol). The reaction with diols produces neutral aldehydes. The amount of formic acid generated by this reaction is determined by titration against sodium hydroxide.

Determination of calcium and magnesium in high-purity sodium chloride using cation chromatography with direct conductivity detection.

Determination of sodium, potassium, iron(II), magnesium, and calcium in an extract of monoethylene glycol using cation chromatography with direct conductivity detection.

Determination of sodium, potassium, DMEA (dimethylethanolamine), calcium, choline, and magnesium in a saline solution using cation chromatography with direct conductivity detection.

Determination of calcium and magnesium in a dolomite sample using cation chromatography with direct conductivity detection.

Determination of trimethylamine in hydrogen peroxide (31 %) using cation chromatography with direct conductivity detection after inline matrix elimination, inline preconcentration, and inline calibration.

Determination of magnesium, manganese, and zinc in a zinc sulfate solution using cation chromatography with direct conductivity detection.

Determination of strontium and barium in monoethylene glycol using cation chromatography with direct conductivity detection.

Determination of sodium, potassium, iron(II), magnesium and calcium in antifreeze (monoethylene glycol) using cation chromatography with direct conductivity detection. Ascorbic acid reduces iron(III) to iron(II). In this way total iron is determined as iron(II).

Determination of lithium, sodium, ammonium, potassium, calcium, magnesium, and strontium in brine using cation chromatography with direct conductivity detection.

Determination of magnesium, cadmium, and iron in phosphoric acid using cation chromatography with direct conductivity detection.

As a rule, brine samples are diluted extremely in order to avoid overloading the column. Manual dilution is very error-prone, which is why this application relies on injection with a 0.25 µL internal loop, thus saving an additional dilution step. Sodium, potassium, magnesium and calcium in brine are determined on a Metrosep C 6 - 150/4.0 column with subsequent direct conductivity detection.

Microbore ion chromatography offers better sensitivity, shorter retention times, and consumes less eluent, increasing sample throughput and reducing running costs.

Cyclohexane is an important organic solvent. Recycled cyclohexane must be tested for trace substances, e.g., chloride and sulfate. Metrohm Combustion Ion Chromatography with flame sensor and Inline Matrix Elimination is the method of choice.Keyword: pyrohydrolysis

Determination of the sulfate content of wet process phosphoric acid.

Determination of the sulfate content of brines.

Determination of acetic anhydride in the presence of acetic acid in acylation mixtures.

Determination of sulfate and total acids in a nitrating mixture.

Determination of sodium, potassium, and silica values in sodium and potassium silicates.

Determination of bicarbonate and carbonate in a mixture by sequential thermometric titrations.

Determination of phosphoric and nitric acids in liquors from the Nitrophos fertilizer manufacturing process.

Dissolution of urea in glacial acetic acid, and titration with standard 0.1 mol/L trifluoromethanesulfonic acid in acetic acid using isobutyl vinyl ether as a thermometric endpoint indicator.

A sample of concentrated mineral acid is dissolved in anhydrous acetonitrile, and the water content titrated with a solution of TEOF in acetonitrile. The TEOF reacts exothermically with water in the presence of a strong acid (acting as a catalyst).

Hypochlorite ions react with bromide ions to form hypobromite ions, which in turn rapidly oxidize ammonium ions to nitrogen. Hypobromite reacts more rapidly with ammonium than hypochlorite, and is formed in situ (Vogel, 1961). The titration is carried out with in a solution containing bromide and bicarbonate.

This Application Note supplements AN-H-003 with the treatment of the standard addition of sulfate as sulfuric acid. This technique may be contemplated when either sulfate levels are too low for a satisfactory direct titration, or when the sample matrix hinders endpoint detection, leading to poor precision and accuracy.

Weak, organic bases that are soluble in nonaqueous solvents (including nonpolar solvents) are determined in glacial acetic acid using titration with strong acids, e. g., anhydrous perchloric acid or trifluoromethanesulfonic acid. The endpoint of such titrations can be determined thermometrically, insofar as a suitable thermometric endpoint indicator exists. The exceptional suitability of isobutyl vinyl ether (IBVE) as indicator has been demonstrated.

Hydrogen peroxide solutions can be determined through thermometric endpoint titration (TET) using iodometry. Iodide is oxidized to become iodine, which is then titrated with a standard thiosulfate solution in an exothermic reaction.

This Application Note covers the formation of calcium carbonate from solution.

The water content of potassium chlorate is determined according to Karl Fischer using the oven method (300 °C).

In this application note, Karl Fischer titration is used to determine the water content of urea.

The water content of ethylene dichloride is determined according to Karl Fischer. As the sample may contain free chlorine, which interferes with the determination, separate KF reagents have to be used.

The water content of lime is determined according to Karl Fischer using the oven method (150 °C).

Determination of the water content of liquid ammonia according to Karl Fischer after absorption of the water in ethylene glycol.