Application Finder

The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. Recommendations for the validation of analytical methods can be found in ICH Guidance Q2(R1) Validation of Analytical Procedures: Text and Methodology and in USP General Chapter <1225> Validation of Compendial Procedures. The goal of this white paper is to provide some recommendations for the validation of titration methods.

Haemophilus influenzae type B (Hib) is a major cause of bacterial meningitis in children in many countries. The capsular polysaccharide (PS) of Hib plays an important role in the virulence of the organism. The polysaccharide capsule hides cell surface components from elements of the mammalian immune system, such as antibodies and complement proteins that otherwise would activate mechanisms to kill the pathogen. Vaccines require rigorous characterization and assays to ensure final product quality and consistency. For glycoconjugate vaccines, it is important to measure both free and total PS to ensure the quality. A large amount of unconjugated PS may suppress immunity to the antigen. Additionally, the presence of free PS is a key indicator of process consistency. Current methods to determine PS content in vaccines such as Hib are imprecise and unreliable, especially if the vaccine contains a sugar stabilizer (e.g. lactose). Ion chromatography with pulsed amperometric detection (IC-PAD, or HPAEC-PAD) offers a simpler procedure and better sensitivity than other assays to quantify PS (here, polyribosylribitol phosphate [PRP]) in Hib vaccine.

This White Paper discusses the concept and benefits of NIR spectroscopy and outlines several real-life laboratory application examples with the use of OMNIS NIRS, the cutting-edge NIR spectrometer from Metrohm.

This White Paper discusses USP <1225> and how ion chromatography determines active ingredients in pharma products (assays) as well as identifies impurities and degradation components.

OMNIS Client/Server boosts business performance with scalable server management, cutting costs by reducing hardware, energy use, and maintenance across locations.

Benzbromaron is one of the main uricosuric drugs currently used. In addition to sophisticated and expensive LC-MS and GC-MS methods, benzbromaron can be effectively determined by titration with sodium hydroxide solution using a straightforward, fully automated sample preparation method. A high-frequency homogenizer comminutes one or three tablets within 90 or 120 s respectively. The overall analysis time is 8 minutes. Ten-fold determinations with one and three tablets resulted in a benzbromaron content of 99.2 and 98.7 mg per tablet respectively. Increasing the number of tablets from one to three lowers the RSD from 1.36 to 0.88%. These results show an excellent agreement with the benzbromaron content indicated by the manufacturer (approx. 100 mg/tablet).Besides the presented Titrando/homogenizer combination, the other two members of the 815 Robotic Soliprep Sample Processor family offer comprehensive sample preparation possibilities within the fields of IC, HPLC, ICP or voltammetry.

By means of azide analysis in Irbesartan a simple, fast, precise and accurate ion chromatographic method for the determination of traces of inorganic contaminants in pharmaceuticals is described. Traces of toxic azides in pharmaceutical products can accurately be determined in the sub-ppb range after Metrohm Inline Matrix Elimination using isocratic ion chromatography (IC) with suppressed conductivity detection. While the azide anions are retained on the preconcentration column, the interfering pharmaceutical matrix is washed away by a transfer solution, ideally consisting of 70% methanol and 30% ultrapure water. The analytical setup provides a well-resolved azide peak and thus alleviates the common drawback of excipient interferences, especially from the nitrate anion. Calibration with azide standards is linear over the range of 5…80 ppb, providing a coefficient of determination of 0.9995. The limit of detection (LOD) and the limit of quantification (LOQ) of azide in Irbesartan are 5 and 30 µg/L respectively; the relative standard deviations (RSD) for the peak area, peak height and retention time being smaller than 3.9%. Robustness testing involved variation of column oven temperature and composition of the transfer solution and, in terms of peak area, provided RSDs smaller than 2.8% and 3.1% respectively.

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.

Potassium iodide (KI) is used to treat overactive thyroid and to protect the thyroid gland from the effects of radiation from inhaled or swallowed radioactive iodine. Currently, in the USP Potassium Iodide Monograph, iodide identification is performed by wet chemistry and assay by manual titration, which has a history of reduced precision and accuracy. As part of USP’s global monograph modernization initiative, an alternative selective and sensitive method was developed and validated – ion chromatography (IC). The proposed IC method can also be used for the identification test as an alternative to wet chemistry.

A high throughput automated system was developed to determine pH of culture media using a pH module equipped with an external flow cell. A custom septum-piercing, vented needle was developed to accommodate the shape and size of the customer sample vials. For this application, both accurate and precise pH measurements were required. The data presented in this document was collected by a customer as a part of their validation process and was provided for use with their consent.

Moisture in cannabis impacts potency and must be accurately determined. Loss on drying (LOD) is the most popular method for determining moisture in cannabis. Unfortunately, this technique is not specific to moisture and the loss of any volatile components, such as terpenes, will be incorrectly classified as moisture. Karl Fischer (KF) titration is the only chemically specific test for moisture. This poster describes the instrument used to determine moisture content by Karl Fischer titration and compares the results of this data to loss on drying.

On the basis of the experiments that have been performed, it is possible to determine the effectiveness of the ozonization of iodized X-ray contrast media using IC-ICP-MS via the amount of iodate formed. Whereas a 120-minute ozonization guarantees a practically quantitative decomposition of amidotrizoic acid to iodate, approximately 16% of the Iomeprol is still present under the same ozonization conditions. Given that only 14% is present in iodate form in the absence of iodide anions and given that additional, not yet identified peaks occur in the ion chromatogram, the presence of additional decomposition products containing iodine must be assumed. Nonetheless, it is not possible to detect the intact iodized X-ray contrast media with the selected ion chromatographic conditions. Furthermore, the possibility exists of identifying the peak of the unknown decomposition product of the Iomeprol using IC-ESI-TOF-MS.

This article describes the investigation using ion chromatography and subsequent inductively coupled plasma mass spectronomy (ICP/MS) to determine the extent to which the iron(III) flocculation carried out in the context of wastewater treatment releases toxic gadolinium(III) ions as the result of recomplexing.

The NanoRam is a state-of-the-art, handheld Raman spectrometer for the rapid identification of chemicals used in the pharmaceutical manufacturing process. It has been specifically designed for these applications and is fully compliant with all the major global regulatory, safety, and commercial testing agencies applicable to the pharmaceutical industry.

Today’s Raman instrumentation is faster, more rugged, and less expensive than previous instrumentation.The design of high performance, portable and handheld devices has introduced the technology to new application areas that were previously not possible with older, more cumbersome instruments. Handheld Raman instruments such as the NanoRam® from B&W Tek are well-suited for pharmaceutical applications such as the testing of raw materials, verification of final products and the identification of counterfeit drugs due to the technique’s extremely high molecular selectivity.

The two most common mathematical representations used with handheld Raman spectroscopy as decision-making tools for spectroscopic data: Hit Quality Index (HQI) and significance level (p-value) are presented.

Handheld Raman is used for raw material testing of different sample types and forms. The use of optimized sampling accessories enhances the utility of handheld Raman without compromising data quality or complicating testing.

Conventional Raman typically has a very small sampling area with a high power density (PD) at the laser focal point on the sample, which means that only a limited portion of a sample is measured, and the result tends to be irreproducible for heterogeneous sample. The high power density may also cause samples to heat up or burn. The large spot adaptor (LSA) for B&W Tek’s handheld Raman products, featuring a much larger sampling area of 4.5 mm in diameter, is designed to overcome these issues.

Patented STRaman technology is a new Raman technique that can identify chemical species nondestructively beneath diffusely scattering packaging material such as plastics or tablet coatings.

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

This Application Bulletin compares the unique focusing technology of the portable Metrohm Raman system "Mira" with conventional methods. The method described here is called Orbital Raster Scan (ORS). Experiments show the advantages of ORS technology, using determination and quantification of medicines as an example. It improves the reproducibility of the Raman signals from targeted, active, pharmaceutical ingredients (APIs) in effervescent, cold medicines. Shorter analysis times and an improved, consistent assignment of spectra of the known medicine with the help of a spectral library are further advantages of ORS technology.

This Application Bulletin describes the polarographic determination of folic acid, a vitamin of the B series, also known as vitamin B9 or vitamin BC. Instructions for the determination in solutions (e.g. fruit juice), vitamin capsules and multivitamin tablets are given. The linear range of the determination is also specified. The limit of detection is approx. 75 µg/L folic acid.

Cinchocaine (dibucaine) is used in the form of ointments or injection solutions as a local anaesthetic. Its base is soluble in diethyl ether; its hydrochloride, on the other hand, is insoluble in diethyl ether but easily soluble in water. This Bulletin describes the determination of cinchocaine in ointments, creams and injection solutions by means of differential pulse polarography. An acetate buffer pH = 4.8 is used as the supporting electrolyte. The limit of quantitation and the linear working range of the method are given. The necessary sample preparation steps are also dealt with in this Bulletin.

This Application Bulletin describes the method of near-infrared spectroscopy in diffuse reflection for the purpose of determining residual moisture in a lyophilized pharmaceutical product. Numerous sample vials containing freeze-dried pharmaceuticals were spiked with varying amounts of water for calibration purposes. The resulting differences in the absorption wavelengths of the OH-oscillation were correlated with the water content determined by Karl Fischer titration using the algorithm of multiple linear regression (MLR).

The present Application Bulletin contains NIR applications and feasibility studies using NIRSystems devices in the pharmaceutical 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.

This Application Bulletin provides information regarding the MATi 10 (Metrohm Automated Titration) system. MATi 10 is a completely configured system for automatic volumetric Karl Fischer titration with which the water content in liquid and solid samples can be determined. Up to 24 samples can be analyzed directly in 75 mL titration vessels. The samples are weighed into the titration vessels and covered with an aluminum foil. This prevents falsification of the water content.

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.

The iodine content in numerous iodized X-ray contrast media (ICM) is around 50% and is determined with great accuracy using Combustion Ion Chromatography. Large quantities of H2O2 (1,000 mg/L) are required for complete absorption of the iodine. Similarly, the concentration of the internal standard should be 50 mg/L. The water content of the X-ray contrast media is determined by means of Metrohm's Karl Fischer oven method and incorporated in the final calculation.Keyword: pyrohydrolysis

Halobutyl rubber is frequently used in the production of pharmaceutical stoppers. It is ideal for this application due to its low permeability to gases and its chemical resistance. Chlorinated and brominated butyl rubber stoppers are analyzed for their halogen and sulfur content. Halogen and sulfur compounds are released by pyrohydrolysis and analyzed by subsequent ion chromatography (IC).

This Application Note demonstrates that a calibration model for caffeine and microcrystalline cellulose developed on the NIRS XDS Rapid Content Analyzer (RCA) is transferable to other NIRS XDS RCA. Due to the improved signal-to-noise ratio, reduced bandwidth and improved wavelength precision of the NIRS XDS, the transferability of the calibration model can be easily and efficiently performed.

The determination of the water content of soft contact lenses using NIR spectroscopy is described in this Application. A liquid sample kit with gold diffuse reflector was used for measuring the lenses in transflexion mode. A PLS model was developed for predicting the water content.

This Application Note shows that NIR "predictive models" are optimally suitable for the non-destructive measurement of the release profiles of active ingredients from tablets. This is in accordance with the Process Analytical Technology (PAT) initiative of the FDA. The results demonstrate how NIRS considerably reduces the work involved for release studies in the laboratory.

The quantification of residual moisture in lyophilized pharmaceutical peptides is an important measure for quality control in the pharmaceutical industry. For development purposes, such measurements are necessary and routinely performed during stability studies and to optimize the freeze-drying process (lyophilization). Currently, Karl Fischer titration is widely used for moisture determination in routine analysis. However, this method is time consuming and destroys the sample during analysis. This Application Note shows that near-infrared spectroscopy (NIRS) is a fast, reagentless, non-destructive method to determine moisture content in lyophilized pharmaceutical products.

Typically, cannabis potency testing is performed by HPLC, but the drawback is that it requires chemicals and it is time-consuming. Near-infrared spectroscopy (NIRS) is a preferred method for quantification of THC, CBD and CBG in dried cannabis because it provides results in less than a minute and does not require any chemicals.

This Application Note shows the rapid, non-destructive identification of isopropyl alcohol from two manufacturers using Raman spectroscopy following the creation of a suitable library. The measurements with the hand-held Raman spectrometer Mira M-1 require no sample preparation and provide immediate results that identify the samples unambiguously.

Producers of generic brands offer cosmetics, medicines and other goods in competition with name brands, often at a lower price point. This lower cost may reflect a lack of research, development, and advertising costs, but should never imply lower quality, especially in the case of over-the-counter drugs. As an example, Equate (a Walmart brand) effervescent cold tablets promise customers the same active ingredients in the same proportions and with identical effectiveness as Alka-Seltzer, at a much lower price. This Application Note demonstrates that Raman spectroscopy can successfully verify that these competing cold tablets are not identical. The process of ingredient verification involves a p- test, which measures the acceptable variability of a sample spectrum, as compared to a representative training set.

Determination of dimethylamine in Metformin (N,N-dimethylimidodicarbonimidic diamide, anti-diabetic drug) using cation chromatography with direct conductivity detection.

Determination of benzylamine in a beta blocker (Nebivolol) using cation chromatography with direct conductivity detection. A step gradient for fast elution of the main component is applied.

Calcium carbonate has a wide applicability in the pharmaceutical industry as an excipient and also as an active ingredient, and in the food industry as a major dietary supplement. The U.S. Pharmacopoeia (USP) monographs for calcium and magnesium carbonates tablets as well as calcium carbonate and magnesia chewable tablets currently describe manual titration as the assay procedure for calcium and magnesium. The USP has embarked on a global initiative to modernize many of the existing monographs across all compendia. In response to this initiative, two alternative analytical methods were developed to determine the analytes calcium and magnesium. This Application Note presents ion chromatography (IC) procedures using conductivity detection that provide better accuracy and specificity and are suitable for the intended purpose. These validated IC methods (according to USP General Chapter <1225>) offer a significant improvement to the existing assays because they can simultaneously determine both analytes calcium and magnesium, saving both time and effort.

The determination of the potassium content in foodstuffs plays a major role in the food and dietary supplement industry, as potassium is an essential mineral nutrient for humans. It is an important intracellular cation and also plays a important role in processes within cells, where it is involved in the regulation of numerous body functions like blood pressure, cell growth and muscle control.As a dietary supplement, potassium is present in e.g., electrolyte powder, electrolyte drinks and food supplements. To quantify the potassium content in such products, e.g. flame photometry can be used. In this work, an alternative, ion measurement by standard addition, is described, which is fast, inexpensive and simple to use.

The water content of piperidine and piperazine is determined according to Karl Fischer using a buffered solvent mixture.

Karl Fischer titration can be used to determine the water content in N-acetyl-L-cysteine. Special solvent mixtures can be used to prevent unwanted side reactions in the Karl Fischer titration. The water content of N-acetyl-L-cysteine can thus be determined quickly and accurately, as is shown in this Application Note.

Determination of acetate, chloride, citrate, and sulfate in a concentrate of an infusion solution using anion chromatography with direct conductivity detection. Non-suppressed IC is used to avoid interferences by the amino acids.

Determination of acetate, phosphate, chloride, and citrate in an infusion solution using anion chromatography with direct conductivity detection.

Gentamicin is an aminoglycoside antibiotic and is composed of a number of related gentamicins. It is applied for several types of infections. For the determination of the major components, USP asks for chromatographic separation with pulsed amperometric detection using a gold working electrode. A post-column addition of NaOH is performed prior to the detection.

Determining the oxidation stability of raw materials for the cosmetic and pharmaceutical industry.

Determination of bromide and sulfate using anion chromatography with conductivity detection after chemical suppression.

Determination of fluorophosphate in effervescent tablets using anion chromatography with conductivity detection afterchemical suppression applying a step gradient to elute strongly retained components.

β-glycerophosphate and malate are determined in a pharmaceutical formulation. Excellent separation of β-glycerophosphate and malate from α-glycerophosphate and phosphate is possible with the aid of a carbonate eluent and the Metrosep A Supp 7 - 250/4.0 column.

Sodium fluoride tablets for pharmaceutical use need to comply with U.S. Pharmacopeia (USP) requirements. Ion chromatography (IC) with suppressed conductivity detection has been approved by the USP as a validated method to quantify fluoride content in sodium fluoride tablets. In the course of the USP monograph modernization, using automated IC makes this type of analysis even easier.