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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.

The NanoRam is able to test material through multiple layers of transparent plastic bags. Postive identification of material on PE bags from 1 to 9 layers were obtained, demonstrating minimum interference from the PE bags on the material identification result.

The emergence of counterfeit prescription drugs has become a concern for the pharmaceutical industry. Because of the low concentrations of APIs found in pharmaceutical drugs, normal Raman spectroscopy is typically not sensitive enough to detect the API from the surface of a pill. In this study we develop a surface-enhanced Raman spectroscopy (SERS)-based approach to identify a low-dose of the API alprazolam in a Xanax tablet using a handheld Raman spectrometer. If no SERS peaks consistent with alprazolam are observed from a Xanax tablet, the pill is a suspected fake. The method demonstrates the power of SERS to quickly verify the presence of alprazolam in the tablet for anti-counterfeiting purposes.

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.

A new Raman system design is presented that expands the applicability of Raman to See Through diffusely scattering media such as opaque packaging materials, as well as to measure the Raman spectrum and identify thermolabile, photolabile, or heterogeneous samples.

Edible oils are not only a major source of nutrition but also a key basic material in the food industry. Vegetable oils are increasingly important because of their high content in mono- and polyunsaturated fatty acids in comparison with animal fats. In this application note, the main ingredients of olive oil, camellia oil, arachis oil, sunflower seed oil, and colza oil are analyzed using a portable Raman spectrometer combined with chemometrics software.

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.

Metrohm’s ST Raman technology enables fast, contactless identification of substances through opaque packaging, expanding safe, field-ready use of Raman spectroscopy.

Analytical methods to perform CU testing should ideally be fast, noninvasive and achieved with limited sample preparation. Recently, transmission near-infrared (NIR) spectroscopy and transmission Raman spectroscopy have both been explored as alternative methods for rapid and non-destructive on- and at-line CU testing with no sample preparation. Although quick and nondestructive, transmission NIR spectroscopy suffers from poor chemical selectivity and is sensitive to changes in the testing environment. Transmission Raman spectroscopy combined with chemometric modeling is quickly emerging as a valued technique for CU testing due to its high chemical specificity, which is particularly useful when dealing with complex pharmaceutical formulations that contain multiple components.

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 solutions have improved the ability to do complete incoming raw material testing quickly without the need for sample preparation. The NanoRam handheld Raman contributes to increased quality testing with a cost-effective technology used at point of receipt, thus minimizing steps to material acceptance, giving a high return on investment (ROI).

The combination of Raman spectroscopy and vapor sorption techniques provides a comprehensive understanding of vapor-solid interactions of pharmaceutical materials as it relates to the structural properties.This paper investigates the in-situ monitoring of a moisture-induced polymorphic transformation (D-mannitol from delta to beta form) using a combined Raman-vapor sorption technique.

This technical note is to demonstrate the NanoRam material identification through dark brown plastic bags. NanoRam is shown to work for material identification inside dark brown polyvinyl bag.

Ternary mixtures of aqueous sugar solutions are measured and multivariate models of the concentration of analytes developed using BWIQ software.

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.

The RVM method requires only a few spectra to make a model and can be quickly developed on the NanoRam-1064. Multivariate analysis of the Raman spectra on handheld Raman instruments provides more robust methodologies for identifying samples.

In this note, we use a model drug, acetaminophen, to demonstrate the capability of QTRam® to quantify low concentrations of API in compressed tablets.QTRam® is a compact transmission Raman analyzer designed specifically for content uniformity analysis of pharmaceuticals in solid dosage forms.

Cellulose is a common naturally-derived raw excipient found in the majority of pharmaceutical products. Raw material testing is required to ensure that consumers are receiving quality cellulose and its derivatives. The NanoRam®-1064 is an asset for pharmaceutical identity testing, minimizing fluorescence generated by typical handheld Raman systems with 785 nm lasers. As such, the NanoRam®-1064 is used here to identify cellulose derivatives that would normally fluoresce with a 785 nm laser.

Botanicals are derived from plant materials and used for their medicinal and therapeutic properties in the nutraceuticals market. They are not as heavily regulated by the U.S. Food and Drug Administration (FDA) like the pharmaceuticals drug market, but they are required to follow Good Manufacturing Practice (GMP Requirements).The NanoRam®-1064 is an asset for pharmaceutical identity testing, minimizing fluorescence generated by typical handheld Raman systems with 785 nm lasers. As such, the NanoRam®-1064 is used here to identify botanicals that would normally fluoresce with a 785 nm laser.

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.

In this case study, a suspected counterfeit Adderall pill was measured directly with a TacticID Mobile using a point-and-shoot adapter. The spectra of the suspected couterfeit pill was found to contain cellulose and caffeine, but not the active ingredient. The TacticiD Mobile with 1064-nm laser excitation provides fluorescence suppression, giving those on the front lines a tool in the fight against dangerous counterfeit drugs.

Raman spectroscopy’s use for process analytics in the pharmaceutical and chemical industries continues to grow due to its nondestructive measurements, fast analysis times, and ability to do both qualitative and quantitative analysis. Spectral preprocessing algorithms are routinely applied to quantitative spectroscopic data in order to enhance spectral features while minimizing variability unrelated to the analyte in question. In this technical note we discuss the main preprocessing options pertinent to Raman spectroscopy with real applications examples, and to review the algorithms available in B&W Tek and Metrohm software so that the reader becomes comfortable applying them to build Raman quantitative models.

100% starting materials identification testing is one of the FDA’s directives as per 211.84 for FDA regulated industries such as Pharmaceutical, Vaccines, Cosmetics, Tobacco, Animal veterinary products, Food, etc. STRam®-1064 is a Raman analyzer uniquely suited for this purpose. It measures samples through thick packaging materials such as plastics, multilayer kraft paper sacks, and HDPE containers. A long wavelength laser is used to suppress fluorescence. The ID algorithm isolates the sample signature by subtracting that of the packaging material and compares that with library spectra to achieve identification.

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.

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.

The water content of tablets determines the release of their active ingredients as well as their chemical, physical, microbial and shelf-life properties. Accordingly, the water content is of crucial importance and has to be accurately determined. This paper describes the straightforward determination of the water content using automated volumetric Karl Fischer titration (KFT). Tedious sample preparation steps are eliminated by using a high-frequency homogenizer that additionally serves as a stirrer. Prior to titration, the homogenizer comminutes the tablets directly in the KF solution. As the comminution process takes place directly in the hermetically sealed titration vessels, interference from atmospheric humidity does not occur. Even after 24 h in the vessels, the moisture content of four different tablet type samples was within 93…108% of the initially determined values. With a coefficient of determination of 0.99993 the KF method is highly linear for water amounts between 4 and 215 mg. For all investigated tablet types, KFT provides results that lie within the range expected by the manufacturer.

Inline coupling of the 815 Robotic Soliprep with an ion chromatograph (IC) allows the straightforward determination of anions and cations in tablets. After automatic solvent addition and subsequent comminution, the homogenized tablet samples (Singulair and Bezafibrat) are filtered and subsequently transferred to the injector. The completely automated sample preparation saves both time and money, guarantees traceability of each sample preparation step and yields correct and precise results. In the range of 0.2…50 mg/L, six-point calibration curves for anions and cations yield correlation coefficients better than 0.99990 and 0.99991, respectively. While relative standard deviations (RSDs) for sub-ppm levels of nitrate, sulfate, calcium and magnesium in Singulair and Bezafibrat are smaller than 3.64%, RSD of ppm levels of chloride is better than 0.83%. The application of further inline sample preparation steps such as pulverizing, extracting, filtering or diluting facilitates numerous custom-tailored setups for ion determinations in exacting matrices such as animal feed, sediments or food.

The analytical challenge treated by the present work consists in detecting sub-ppb concentrations of low-molecular-weight amines in the presence of strongly retained cationic drugs by using ion chromatography (IC) with upstream inline coupled-column matrix elimination (CCME). In contrast to direct-injection IC, where the late elution of strongly retained drugs requires eluents with added acetonitrile, the CCME technique uses two preconcentration columns in series. In an «inverse matrix elimination step, cationic drug and target amines are trapped on a high-capacity and a very-high-capacity preconcentration column, respectively. During amine determination, a rinsing solution flushes the drug to waste. This significantly shortens the analysis time and improves sensitivity as well as selectivity. Besides the determination of monomethylamine in Nebivolol hydrochloride discussed here, the CCME technique is a promising tool for detecting further low-molecular-weight amines in a wide range of drugs.

The 800 Dosino controlled by tiamo™ or Touch Control can be used universally for dosing and liquid handling tasks in both the analytical laboratory or directly in the synthesis laboratory. This poster looks at three typical liquid handling applications, the synthesis of metal-organic compounds, the preparation of standards, and the determination of pharmaceutical ingredients.

The poster describes the water determination in pharmaceuticals using the Karl Fischer oven technique.

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.

Pharmaceutical analysis guarantees drug safety by providing information on the identity, content, quality, purity, and stability of pharmaceutical products using analytical chemistry. Ion chromatography (IC) offers a broad range of pharmacopeia-compliant applications for quality control, monitoring, and improving drug manufacturing.As a very accurate and versatile technique, IC meets the requirements of many pharmaceutical applications. IC is a USP-accepted standard method for the determination of active pharmaceutical ingredients (APIs), excipients, impurities,pharmaceutical solutions as well as pharmaceutical starting materials, finished pharmaceutical products (FPPs) and even body fluids.This poster describes some typical examples.

This poster presented jointly with USP at AAPS meeting shows the new USP method for zinc as per <591> using Ion Chromatography which is highly selective and sensitive. Selectivity is achieved by separation and further improved with PCR reaction. Sensitivity and wide linear quantification limit make the new USP method ideal for QA/QC. Automated PCR delivery makes the overall method performance easy to validate.

This poster presented jointly with USP at AAPS meeting shows, that we successfully developed and validated a single IC procedure for potassium assay and identification in potassium bicarbonate and potassium chloride for effervescent oral suspension. The optimized chromatographic conditions could be used for other cationic impurities, such as magnesium, calcium, sodium, and ammonium in potassium bicarbonate and potassium chloride for effervescent oral suspension. Single chromatographic method for assay and identification simplifies the overall QA/QC workflow.

This poster presented jointly with USP at AAPS meeting shows, that we successfully validated an IC method to determine chloride and sulfate in drug substances, potassium bicarbonate and potassium carbonate. The proposed IC method overcomes limitations of the turbidimetry/visual comparison methods.

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.

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.

Fluoride is commonly used in dental products to help prevent tooth decay. When fluoride is present in high concentrations, these products are regulated by 21 CFR 355. Three fluoride compounds used in over the counter (OTC) anti‐cavity dental products are sodium fluoride, stannous fluoride and sodium monofluorophosphate (MFP). The assay of fluoride in these active ingredients and finished formulations are determined by manual titration, or by ion‐selective electrodes. As a part of USP’s global monograph modernization initiative, an alternative selective and sensitive method has been developed and validated – ion chromatography (IC). The proposed IC method can also be used for the identification test as an alternative to the wet chemistry method.

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.

This Bulletin is a supplement to Application Bulletin no. 36 (Half-wave potentials of inorganic substances) in the sense that the half-wave potentials of 100 different organic substances are listed. At the same time the supporting electrolytes used and the limits of determination are given.The various substances are listed in alphabetical order. The most important polarographically active functional groups are taken into consideration. This means that substances for related structures can also be determined polarographically in the same or similar supporting electrolytes, although they may not appear in the list.Unless otherwise stated, the half-wave potentials refer to a temperature of 20 °C, and the potentials are given in volts, measured with a sat. KCI-Ag/AgCl electrode assembly.The determination limits give the smallest concentrations which can be measured without risking serious errors in the results. In all cases, the limit of detection lies below the limit of determination.

This Application Bulletin describes the voltammetric determination of the elements antimony, bismuth, and copper. The limit of detection for the three elements is 0.5 ... 1 µg/L.

This Application Bulletin gives an overview of the volumetric 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 E203.

This Application Bulletin describes the determination of mercury by anodic stripping voltammetry (ASV) at the rotating gold electrode. With a deposition time of 90 s, the calibration curve is linear from 0.4 to 15 μg/L; the limit of quantification is 0.4 μg/L.The method has primarily been drawn up for investigating water samples. After appropriate digestion, the determination of mercury is possible even in samples with a high load of organic substances (wastewater, food and semi-luxuries, biological fluids, pharmaceuticals).

In addition to its natural occurrence in fruit and vegetables, ascorbic acid (Vitamin C) is used as an antioxidant in foods and drinks. Ascorbic acid is furthermore also to be found in numerous drugs.Ascorbic acid and its salts and esters can be determined with titration or by using polarography, for which ascorbic acid is oxidized to form dehydroascorbic acid.Bi-voltammetric or photometric equivalence point indication can be used for titrimetric determination. It must be taken into account here that only bi-voltammetric indication is independent of the inherent color of the sample. Polarography is the most selective of the methods described, as other reducing or oxidizing substances are not recorded.

This Bulletin describes the complexometric potentiometric titration of metal ions. An ion-selective copper electrode is used to indicate the endpoint of the titration. Since this electrode does not respond directly to complexing agents, the corresponding Cu complex is added to the solution. With the described electrode, it is possible to determine water hardness and to analyze metal concentrations in electroplating baths, metal salts, minerals, and ores. The following metal ions have been determined: Al3+, Ba2+, Bi3+, Ca2+, Co2+, Fe3+, Mg2+, Ni2+, Pb2+, Sr2+, and Zn2+.

Potentiometric titration is an accurate method for determining chloride content. For detailed instructions and troubleshooting tips, download our Application Bulletin.

This Application Bulletin describes a voltammetric method for the determination of aluminum in water samples, dialysis solutions, sodium chloride solutions and digestion solutions (e.g. of lyophilisates). The method utilizes the complexation of the Al3+ ion by Calcon (Eriochrome blue black R). The formed complex can easily be reduced electrochemically at 60 °C. The limit of quantitation depends on the purity of the reagents used and is approx. 5 µg/L.

Although the known photometric methods for the determination of ammonia/ammonium are accurate, they require a considerable amount of time (Nessler method 30 min, indophenol method 90 min reaction time). A further disadvantage of these methods is that only clear solutions can be measured. Opaque solutions must first be clarified by time-consuming procedures. These problems do not exist with the ion-selective ammonia electrode. Measurements can be easily performed in waste water, liquid fertilizer, and urine as well as in soil extracts. Especially for fresh water and waste water samples several standards, such as ISO 6778, EPA 350.2, EPA 305.3 and ASTM D1426, describe the analysis of ammonium by ion measurement. In this Application Bulletin, the determination according to these standards is described besides the determination of other samples as well as some general tips and tricks on how to handle the ammonia ion selective electrode. Determination of ammonia in ammonium salts, of the nitric acid content in nitrates, and of the nitrogen content of organic compounds with the ion-selective ammonia electrode is based on the principle that the ammonium ion is released as ammonia gas upon addition of excess caustic soda:NH4+ + OH- = NH3 + H2OThe outer membrane of the electrode allows the ammonia to diffuse through. The change in the pH value of the inner electrolyte solution is monitored by a combined glass electrode. If the substance to be measured is not present in the form of an ammonium salt, it must first be converted into one. Organic nitrogen compounds, especially amino compounds are digested according to Kjeldahl by heating with concentrated sulfuric acid. The carbon is oxidized to carbon dioxide in the process while the organic nitrogen is transformed quantitatively into ammonium sulfate.

Potassium is one of the most common elements and can be found in many different minerals and other potassium compounds. It is of importance for humans, animals and plants as it is an essential mineral nutrient and involved in many cellular functions like cell metabolism and cell growth. For these reasons, it is important to be able to declare the potassium content of food or soil to reduce problems that may arise by a potassium deficiency or extensive consumption.This bulletin describes an alternative to flame photometric method using an ion selective electrode and direct measurement or standard addition technique. Several potassium determinations in different matrices using the combined potassium ion-selective electrode (ISE) are presented here. Additionally, general hints, tips and tricks for best measurement practice are given.

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

As the determination of the exact content of individual glycerides in fats and oils is difficult and time-consuming, several fat sum parameters or fat indices are used for the characterization and quality control of fats and oils. Fats and oils are not only essential for cooking, they are also an important ingredient in pharmaceuticals and personal care products, such as ointments and creams. Consequently, several norms and standards describe the determination of the most important quality control parameters. This Application Bulletin describes eight important analytical methods for the following fat parameters in edible oils and fats:Determination of water content in accordance with the Karl Fischer method; Oxidation stability in accordance with the Rancimat method; Iodine value; Peroxide value; Saponification value; Acid value, free fatty acids (FFA); Hydroxyl number; Traces of nickel using polarography; Special care is taken to avoid chlorinated solvents in these methods. Also, as many of the mentioned methods as possible are automated.

Mixtures of aluminum and magnesium ions can be analyzed automatically using potentiometric titration. The excess DCTA is back-titrated with copper(II) sulfate solution after the addition of 1,2-diaminocyclohexanetetraacetic acid (DCTA) and complex formation. The ion-selective copper electrode is used here as the indicator electrode. First, the aluminum is determined in acidic solution and then the magnesium in alkali solution.

Sulfide and sulfite can be determined polarographically without any problems. For sulfide, polarography is performed in an alkaline solution, for sulfite in a slightly acidic primary solution. The method is suitable for the analysis of pharmaceuticals (infusion solutions), wastewater/flue gas water, photographic solutions, etc.

This Application Bulletins describes the determination of nicotinamide (vitamin PP), a vitamin of the B series. Instructions for the determination in solutions (e.g. fruit juice), vitamin capsules and multivitamin tablets are given. The linearity range of the determination is also specified. The limit of detection is approximately 50 μg/L nicotinamide.

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.

This Application Bulletins describes the polarographic determination of thiamine (vitamin B1). The procedure allows an analysis in monovitamin preparations. The linear range of the determination is also given. The limit of detection is approx. 50 µg/L thiamine.

This Application Bulletin describes the polarographic determination of riboflavin (vitamin B2). The procedure allows an analysis in monovitamin preparations. The limit of determination is approx. 100 μg/L.

Diazepam belongs to the 1,4-benzodiazepine group of compounds, which are used for medical purposes as tranquilizers and antidepressants. This Bulletin describes the determination of diazepam in tablets and body fluids (blood, serum, urine) by means of differential pulse polarography. If a Britton-Robinson buffer pH = 2.8 with a methanol volume fraction of 20% is used as the supporting electrolyte then a pronounced reduction peak is obtained at -0.73 V; this allows diazepam concentrations even below 0.05 µg/mL to be determined in blood. The necessary sample preparation steps are also dealt with in this Bulletin.

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.

The present Bulletin offers an overview of the multitude of surfactants and pharmaceuticals that can be determined with potentiometric titration. Metrohm provides five different surfactant electrodes for indicating the titration endpoint: the Ionic Surfactant, the High Sense, the Surfactrode Resistant, the Surfactrode Refill and the NIO Surfactant electrode. The manufacture of the respective titrants and their titer determination are described in detail. In addition to this, the Bulletin contains a tabular overview of more than 170 proven applications from the area of surfactant and pharmaceutical analysis. This guideline leads you reliably to your destination: At a glance you can see from the table which surfactant electrode and which titrant are optimally suitable for your product.

Generally speaking, the gas extraction or oven method can be used for all samples which release their water when they are heated up. The oven method is indispensable in cases in which the direct volumetric or coulometric Karl Fischer titration is not possible, either because the sample contains disruptive components or because the consistency of the sample makes it very difficult or even impossible to transfer it into the titration vessel.The present Application Bulletin describes automatic water content determination with the aid of the oven technique and coulometric KF titration, using samples from the food, plastic, pharmaceutical and petrochemical industry.

This Application Bulletin describes two methods for the determination of iron at the Multi Mode Electrode.Method 1, the polarographic determination at the DME, is recommended for concentrations of β(Fe) > 200 μg/L. For this method the linear range is up to β(Fe) = 800 μg/L.For concentrations < 200 μg/LMethod 2, the voltammetric determination at the HMDE, is to be preferred. The detection limit for this method is β(Fe) = 2 μg/L, the limit of quantification is β(Fe) = 6 μg/L. The sensitivity of the method cannot be increased by deposition.Iron(II) and iron(III) have the same sensitivity for both methods.These methods have been elaborated for the determination of iron in water samples. For water samples with high calcium and magnesium concentrations such as, for example, seawater, a slightly modified electrolyte is used in order to prevent precipitation of the corresponding metal hydroxides. The methods can also be used for samples with organic loading (wastewater, beverages, biological fluids, pharmaceutical or crude oil products) after appropriate digestion.

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).

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.

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.

MATi 11 (MATi = Metrohm Automated Titration) is a completely configured system for water content determination in solid or liquid samples using automated volumetric Karl Fischer titration. It contains a Polytron PT 1300 D for the homogenization of the samples. Up to 53 samples are analyzed directly in 120 mL titration beakers. The samples are weighed in the titration beaker and sealed with aluminum foil and a foil holder so that they neither lose nor absorb water.

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 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 contains information regarding titer determination in Karl Fischer titration, in particular regarding the water standard suitable for a titer determination and for the correct handling of the same.Titer determination for Karl Fischer titrants is indispensable, because the titer is subject to changes caused by the humidity in the air. The frequency of the determination depends on the titrant and the tightness of the system.The titer has the unit mg/mL in Karl Fischer titration. The value calculated in a titer determination indicates how many milligrams of water react on one milliliter of titrant.

This Bulletin describes the automatic measurement of conductivity in water samples with low electrical conductivity in accordance with USP<645>. Conductivity measurement is demonstrated on the example of ultrapure water, which is used, among other things, to produce injection solutions in the pharmaceutical sector.

Pyrithione complexes, such as zinc pyrithione (ZnPT), copper pyrithione (CuPT), and sodium pyrithione (NaPT), are used as fungicides and bactericides. ZnPT is used in the treatment of skin conditions such as seborrheic dermatitis or dandruff. Furthermore, ZnPT is sometimes used as an antibacterial agent in paints to prevent algae and mildew growth. CuPT is primarily in use as a biocide to prevent biofouling of surfaces submerged in water. Meanwhile, NaPT is used as antifungal agent for treatment of mycosis, such as athlete’s foot. The different pyrithione complexes are determined by iodometric titration using a maintenance-free Pt Titrode for the indication.

Determination of sodium, potassium, calcium, and magnesium in a drip feeding formula using cation chromatography with direct conductivity detection and dialysis as sample preparation.

Determination of sodium, ammonium, potassium, calcium, and magnesium in 4% boric acid using cation chromatography with direct conductivity detection.

Determination of betaine in the presence of standard cations in an Echinacea product using cation chromatography with direct conductivity detection.

Determination of zinc, sodium, potassium, magnesium, and calcium in an infusion solution using cation chromatography with direct conductivity detection.

Determination of trans-4-methylcyclohexylamine in a pharmaceutical product using cation chromatography with direct conductivity detection.

Determination of tributylamine in a pharmaceutical product (gabapentine) using cation chromatography with direct conductivity detection.

Determination of N-methylpyrrolidone (N-MP) in a pharmaceutical product (Cefepime Hydrochloride) using cation chromatography with direct conductivity detection.

Determination of Bethanechol chloride and calcium in tablets using cation chromatography with direct conductivity detection.

Determination of Bethanechol Chloride and HPTA (2-hydroxy-propyl-trimethyl ammonium chloride) besides sodium and calcium 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.

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

Bethanechol is a pharmaceutical compound which is used to treat urinary retention. This API (active pharmaceutical ingredient) can be determined by cation chromatography with direct conductivity detection. A good separation is achieved between bethanechol and its degradation product 2-hydroxy-propyl-trimethyl ammonium (HPTA) and the standard cations. Peak shape and resolution meet the USP requirements for bethanechol.

2-amino-N-(2,2,2-trifluoroethyl)-acetamide is a organic building block for synthesis of pharmaceutical products. Its purity is crucial for the success of the respective synthesis step. 2,2,2-trifluoroethylamine, glycine, and inorganic cations are of interest. Their total peak area is required to be < 2 % of the peak area of all peaks above the reporting level. Separation and quantification is achieved on a Metrosep C 4 - 250/4.0 cation column.

A cardioplegic solution protects the ischemic myocardium from cell death. It is applied together with hypothermia e.g. in open heart surgery. Here the simultaneous determination of aspartic acid, glutamic acid, tris(aminomethyl)aminomethane (TRIS), sodium and potassium in such a solution is given. The two amino acids can be determined as they are partially in the triple protonated ammonium form at the eluent pH. Determination is achieved by direct conductivity detection.

Within the scope of the USP monograph modernization, potassium is determined in potassium bitartrate applying cation chromatography with direct conductivity detection. The USP41 monograph for “Potassium bitartrate” does not yet mention an assay for potassium. The separation is performed on a Metrosep C 6 - 150/4.0 column (L76). The assay of potassium is performed with two commercially available products according to USP definitions. All acceptance criteria are fulfilled.

Within the scope of the USP monograph modernization, potassium is determined in potassium sodium tartrate applying cation chromatography with direct conductivity detection. The USP41 monograph for “Potassium sodium tartrate” does not yet mention an assay for potassium. The separation is performed on a Metrosep C 6 - 150/4.0 column (L76). The assay of potassium is performed with two commercially available products according to USP definitions. All acceptance criteria are fulfilled.

Within the scope of the USP monograph modernization, potassium is determined in potassium bicarbonate effervescent tablets for oral suspension applying cation chromatography with direct conductivity detection. The separation is performed on a Metrosep C 6 - 150/4.0 column (L76). All acceptance criteria are fulfilled.

As an alternative to flame photometry, ion chromatography with non-suppressed conductivity detection has been approved by the USP as a validated method to quantify potassium and sodium content in potassium and sodium bicarbonates and citric acid effervescent tablets for oral solution. The present IC method has been validated according to USP General Chapter <621>.

As an alternative to flame photometry, ion chromatography with non-suppressed conductivity detection has been approved by the USP as a validated method to quantify potassium content in potassium bicarbonate and potassium chloride effervescent tablets for oral solution. The Metrosep C 6 - 150/4.0 column (L76) provides the required separation of potassium and magnesium. The present IC method has been validated according to USP General Chapter <621>.

Within the scope of the USP monograph modernization, sodium is determined in potassium sodium tartrate applying cation chromatography with direct conductivity detection. The USP41 monograph for «Potassium sodium tartrate» does not yet mention an assay for sodium. The separation is performed on a Metrosep C 6 - 150/4.0 column (L76). The assay of potassium is performed with two commercially available products according to USP definitions. All acceptance criteria are fulfilled. See AN-C-182 for the respective determination of potassium. Apllying this method allows to determine sodium and potassium simultaneously according to USP.

Potassium bitartrate for pharmaceutical use must comply with USP requirements. The actual monograph (USP 42) uses a colorimetric method for the determination of ammonium impurities. Ion chromatography allows the measurement in a single determination under the same conditions used for the potassium assay (see AN-C-181). In the course of the USP monograph modernization, this ion chromatographic approach makes this type of analysis even easier.

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.

Tris(hydroxymethyl)aminomethane (TRIS) is often used in life science applications and its purity must be monitored. This analysis is possible with ion chromatography.

Potassium citrate and citric acid oral solutions act as systemic alkalizers. Potassium assays, validated per USP <621> and <1225>, use IC with L76 cation-exchange columns.

The assay of calcium acetate, often used as a phosphate binder for dialysis patients, can be performed with ion chromatography (IC) as per USP <621> and <1225>.

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

The manufacture of ultrapure water for the pharmaceuticals industry or the semiconductor industry requires high-quality ion exchangers. Metrohm Combustion Ion Chromatography is an indispensable tool in this connection for testing the purity of anion exchange material. The output sample was wet and had to be dried at 105 °C in a special oven with waste air evacuation.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).

Ezetimibe is a cholesterol-reducing drug. It reduces the cholesterol resorption in the small intestine. The molecule holds two fluorophenyl groups. Applying Combustion IC the amount of fluorine in the drug is determined. To avoid an excessive introduction of fluoride into the system, Ezetimibe is dissolved in ethanol prior to the combustion.

Atorvastatin is a medication that is used for reducing cholesterol levels. A sensitive and reliable method for TBA detection is required, given that trace amounts of tetrabutylammonium (TBA) are to be found in the presence of atorvastatin and its derivatives. One such method is ion chromatographic separation on the Metrosep C Supp 1 - 250/4.0 with subsequent conductivity detection and sequential suppression.

Meropenem is a beta-lactam antibiotic that is classed among the carbapenems; it suppresses murein biosynthesis and thus the buildup of the bacterial cell wall. Dimethylamine is an important precursor in meropenem synthesis and must therefore be monitored as an impurity. Detection is performed on the Metrosep C Supp 1 - 250/4 column with subsequent conductivity detection after sequential suppression.

Sequential suppression in cation chromatography significantly improves detection limits. The determination of the blank value of the sample vial being used is thus essential for being able to achieve such low detection limits. The leaching tests of various sample vials proceed with the intelligent Preconcentration Technique with Matrix Elimination on the Metrosep C Supp 1 - 250/4.0 column with conductivity detection following sequential suppression. The 50 mL Corning® Cell Culture Flasks from Sigma-Aldrich (CLS430168) exhibit the lowest blank values.

Trace cation analysis in high purity water (sub-μg/L range) requires cation chromatography after sequential suppression and intelligent Preconcentration Technique (MiPCT). Trace cations in deionized water (DI) are determined and the method detection limit (MDL according to US EPA) as well as the limit of detection (LOD = 3 x S/N) is calculated. MDL and LOD are very similar in the lowest ng/L range for this setup with 6 mL preconcentration volume.

Succinylcholine is a short-term paralyzing agent used e.g., for tracheal intubation. Choline is a building block of the drug and needs to be determined as an impurity. USP applies cation chromatography with conductivity detection after suppression. Eluent composition and column type do not exactly comply with the USP method. However, the results fulfill the respective requirements. The choline concentration of the sample is out of USP specifications.

Compounded injections of sodium bicarbonate are sterile solutions for correcting metabolic acidosis and other conditions requiring systemic alkalinization. Compounded injections of sodium phosphates serve as a phosphate source to either prevent or correct hypophosphatemia in patients with restricted oral intake. Ion chromatography (IC) with suppressed conductivity detection is the standardized way to accurately quantify sodium in these solutions.

Ion chromatography (IC) provides an automated, fast, and sensitive solution to accurately quantify cationic and anionic components including acetate simultaneously. This comprehensive approach makes IC an economic alternative to traditional techniques for the quality control of pharmaceutical solutions like haemodialysis concentrates. Ease-of use, accuracy, and the high-throughput of IC increase productivity and comply with the demands of modern routine and research labs.

Iron sucrose injections are used during the treatment of iron deficiency anemia. They contain a mixture of ferric iron (Fe3+) and ferrous iron (Fe2+). Ferrous iron content may be determined by subtracting the ferric iron content from the total determined iron content. Yet, this increases the measurement error due to error propagation. Alternative determination of iron(II) with cerium(IV) by potentiometric titration may be hampered, as the equivalence point cannot be determined unequivocally. Determination by thermometric titration is a more robust and therefore more reliable alternative, as this method is unaffected by the sample matrix. Here, the endpoint of the titration is indicated by a fast responding thermometric sensor. Endpoint detection is further improved by spiking the sample with 0.2% ammonium iron(II) sulfate (FAS), increasing the reliability of the determination. Compared to potentiometric titration, thermometric titration is faster and more convenient as no sensor maintenance is required. One determination takes about 2–3 minutes.

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.

Excess sodium intake increases the risk of health issues. Ion-selective electrodes (ISEs) offer a fast, accurate, and cost-effective method for measuring sodium in food.

The water content of lyophilisates contained in vials is determined by Karl Fischer titration. Conditioned solvent (methanol) is injected into the vial to dissolve the sample and extract the water (ultrasonic bath). Afterwards the contents of the vial are transferred to the titration vessel to carry out the automatic determination.

The water content of ointments is determined according to Karl Fischer. Because of their high water and fat content, the samples are prediluted with a 1:1 mixture of chloroform and methanol.

The water content of acetophenone and benzophenone is determined according to Karl Fischer using special KF reagents for ketones/aldehydes to prevent unwanted side reactions.

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.

This application note describes the water content determination in penicillin by using volumetric Karl Fischer titration. Unwanted side reactions can be avoided by using special solvent mixtures.

The water content of aniline is determined according to Karl Fischer in buffered solvent.

The water content in panthenol is determined according to Karl Fischer.

This Application Note describes the determination of the water content in tablets using automated volumetric titration including sample preparation (MATi 11).

The water content determination by volumetric Karl Fischer titration is one of the most important analyses worldwide. Using an OMNIS system consisting of an OMNIS Titrator and an OMNIS Sample Robot, the fully automatic analysis of water content is possible in various products and matrices. The OMNIS Sample Robot is capable of running several different titrations in parallel. In this Application Note, we present the results of a volumetric Karl Fischer titration run in parallel to an aqueous acid-base titration on the same system. The water content is not influenced by the parallel running aqueous titration, allowing the combination of potentiometric titrations and Karl Fischer titrations on the same automated system.

Karl Fischer reagents contain buffer substances (usually imidazole) since the reaction constant is dependent on the pH value. A constant pH therefore ensures the most repeatable results. In 2015, imidazole was classified by European Union the as a CMR (carcinogenic, mutagenic or toxic) substance and the statement H360D was added, stating possible harm to fertility or a fetus. Meanwhile, other reagents free of imidazole are available for purchase. This Application Note summarizes test measurements with 34433 HYDRANAL™ NEXTGEN Coulomat AG-FI.

Test measurements on water standards are performed with an OMNIS KF Titrator and Karl Fischer reagents Aquagent® Complet 5 and Methanol Fast from Scharlau.

Determination of acetate, lactate, and chloride in electrolyte solutions using anion chromatography with direct conductivity detection.

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, chloride, and malate in an infusion solution using anion chromatography with direct conductivity detection.

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

Alendronate, also referred to as alendronic acid, is a biphosphonate used to treat osteoporosis. It is the main ingredient in the tablets and is determined in accordance with the Chinese Pharmacopoeia (2015). Separation takes place in the Metrosep A Supp 4 - 250/4.0 column; direct conductivity detection is used for quantification.

Two of the leading pain remedies, aspirin and acetaminophen, are compared with generic samples for content uniformity testing using near-infrared spectroscopy (NIRS). The method of standard addition is used for quantification. To reduce most of the effects that stem from particle size and packing differences, second derivative spectra are used.

This Application Note shows the potential of NIRS as a rapid (< 30 s) and nondestructive screening tool for solid dosage forms (e.g. tablets). NIRS requires neither sample preparation nor solvent use. Interferences that derive from scattering are minimized by converting to second derivative spectra.

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.

Well-mixed active substances for medications are indispensable in the pharmaceutical industry. This applies not only to the pharmaceutical active ingredient but also for lubricants, binding agents, explosives, oxidants and dyes. Analysis of these active ingredients is expensive; they are also only rarely analyzed as a rule. The progress of the mixing procedures can be followed conveniently with NIR spectroscopy, on the one hand using visual comparisons and on the other by means of spectral algorithms. The progress of mixing processes can be predicted in real time with the help of the spectrum when the latter is used.

This Application Note describes the utilization possibilities of a new sensor design that permits, in combination with an NIRS XDS Process Analyzer, the determination of solvent residues in a High-Shear Granulator during the drying phase. This system configuration reduces the scattering of the density distribution of the powder samples so that it is possible, directly in the process, to model the water and solvent content precisely.

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 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.

The purity of a recovered solvent (dichlormethane/methylene chloride) and two of its most important contaminants (methanol and water) are monitored with NIR spectroscopy.

This Application Note shows how, with the help of Vis-NIR spectroscopy and a special plant library, 46 different medicinal and aromatic plants, e.g., Organicum majoricum and Tilia cordata, can be conveniently identified on the basis of their spectrum. In comparison with alternative methods for the determination of plants, which are elaborate and require experienced scientists for their performance, the Vis-NIR method permits rapid and uncomplicated identification.

Sulfathiazoles are sulfonamides with antibiotic effect that occur in various polymorphous forms and that are often used in veterinary medicine. This Application Note shows the differentiation between commercial and sulfathiazole form I using near-infrared spectroscopy (NIRS) with the help of the overtone frequencies of N-H stretching vibration. Form I is the least stable polymorphous form. Crystallization and polymorphism must be monitored as part of quality controls. In this, NIRS is considerably more rapid and more reliable than conventional laboratory methods.

Heparin acts as an efficient anticoagulant and, in addition to direct injection, is also used as a lock-flush solution for rinsing catheters. Vis-NIR spectroscopy can be used to determine the strength of contaminated and purified heparin. This Application Note demonstrates that heparin strength can be determined reliably with Vis-NIR spectroscopy.

Near-infrared spectroscopy (NIRS) was used as an analysis method for quality control of aqueous xanthan gum solutions. Quantitative models for the determination of optical density, glucose, and xanthan gum were developed, enabling fast and reliable quality control.

This Application Note shows that visible near-infrared spectroscopy (Vis-NIRS) can be used for the quantification of Baicalin content in herbal supplements. Vis-NIRS is a good alternative to the conventional lab method (HPLC) and can save both cost and time.

Uniformity of dosage units must be tested for QC purposes in the pharma industry. NIRS gives results in seconds along with the quantification of APIs and excipients.

This Application Note presents Vis-NIR spectroscopy as a viable alternative to determine API content in cefixime tablets without sample preparation.

Water activity is an important parameter to measure for non-sterile pharmaceutical quality and stability. The OMNIS NIR Analyzer provides this data within seconds.

Polyvinyl alcohol (PVA) is a linear polymer, used in a variety of medical products (e.g. eye drops). Here, the degree of alcoholysis is an important index for the water solubility, viscosity, and adhesion of the product. The degree of alcoholysis is defined as the percentage of hydroxyl functional groups compared to the total functional groups accessible in the molecule. Conventional alcoholysis determination can take up to six hours per sample. Compared to the primary method, analysis with near-infrared spectroscopy (NIRS) only takes one minute. The following application note describes the determination of the degree of alcoholysis by NIRS.

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.

Cannabidiol (CBD) is a popular natural remedy from the cannabis plant used in many pharmaceutical, food, and cosmetic products. Unlike tetrahydrocannabinol (THC), CBD is not psychoactive, making it an appealing option for those who are looking for relief from pain and other symptoms without mind-altering effects. CBD oil is made by extracting the cannabinoid from the plant, then diluting it with a carrier oil (e.g., coconut or hemp seed oil). The standard HPLC method requires 45 minutes to perform by highly trained analysts. In contrast to the primary method, Vis-NIR spectroscopy is a cost-efficient and fast analytical solution for the determination of cannabinoid content in edible oils.

Cell fermentation processes are a reliable production method for small molecules and protein-based active pharmaceutical ingredients (APIs). The fermentation process requires monitoring of many different parameters to ensure optimal production. These quality parameters include pH, bacterial content, potency, glucose, and concentration of reducing sugars. Traditional laboratory analysis takes a significant amount of time and requires different analytical techniques to monitor these different quality parameters. Near-infrared spectroscopy (NIRS) offers a faster and more cost-efficient alternative to traditional methods for the determination of critical parameters in fermentation broths at any stage of the fermentation process.

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 how easy it is to determine water content in the pharmaceutical excipient lactose with reagent-free near-infrared spectroscopy.

Determination of citric acid and ascorbic acid in vitamin tablets using ion-exclusion chromatography with direct conductivity detection.

Determination of citric acid and tartaric acid in fruit salt using ion-exclusion chromatography with direct conductivity detection.

Traditionally, catecholamines are separated using reversed-phase chromatography followed by amperometric detection. This Application Note describes the determination of catecholamines in an emergency medication for life-threatening allergic reactions.

Propylene glycol, also called propane-1,2-diol, is a humectant and applied in topical solutions to increase the solubility of the active pharmaceutical ingredient (API) or the ability to penetrate the skin. In this application, propylene glycol is determined in a placebo and two topical solutions containing diclofenac as the API. The separation is achieved on a Hamilton RCX-30-250/4.0 column with subsequent pulsed amperometric detection (PAD).

The separation of lactose, lactobionic acid, sialic acid*, 6’-sialyllactose, and 3’-sialyllactose is shown as a proof of concept for the control of these components in fermentation process for a pharmaceutical product. The acceptance criterion of a minimum resolution of the peaks (< 1.3) is reached. The separation is achieved on a Metrosep Carb 2 - 250/4.0 column with subsequent pulsed amperometric 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.

Worldwide, milk and dairy products are vital sources for human nutrition. A major component and energy source in dairy products is lactose. To efficiently metabolize lactose, the enzyme lactase is indispensable. However, globally nearly 70% of the population is lactose intolerant and they have difficulties to digest lactose. Lactose malabsorption leads to numerous gastrointestinal and extra-intestinal symptoms and other complaints with varying extents. Therefore, consumers rely on accurate food labels and for manufacturers appropriate sensitive analytical techniques are a must to comply with these demands. Ion chromatography with pulsed amperometric detection (IC-PAD) enables the determination of very low lactose contents. Validation according to AOAC requirements shows the high sensitivity and reliability of this method as a routine analysis.

This Process Application Note provides a detailed account of the inline assessment of moisture during a pilot scale granulation process using a 2060 The NIR Analyzer.

In the pharmaceutical industry, the fluid bed granulator/dryer is an integral point in the manufacture of powdered materials. Residual moisture must be kept within certain specifications to avoid fracturing of particles or caking (stickiness) of the bulk material. Current methods are slow and cumbersome, which can lead to damaged or degraded product. The ability to monitor the residual moisture content inline after drying is possible with near-infrared spectroscopy (NIRS). The 2060 The NIR Analyzer offers fast, reagent-free, nondestructive analysis of residual moisture of powders with a fluid bed probe specifically designed for these applications.

This Process Application Note presents a method to accurately monitor low levels of moisture in tetrahydrofuran (THF) in «real-time» safely, reliably, and optimally with a 2060 The NIR Analyzer from Metrohm Process Analytics. Due to the hazardous and hygroscopic nature of THF, a single explosion-proof inline process analyzer is the preferred solution for industries to reduce chemical treatment, improve product quality, and increase profits.

Accurate analysis of complexing agents in galvanic baths is possible with inline Raman spectroscopy. This Application Note shows an example using a 2060 Raman Analyzer.

This Process Application Note presents a method to accurately monitor lactic acid and glucose inside a bioreactor in «real-time» with the 2060 Raman Analyzer from Metrohm Process Analytics.

The combination of 940 Professional IC Vario, 942 Extension Module Vario LQH and 941 Eluent Preparation Module enables process monitoring with the aid of ion chromatography. Assigned the designation ProfIC Vario 12 Anion, this combination is the anion variant of Metrohm Process IC. Intelligent preconcentration technology with matrix elimination is used for sample preparation. The use of an ELGA PURELAB® Flex 6 guarantees the supply of ultrapure water of the highest quality, particularly in cases of high numbers of samples.

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

Higher antioxidant levels mean longer product viability. The 892 Professional Rancimat determines antioxidant content in many products using a linear regression method.

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.

Raman spectrometers use tightly focused beams to produce high resolution spectra, but fail at analyzing heterogeneous substances because they cannot spatially target all components. ORSTM (Orbital Raster Scan) increases the interrogation area on a sample while maintaining high spectral resolution. Effervescent cold medicines, for example, contain many active ingredients in each heterogeneous tablet. Traditional identification and verification techniques require the collection of several spectra at different points on the tablet. Mira spectrometers equipped with ORS capture a large interrogation area in a very short time, analyzing all of the ingredients in a single scan.

Material verification models with complex algorithms such as Principal Component Analysis (PCA), quasi-infinite parameters, and preprocessing options can be incredibly complex. Each model must be rigorously built, evaluated, and validated before it can be put into routine use. Mira P simplifies material verification for all. With a short, defined user workflow, straightforward results, and a foolproof Operating Procedure-based design, Mira P is already one of the simplest RMID tools available. ModelExpert, in Mira Cal P, does a chemometrician’s work. ModelExpert automatically determines the best model parameters for robust method development. With Mira P and ModelExpert, even non-technical users can achieve better results in a fraction of the time.

This application note presents the Orbital Raster Scan (ORS) technology from Metrohm Raman to overcome low resolution, poor sensitivity, and sample degradation while still interrogating a large sample area.

This Application Note explains how to scale MIRA P usage across an entire manufacturing operation by transferring models between different MIRA P instruments.

This application shows how to seamlessly transition from Metrohm’s NanoRam 785 to the newer MIRA P system, ensuring continuity in raw material identification (RMID).

Metrohm’s MIRA XTR handheld Raman spectrometer enables fast, reagent-free identification of phosphate species, enabling continuous monitoring of dynamic systems.

Undeclared drugs in dietary supplements pose serious health risks. Metrohm’s SERS solutions enable fast, sensitive, on-site detection of adulterants without matrix interference

Low frequency Raman spectroscopy extends conventional Raman analysis by capturing vibrational modes down to 65 cm-1, enabling deeper insights into molecular structure, protein characterization, polymorph identification, and phase changes.

Determination of bromide, nitrate, and phosphate in wastewater using anion chromatography with conductivity detection after chemical suppression and dialysis for sample preparation.

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

Determination of acetate, chloride, phosphate, and succinate in an infusion solution using anion chromatography with conductivity detection after chemical suppression.

Determination of fluoride, sulfate, iodide, and molybdate in mineral tablets using anion chromatography with conductivity detection after chemical suppression.

Determination of chloride, nitrite, bromide, nitrate, and sulfate in water for infusion solution production using anion chromatography with conductivity detection after chemical suppression.

Determination of formate, acetate, chloride, benzoate, and oxalate in phenolic extracts using anion chromatography with conductivity detection after chemical suppression.

Determination of acetate, chloride, sulfate, and citrate in a pharmaceutical product using anion chromatography with conductivity detection after chemical suppression and dialysis for sample preparation.

Determination of chloride in bethanechol tablets 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.

Determination of sulfate in gentamicin sulfate using anion chromatography with conductivity detection after chemical suppression.

Determination of acetate and methanesulfonate (MSA) in olsalazine using anion chromatography with conductivity detection after chemical suppression.

Topiramate is an antiepilepsy drug. According to USP Topiramate tablets have to be tested for impurities. The determination of sulfate and sulfamate is mentioned under 'Specific Tests'. The isocratic method applies a column eluent combination primarily used for non-suppressed IC. But as sulfamate shows a negative peak under theses conditions the use of suppression is advantageous.

Nadroparin is a low-molecular-weight heparin used as a anticoagulant to prevent thrombosis. The determination of sulfate in the sulfur-containing anticoagulant is performed to control the degradation of the product. Thanks to the absence of interfering peaks close to sulfate, a short column could be used.

Azide may be formed during the production of certain pharmaceutical products. It can cause explosions during manufacturing. Therefore, its concentration in the air needs to be monitored in order to prevent such accidents. Azide (N3-) is well separated from standard anions on the Metrosep A Supp 5 - 250/4.0 under standard conditions.

Sodium metabisulfite, also known as pyrosulfite, is used as a preservative and antioxidant in pharmaceutical products. Metabisulfite is not stable in aqueous solutions and quickly converts to sulfite. The peak in the chromatogram originates from the sulfite. This process is however calibrated using metabisulfite standard solutions, which is why the results are specified as sodium metabisulfite. This Application Note describes the determination of metabisulfite as sulfite in an ointment. It is dissolved in an aqueous solution containing formaldehyde to protect the sulfite against oxidation.

4-Hydroxybutyrate (GHB) is numbered among the hydroxycarboxylic acids and is used as a psychoactive drug which is illegal in many countries. GHB can be determined through anion chromatography with suppression. GHB can be separated from the standard anions and the organic acid anions glycolate, acetate and formate on the Metrosep A Supp 16 - 250/4.0 column and under the conditions specific in this Application Note.Key words: Liquid Ecstasy, KO drops

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.

Eltrombopag is a pharmaceutical agent used in certain conditions of thrombocytopenia. As such it is an orphan drug. The molecule of Eltrombopag is a protonated aromatic carboxyl compound. Under ion chromatography condition (alkaline eluent), it can be deprotonated and can thus block ion exchanger sites on the column. This results in decreasing retention times over time. To avoid this, Inline Matrix Elimination is applied, where the protonated Eltrombopag is washed off the preconcentration column before injection. Nitrite is then analyzed with conductivity detection after sequential suppression.

Pamidronate is applied to treat osteoporosis by strengthening the bones. It is a bisphosphonate containing a primary amine group. Phosphite and phosphate are related compounds, which need to be quantified. USP requires the use of formic acid eluent with refractive index detection. But a standard IC procedure offers an alternative with better sensitivity. Phosphite and phosphate are analyzed with conductivity detection after sequential suppression.

Within the scope of the modernization of USP, chloride and sulfate are determined as impurities in potassium hydrogen carbonate (bicarbonate). USP41 monograph for potassium bicarbonate does not check for chloride and sulfate. Applying ion chromatography with conductivity detection after sequential suppression allows quantifying these impurities.

Potassium chloride and potassium bicarbonate effervescent tablets are used to prevent potassium deficiency. Pharmaceutical manufacturers and labs adhere to strict quality regulations using USP-NF monographs. Ion chromatography with suppressed conductivity detection, utilizing the Metrosep A Supp 16 - 100/4.0 (L91) column, is approved by the USP to quantify chloride content in these tablets, following validation per USP General Chapter <621>.

Fluoride is commonly used in dental products to help prevent tooth decay. If the products are intended to prevent the formation of cavities (carries), then it is regulated by the US Food and Drug Administration (USFDA) as an Over-the-Counter (OTC) Drug. Previously, the assay of Fluoride in oral solution was done by Ion selective electrode and identification was done by tedious wet chemistry method. USP has updated this monograph for Assay and identification tests with Ion Chromatography using L46 packing. The Metrosep A Supp 1 - 250/4.6 column fulfills all USP acceptance criteria. It therefore is a viable alternative separation column for the determination of sodium fluoride in oral solutions.

Dental care products often contain sodium fluoride as an active ingredient. Manufacturers use the United States Pharmacopeia and National Formulary (USP-NF) Monograph «Sodium Fluoride» to quantify sodium fluoride and its anionic contaminants chloride and acetate in these products. The validated USP method proposes ion chromatography (IC) with suppressed conductivity detection to carry out the fluoride assay as well as the impurity determination in a single chromatogram.

Sodium fluoride gel for pharmaceutical use needs to comply with USP requirements. The actual monograph (USP 42) uses two different methods for the identification and the assay. Ion chromatography allows the analysis of these two parameters in one single determination. In the course of the USP monograph modernization, this ion chromatographic approach makes this type of analysis even easier.