Pharmaceutical analysis Quality control of pharmaceuticals 02 Metrohm ... • is the global market leader in titration • offers a complete portfolio for NIR and Raman analysis, in addition to all of the methods of • ion analysis – titration, voltammetry, and ion chromatography • is a Swiss company and manufactures exclusively in Switzerland • grants a 3-year instrument warranty and a 10-year warranty on chemical suppressors for anion chromatography • provides you with unparalleled application expertise • offers you more than 1800 applications free of charge • supports you with dependable on-site service worldwide • is not listed on the stock exchange, but is owned by a foundation • takes a sustainable approach to corporate management, putting the interests of customers • and employees ahead of maximizing profit Metrohm – customized analysis for the pharmaceutical industry The high standards of approval authorities You can count on our support 03 Authorities around the globe hold the pharmaceutical As a leading manufacturer of instruments for chemical industry to very high standards of drug quality and safety. analysis, we are well aware of the challenges you face. The standards are documented in official collections of For this reason, Metrohm offers you not only the most recognized pharmaceutical rules in pharmacopoeias. advanced instruments, but also complete solutions for They provide a legal consumer protection framework for analytical studies. Your partners at Metrohm are compe-ensuring that drugs are used safely. Measurement and tent specialists who develop customized applications and testing procedures used in the context of drug testing offer competent support in every aspect of regulatory identify drugs and determine whether they can be compliance. released. Discover the solutions Metrohm offers the pharmaceuti- Reliable instruments and methods are required to guar- cal industry and you in particular for ensuring the quality antee these strict quality and safety standards. and safety of your products. Chemical pharmaceutical analysis The history of pharmacology 04 Determination of active ingredients, excipients, The search for medicines is nearly as old as humanity and impurities itself. Documentary evidence exists to show that active Pharmaceutical analysis provides information on the pharmaceutical ingredients from plant, mineral, and ani-identity, purity, content and stability of starting materials, mal sources were already being used for medicinal pur-excipients, and active pharmaceutical ingredients (API). A poses by the earliest advanced civilizations (China, India, distinction is made between analysis of the pure active Mesopotamia and Egypt). Systematic descriptions of pharmaceutical ingredients used to cure, alleviate, pre-medicines have been handed down to us from Greek vent, or identify illnesses and diseases (active ingredient antiquity (Hippocrates, Theophrastus) and from the analysis) and analysis of drug products (drug product Roman Empire (Dioscorides, Galen). This knowledge was analysis). Drug products come in various forms (oint-adopted and further developed by Arab scholars (e.g., ments, tinctures, pills, lotions, suppositories, infusions, Avicenna). This body of knowledge served for a long time drops, etc.) and consist of the pharmaceutically active as an important basis for pharmacology. It was not until substance and at least one pharmaceutical excipient. the 16th century that the science began its departure Impurities are mainly introduced during the synthesis of from the models passed down from antiquity. A typical the active ingredient, and are usually monitored accord-representative of the new direction was Paracelsus, who ing to both the directives of the ICH (International – in 1537 – coined the famous phrase: «The dose makes Conference on Harmonisation of Technical Requirements the poison» («dosis sola facit venenum»). for Registration of Pharmaceuticals for Human Use) and the pharmacopoeias. The path to organic synthetic drugs The significance of the advances that came with the Pharmacopoeias and drug safety emergence of organic chemistry at the dawn of the 19th According to the World Health Organization (WHO), century cannot be overstated. Although drug therapies specifications and test methods for commonly used up to that point had been limited to naturally occurring active ingredients and excipients are outlined in detail in substances and inorganic chemicals, this changed with monographs contained in the national pharmacopoeias the targeted production of organic synthetic drugs based of more than 38 countries. These include the United on substances isolated from medicinal plants. Within a States Pharmacopeia (USP), the European Pharmacopoeia very short period, an unprecedented advance in pharma- (Ph.Eur.), derived from a harmonization of the regulations ceutical synthesis led to a vast number of synthesized of a number of individual states, and the Japanese active pharmaceutical ingredients. Researchers had final-Pharmacopoeia (JP), to name just a few examples. The ly come to understand the relationship between the pharmacopoeias are official compendia containing statu-action of these substances and their chemical structures. tory requirements pertaining to identity, content, quality, purity, packaging, storage, and labeling of active pharmaceutical ingredients and other products used for therapeutic purposes. They are essential for anyone seeking to produce, test, or market medicinal products. 05 Test methods, tests, and USP-NF monographs Applications in accordance with pharmacopoeias Structure of the USP-NF Metrohm is your qualified partner for all chemical-phar- Four chapters form the backbone of the USP-NF. One maceutical analysis issues and for analytical methods chapter provides the analytical tools of the pharma-validation. In addition to their compliance with official copoeia with a detailed description of test methods and directives, Metrohm instruments and applications comply tests. Test methods numbered from <1> to <1000> are with many of the quality control and product approval mandatory, whereas the procedures with numbers above test methods cited in pharmacopoeias. <1000> are recommended. Harmonization efforts The most comprehensive chapter of the USP-NF contains Based on the harmonization efforts of the a list of the USP monographs, listed alphabetically Pharmacopoeial Discussion Group (PDG), this brochure according to active pharmaceutical ingredient, which relates primarily to selected test methods and mono-provide detailed descriptions of test methods, tests, graphs of the USP as representative of the pharma- requirements, and storage conditions. The scope of the copoias not mentioned here. The National Formulary NF monographs is an order of magnitude smaller and is (NF) is the official compendium of standards for excipi-contained in a separate chapter. Another chapter defines ents and plant-based drugs. the reagents, indicators, and solutions to use. Test methods referenced in USP-NF monographs Application/parameters USP monograph Citation frequency of the test method Test methods Page In approx. 1400 USP monographs pH value USP<791> pH value measurement 6 In approx. 250 NF monographs Conductivity USP<645> Ultrapure water (pharma) Conductivity measurement 6 Various APIs In approx. 250 USP monographs USP<541> Titration 7–11 Various excipients In approx. 130 NF monographs USP<921> In approx. 630 USP monographs Water content Karl Fischer titration 12–13 Method I In approx. 110 NF monographs Various APIs USP<621> In approx. 58 USP and 13 NF monographs Various excipients USP<1065> In 3 NF monographs Ion chromatography 18–21 Amino acids USP<1052>, Method I In 5 USP monographs Various APIs USP<801> In 8 USP monographs 22–23 Thiomersal USP<341> Various antimicrobial agent determinations Polarography Heavy metals USP<232>, <233> In approx. 780 USP and 230 NF monographs 23 Various parameters USP<1119> Various Near-infrared spectroscopy 26–28 Various process parameters Process-dependent Various Process analysis 29–33 In addition to the above-mentioned methods, this bro- electroactive pharmaceuticals using electrochemistry chure contains chapters on automated sample prepara- (page 24). The brochure concludes with a final chapter tion (pages 14–15), determination of oxidation stability on the comprehensive services provided by Metrohm in ointments and creams (pages 16–17), and analysis of Quality Service on pages 34 and 35. 06 Water for pharmaceutical use (water for injection) pH value Conductivity measuring cell with Pt1000 The 867 pH Module provides everything you need to This measuring cell was developed especially for mea-measure the pH value according to USP<791>: it meets surements in water with very low conductivity. The the requirements of FDA Regulation 21 CFR Part 11 robust stainless steel construction is easy to clean and thanks to either 900 Touch Control or tiamo full soft-ideal suited for conductivity values < 300 μS/cm, and ware. An electrode test can be performed in conjunction thus for measuring waters for pharmaceutical use. with tiamo or 900 Touch Control. Conductivity and pH value can be measured in the same vessel when the 856 Conductivity Module is combined with the 867 pH Module. Conductivity Particularly strict regulations apply to the measurement of the conductivity of water for pharmaceutical use (water for injection) in accordance with USP<645>. In addition to the highest level of precision, the test must fulfill all of the requirements of U.S. FDA Regulation 21 CFR Part 11. Compliance is assured using the 856 Conductivity Module in combination with the 900 Touch Control or tiamo full. Application know-how from the experts Because of their simplicity and accuracy, titration meth-Some older USP methods are still based on high sample 07 ods are used for a large proportion of the content deter-weights with a titrant consumption of up to 50 mL. minations described in the monographs, for example in Based on Ph. Eur., Metrohm has reduced the sample accordance with USP<541>. Taking into account the weights considerably, reducing titrant consumption to at latest methodological findings, Metrohm has developed most 10 mL. hundreds of titration methods with Metrosensors based on the U.S. Pharmacopeia (USP) and European All the methods were developed to enable you to adopt Pharmacopoeia (Ph. Eur.). them as SOPs (Standard Operating Procedures) in your titration laboratory. Titrations with bases or acids Aqueous acid-base titrations Indirect titration (back titration) Determination of enzyme activity (lipase, trypsin, etc.) Alkaline titrants In ethanol with the addition of HCl In dimethylformamide (DMF) In acetone In pyridine In ethanol or methanol In special solvents Nonaqueous acid-base titrations Acidic titrants In glacial acetic acid, with HClO4 In glacial acetic acid/acetic anhydride, with HClO4 In glacial acetic acid plus mercury acetate, with HClO4 In glacial acetic acid/methyl ethyl ketone, with HClO4 In formic acid/glacial acetic acid or acetic anhydride with HClO4 In other solvents or solvent mixtures Iodine/thiosulfate (iodometry) Iodine/arsenite (iodometry) Diazotization with NaNO2 Cer(IV) (cerimetry) Redox titrations KBrO (bromatometry) 3 KMnO (permanganometry) 4 KIO3 Reducing sugars AgNO (argentometry) Precipitation titrations 3 Surfactant titrations Photometric EDTA titrations Photometric titrations (chelatometry/complexometry) Acid number and free fatty acids (FFA) Hydroxyl number Characteristic fat and oil values Iodine value Peroxide value Saponification number Titrando – the smart titrator with comprehensive security 08 Thanks to its modular design, the Titrando System can be optimally adapted to any application. Both as a stand-alone titrator and in combination with the 900 Touch Control or tiamo, it is in compliance with FDA Regulation 21 CFR Part 11. Certified and smart dosing elements Metrohm dosing elements set new standards in reliabili- ty. An inconspicuous data chip contains all the data that the Titrando needs to perform titrations, i.e., serial number, cylinder number, type of reagent, titer, last titer determination, shelf-life data, and much more. But that's not all – the Titrando compares the data it has obtained with that of the selected method and issues an error Flexibility – from individual instruments to fully message if they do not agree. automated systems Increasing numbers of samples, time-consuming sample iTrodes – intelligent electrodes preparation, and unattended overnight operation are all The electrode is the most important part of any titration good reasons for using sample changers. When com-system. The Titrando with iConnect and iTrodes guaran- bined with the 814 USB Sample Processor, the 815 tees complete traceability of the analytic result to every Robotic USB Sample Processor XL, and the 898 XYZ participating component in the analysis. The chip inte- Sample Changer, the Titrando offers a high degree of grated in the electrode head enables the storage of automation at a low investment cost. The 855 Robotic important sensor data such as article number, serial Sample Processor combines a first-rate Robotic Sample number, calibration data, calibration history, and calibra-Processor with a Titrando and takes up minimal space. tion interval. All of the sensor data is uploaded auto- matically when the sensor is connected to the Titrando. Sample preparation at the press of a button This provides added security because the user is informed Metrohm instruments not only handle analysis itself, but if the electrode type does not match the type specified in as demonstrated by the 815 Robotic SoliPrep (see the method. pages 14 and 15), also perform the most frequent sam- ple preparation steps. STAT titration with tandem dosing The determination of enzyme activity (lipase, trypsin, • Homogenization etc.) or the release of active ingredients from antacid The Polytron PT 1300 D made by Kinematica ensures tablets requires a titrator that rapidly adjusts to a preset reproducible particle size reduction and homogeniza-pH value and keeps it constant over a long period. tion of all samples. Tandem dosing prevents dosing interruptions when • Filtration burets are refilled during titration – a second burette Commercially available syringe filters with standard immediately takes over dosing. This means that rapid and Luer connectors can be used directly with the Robotic consumption-intensive reactions can be monitored in Soliprep. real time. • Liquid Handling From dilution series to sample filling in sealed vessels, there are no limits to Liquid Handling with Metrohm. 09 tiamo – titration and more tiamo is the leader in control and database software, able Office applications, databases, and long-term not only for titrators and dosing devices, but also for archiving programs. total laboratory automation that includes the client/ • Reprocessing a determination server system. The name tiamo stands for "titration and Incorrect sample size? No problem. With the repro-more" – tiamo can do more than just titrate. cessing function you do not have to worry about your tiamo is a titration network (NTDS = Networked documentation. tiamo automatically records all Titration Data System). changes, thus providing a comprehensive overview. • Report generator • tiamo guarantees data security The report generator gives you full control over the Whether you need to satisfy GMP or GLP rules, regula- design of your analytical reports. Modify one of the tions regarding the security of electronic data, or many report templates to suit your needs, and conve- traceability requirement for results in accordance with niently send the report by e-mail. the FDA’s Regulation 21 CFR Part 11, tiamo has been • Data security developed from the ground up to comply with all of tiamo helps you ensure data security. When you acti-these requirements and is setting new standards. vate the automatic backup function, tiamo will then • Signatures automatically make complete copies of all determina- You can add digital signatures to determinations. tions and configurations. tiamo offers two levels of signatures. The data • Client/server functionality becomes write-protected as soon as the determination In the simplest case you install the databases on your is assigned a level 2 signature. local measurement computer. tiamo grows along • User administration with your requirements. You can configure tiamo Assign the access rights of each user according to your later as a client/server whenever data security and company’s in-house security policy. tiamo sets no central data management make this a requirement. limits and impresses with its unique flexibility. • Plug and play • Complete audit trail Our modern USB devices ensure that all connected Every user-performed action is automatically stored in devices appear in the devices window. Monitoring the audit trail. Audit data is available at the press of a options rule out the use of system components that button. are wrong or have expired. • Traceability • Parallel titration Play it safe and entrust your titration work only to the tiamo and Titrando make a powerful team. Parallel traceability of Metrohm software and hardware. Every titrations − if necessary, carried out by different users data record contains all the raw data necessary to − increase efficiency. ensure traceability. • Data export tiamo offers you a wide selection of export formats, including XML. Your data are available to all conceiv- Automatic nonaqueous titration with the MATi 03 10 Enormous time savings and results that are more accu- Series of up to 59 samples can be accommodated on the rate and precise are the crucial benefits of automation. 815 Robotic USB Sample Processor XL. tiamo is respon-The MATi 03 (Metrohm Automated Titration) is specially sible for all of the controls. The system is noteworthy for designed for nonaqueous titrations in the pharmaceuti-its high resistance to organic solvents. cal industry – both potentiometric and photometric. The MATi 03 with 815 Robotic USB Sample Processor XL (left) and 907 Titrando (center) 11 Photometric titrations with the Optrode Maximum precision Titrations using color indicators are still widely used in broad spectrum of color indicators. The great advantage pharmacopoeias (chelatometry/complexometry), but of this is that the chemistry does not change – that is, the when performed manually, the results depend, quite lit-standard operation procedure generally does not have to erally, on the eye of the beholder. The new Optrode be adapted. In addition to the determination of chon-makes it possible to replace this subjective determination droitin sulfate (T-083) described below, bismuth nitrate of the equivalence point with an objective process that is (T-088), manganese sulfate (T-089), and zinc sulfate completely independent of the human eye. Its eight (T-090) can also be determined in accordance with wavelengths, ranging from 470 to 660 nm, cover a Ph. Eur. and USP. In accordance with Ph. Eur. and USP: photometric determination of chondroitin sulfate using the Optrode (660 nm) and with 1-hexadecylpyridinium chloride (also called cetylpyridinium chloride, CPC) as titrant More information and more than 1800 other applica- The Optrode – highest measurement precision in photometric tions can be downloaded free of charge at: titration www.metrohm.com/applications/ Water determination according to Karl Fischer 12 The quality, effectiveness, and shelf life of pharmaceutical products depends to a very great extent on their water content, which is why a great deal of importance is attached to water determination in pharmaceutical analysis. Thanks to its specific and selective reaction with water, Karl Fischer titration (KFT) is one of the most accurate and reproducible water determination methods, which is why numerous pharmacopoeias have prescribed it for years as a standard method for fast, automation- ready water determination. 901 Titrando with 900 Touch Control If the test substance is completely soluble in the Karl Fischer reagent and if it does not enter into any side reactions with the solvent, the sample can be added directly into the titration cell. The water content can then be determined directly using volumetry or coulometry. Not all substances dissolve completely in methanol, but that is an important prerequisite for correct determina- tion of a sample's water content. Some techniques for improving the solubility of samples are listed below. These techniques can also be combined with one another. Solubility promoters The 852 Titrando for volumetric and coulometric water determination Solubility promoters can be added, depending on the test substance. For samples containing fat or oil, such as ointments or creams, chloroform is added to the KF reagent to ensure that the sample dissolves completely. High-frequency homogenizers Tablets must be pulverized before titration. This can either be done manually with a mortar or, more conve- niently and above all more reproducibly, using a high- frequency homogenizer directly in the closed titration cell. The latter method prevents any changes to the water content of the sample during preparation. In some cases, it can also eliminate the need for toxic solubility promoters. 860 KF Thermoprep with 901 Titrando, 803 Ti Stand, and 900 Touch Control Higher temperatures in the titration cell Another option is titration of the water at a higher temperature (e.g., at 50 °C). Thermostatically controlled titration cell 13 901 Titrando with 900 Touch Control Karl Fischer oven method Many substances release their water only very slowly or only at high temperatures. Some react with KF reagents to form water or consume iodine, thus resulting in an erroneous determination of water content. Such samples are unsuitable for direct Karl Fischer titration. Both the U.S. Pharmacopeia and the European Pharmacopoeia require determination of the drying loss in a drying oven or desiccator for such substances. The drawback of this method, however, is that it determines not only the water content, but also that of other volatile constituents contained in the sample. The 874 Oven Sample Processor with 852 Titrando In the KF oven method, the test substance is heated in a tightly sealed vessel in an oven. The water driven off from the sample is transferred with a stream of dry car- rier gas into the titration cell, where it is determined as a rule with coulometric Karl Fischer titration. The possibility of side reactions and matrix effects can be excluded because the sample itself remains in the vessel and only water enters the titration cell. MATi 11 – fully automatic Karl Fischer titration including sample preparation Sample preparation 14 The complete range of automatic sample preparation from a single source Normally, accurate pipetting and dilution of the sample is enough to determine the liquid forms of drugs (tinctures, infusions, drops, etc.). Metrohm offers you a wide range of products for automated, precise, and time-saving preparation of liquid samples. Sample preparation becomes more demanding, however, when solid or semisolid samples are involved, i.e., tablets, suppositories, and ointments. As a specialist in the field of laboratory automation, we also offer you a wide range of solutions for the preparation of solid samples – customized to your needs upon request. Fully automated sample preparation and analysis of tablets: Automation: time savings and more accurate following the addition of a solvent, the Polytron high-frequency results homogenizer pulverizes the tablets directly in the sample beaker. In addition to direct titration, chromatographic methods Every sample gets the same treatment. such as IC, HPLC, and GC are of primary use in pharma- ceuticals analysis. These techniques require that the sample is available as a filtered liquid before it is injected on to the column. When carried out manually, as is often the case, sample preparation steps such as • pulverization and homogenization • filtration • pipetting and dilution are tedious and time-consuming. Furthermore, manual sample preparation involves the risk of inaccurate results. Consistent sample preparation quality can hardly be guaranteed, particularly in cases of high sample throughput and when several people are involved. The 815 Robotic Filtration Soliprep Robotic Soliprep – automatic sample preparation 15 tailored to your needs With the instruments of the Robotic Soliprep family, neither deviation in results nor time-consuming manual rou- tines are an issue any longer. The solid substance is simply weighed out and placed on the sample rack – everything else is completely automated. Depending on the version selected, different steps can be combined – including the direct connection to a chromatograph or the titration of the homogenized sample. Robotic Robotic Robotic Robotic Titration Filtration Flexible Soliprep Soliprep Soliprep Soliprep for LC Homogenization + + + + Fully automated filtration: The 815 Robotic Filtration Soliprep filters out residual solid matter from the homogenized sample. Titration + What remains is a clear filtrate that can be either injected directly Filtration + + + into an analyzer or subjected to further dilution. HPLC/GC vial + filling Connection to + an LC instrument Oxidation stability 16 Ointments, lotions, and cosmetics Natural fats and oils have limited storage stability The method is used to monitor natural fats and oils that because they are slowly oxidized by atmospheric oxygen. are used in the manufacture of aliphatic pharmaceutical The oxidation stability of fats and oils has been a default products such as ointments, creams, and lotions. In parameter in quality assurance for many years. To deter-many cases, however, it is also possible to investigate the mine oxidation stability with the Rancimat method, air is oxidation stability of the finished formulations. For this to passed through the test sample at a high temperature to work properly, the proportion of fat in the sample must cause artificial aging. During this process, the fatty acids be significantly higher than the proportion of water. are oxidized by oxygen, forming volatile organic com- pounds and other products. These are driven off by the 892 Professional Rancimat and StabNet software air flow and absorbed in water, where they are detected The 892 Professional Rancimat enables simple and reli-with conductivity measurement. The time it takes for able determination of oxidation stability in natural fats these decomposition products to form is known as the and oils for up to eight samples. The instrument is con-induction time and characterizes the resistance of the trolled by a PC using StabNet software to plot measure-sample to oxidative aging processes, i.e., its oxidation ment curves, evaluate them automatically, and calculate stability. the result. 17 Rancimat control with StabNet software: Up to eight samples can be analyzed simultaneously for oxidation stability – and all in conformance with FDA and GLP requirements. Ion chromatography Ion chromatography (IC) is the method of choice for 18 The intelligent ion chromatographs with their automa- determining active pharmaceutical ingredients, excipi- tion devices and peripheral equipment are controlled by ents, traces of impurities, and metabolites in the form of the user-friendly MagIC Net software. Complete docu-organic and inorganic ions or polar substances – not only mentation on the status of the analytical instruments and in a broad range of pharmaceuticals and pharmaceutical user activities enables complete traceability of the ana-solutions, but also in bodily fluids. Ion chromatography lytical results. MagIC Net supports FDA Regulation can determine chemically similar substances in a very 21 CFR Part 11, and offers numerous tools for compli-short time in just a single analysis. The concentration ance with GLP guidelines. range of the analytes can extend from ng/L up to the percentage range. Another advantage is the large selec- Metrohm ion chromatographs can also be operated with tion of separation columns and elution systems available. EmpowerTM software from Waters. In a certified environ-Interfering matrix effects can be avoided by using a suit-ment, uniform software minimizes training requirements able inline sample preparation method or through the and reduces expenses associated with GLP compliance. choice of detection method: Pharmaceutical solutions • Conductivity detection with or without chemical The term «pharmaceutical solutions» denotes isotonic suppression solutions, hemodialysis solutions, or infusion solutions. • Amperometric detection They contain anions, cations, carbohydrates, and organic • Spectrophotometric detection – direct or with acids, the concentrations of which frequently differ from post-column derivatization (UV/VIS) one another by several orders of magnitude. In the con- • Coupled detection methods such as IC-MS and text of production monitoring and final quality control, IC-ICP/MS these ingredients need to be determined easily, quickly, and with a high degree of precision. Ion chromatography is well up to this task with its intelligent analysis technique and automatic inline sample preparation. 940 Professional IC Vario with 941 Eluent Production Module Cation analysis of a solution of Ringer’s lactate. Column: and 858 Professional Sample Processor: an intelligent ion Metrosep C 4 - 100/4.0; Eluent: 1.7 mmol/L HNO , 0.7 mmol/L 3 chromatography system for parallel determination of anions and dipicolinic acid, 0.9 mL/min; sample volume: 10 μL; 1:20 (v/v) cations in pharmaceutical products Inline Dilution 19 Active pharmaceutical ingredients Impurities in pharmaceuticals Active pharmaceutical ingredients in tablets such as gen-In addition to active pharmaceutical ingredient analysis, tamicin, neomycin, cefadroxil, or bethanechol chloride ion chromatography can also be used to determine can be determined by ion chromatography in accordance impurities in pharmaceutical products. Even small con-with the regulations of the U.S. Pharmacopeia and centrations of an impurity can cause significant side European Pharmacopoeia. Requirements with regard to effects. The azide used in the synthesis of the antihyper-precision, separation, and recovery of the analytes are tensive Irbesartan can be detected in trace amounts as described in detail in the pharmacopoeias. an impurity in the product. The U.S. Pharmacopeia rec- ommends ion chromatographic azide determination after direct injection in accordance with USP<621>. The azide determination is more selective, more sensitive, and most importantly – faster – when using Inline Matrix Elimination, whereby the interfering pharmaceutical matrix is already separated from the target analyte during the sample preparation step. IC determination of the antibiotic gentamicin with pulsed amperometric detection. Column: Polymer Laboratories RP-S; eluent: 60 g/L Na SO , 1.75 g/L sodium octane sulfonate, 2 4 1.34 g/L NaH PO , 8 mL/L THF (pH = 3, H PO ), 1.0 mL/min; 2 4 3 4 column temperature: 55 °C; sample volume: 20 μL; post-column addition: 300 mmol/L NaOH (0.4 mL/min) Irbesartan sample spiked with 5–80 μg/L azide; Column: Metrosep A Supp 10 - 250/4.0; eluent: 5 mmol/L Na CO , 2 3 5 mol/L NaHCO , 1.0 mL/min; column temperature: 60 °C; 3 sample volume: 1000 μL; Inline Matrix Elimination with 70:30 (v/v) methanol/water Precision and recovery of the azide Peak area Mean value RSD Recovery [µS/cm] [%] [%] 5 μg/L spike 0.4223 1.96 101.71 30 μg/L spike 2.5754 0.14 103.38 n = 3 measurements Radio IC 20 Radiopharmaceuticals in nuclear medicine Radiopharmaceuticals are radioactive substances used in make it possible to create three-dimensional images of a diagnostic procedures such as positron emission tomo- wide variety of tissues. This provides a unique picture of graphy (PET). They consist of an inert or biologically physiological, biochemical, and pharmacological pro-active molecule bonded with a radioactive isotope, a cesses taking place in the body, even at the molecular so-called radionuclide. Radiopharmaceuticals participate level. in metabolic processes, which is why they are critical for gaining an understanding of biochemical and physiolo- [18F]Fluorodeoxyglucose ([18F]FDG) gical processes in oncology, cardiology, and neurology. [18F]Fluorodeoxyglucose is a glucose analog in which the 18F nuclide is substituted for the hydroxyl group at the Useful annihilation radiation 2‘ position. FDG, which makes possible the determina- PET is based on the fact that every time a nuclide decays, tion of regional glucose consumption, is the most com-a positron is emitted that annihilates with its antiparticle, monly used radiopharmaceutical. the electron. In doing so, the masses of each of these elementary particles are converted directly into energy, Sophisticated quality control thereby emitting two gamma rays in opposite directions. Quality control in radiopharmaceuticals is demanding, This so-called annihilation radiation can be detected with not least due to the strict time requirements, the safety high-sensitivity detectors aligned in a ring surrounding regulations, and the concentrations in the nanomolar the patient. range. Metrohm's ion chromatographs fulfill these re quirements and the regulations contained in many Positron emission tomography pharmacopoeias. A single multichannel radio ion chro- Computers use the PET data to calculate the origin of the matograph is capable of performing quality control on gamma rays and thus the location where the radio-different production lines. In addition to the highest pharmaceutical decayed. A selection of available radio- analysis quality, ion chromatography provides users with pharmaceuticals and sophisticated detector systems safety, low maintenance costs, and extreme robustness. 2400 2200 F]FDG 18 [ 2000 1800 1600 1400 1200 Current [nA] 1000 800 600 chlorodeoxyglucose (ClDG) 400 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time [min] Principle of positron emission tomography (PET): Disintegration The IC-PAD chromatogram shows the peaks of the ra-of the radionuclide releases two photons that can be sensitively dio tracer [18F]FDG and the impurity chlorodeoxyglucose. registered by coincident detection. By tracking the photons, [18F]FDG is used to trace organism’s glucose metabolism. In case powerful computers generate three-dimensional images of the of diseases, this metabolism shows irregularities that emerge in photon source. the PET scan. Column: Metrosep Carb 2 - 150/4.0; Eluent: 0.1 mol/L NaOH, 1 mL/min; column temperature: 30 °C; sample volume: 20 μL; pulsed amperometric detection Numerous other applications Ion chromatography from Metrohm has much more to quality control. If you do not see your application, please offer. The following table presents a selection of contact your local Metrohm representative. additional key determinations relevant to pharmaceutical Pharmaceutical or excipient Analyte Pharmaceutical or excipient Analyte 21 Acamprosate calcium Acetate Glycine carbonate, sodium salt Carbonate Acifluorfen, sodium Acetate Glimepiride Trans-4-methylcyclohexylamine Adrenaline Adrenaline Guaifenesin Epichlorhydrine Amisulpride Dimethyl and diethyl sulfate Heparin sodium Glucosamine and galactosamine Anticoagulation solution Phosphate, citrate Ibandronic acid sodium Ibandronate, phosphite, phosphate Arsenic trioxide Arsenate, arsenite Indinavir sulfate Ethyl sulfate Atovaquone Acetate Indomethacin sodium 2-ethylhexane acid Atorvastatin calcium salt Cyanide, tetrabutylammonium Irbesartan Cyanide, azide Sulfobutylether-ß-cyclodextrin ß-cyclodextrin Ibuprofen Ibuprofen, valerophenone Bethanechol, sodium, calcium, Lamotrigine Cyanide Bethanechol chloride decomposition product (HPTA) Lanthanum carbonate Nitrate Bromide salt Chloride Levetiracetam Tetrabutylammonium Busulfan Methanesulfonic acid Levofloxacin Fluoride Calcium gluconate Oxalate Linezolid Morpholine Calcium salt Borate Losartan potassium Azide Camphorsulfonic acid Camphorsulfonic acid Meropenem EDTA, dimethylamine Carbamazepine Chloride, bromide Metformin hydrochloride Dimethylamine Carbidopa EDTA, hydrazine, sodium disulfite (Mono)sulfiram (temosol) Cyanide Cefadroxil Cefadroxil Montelukast sodium Methanesulfonic acid, acetate Cefdinir Iron, EDTA Multivitamin tablets Cations, Vitamin C Cefepime hydrochloride N-methyl-pyrrolidinium Mycophenolate mofetil Morpholine Ceftazidime sodium Sodium Nebivolol hydrochloride Monomethylamine Clopidogrel besylate Anions, carbonate, cations Neomycin sulfate Neomycin Colesevelam Quaternary alkylamines Oxaliplatin Chloride Copovidone EP Acetate, formate Pioglitazone hydrochloride Piperidine Dasatinib Ethylenediamine Piperacillin Chloride Dextromethorphan HBr Formic acid Piperazine Piperazine, N-methylpiperazine (2,3-Dichlorophenyl) oxoacetonitrile Cyanide, tetrabutylammonium RA-Thermoseal toothpaste Potassium, zinc Diclofenac sodium Sodium, potassium Ribitol Ribitol (adonitol) Dicyclopropylmethylamine Dicyclopropylmethylamine S-Adenosyl methionine Sulfate Doxazosin, methanesulfonic acid Bromide Sevelamer Binding capacity of phosphate Drospirenone Propargyl alcohol Suxamethonium chloride Choline chloride Enoxaparin sodium Sulfate Tadalafil Methanolic methylamine Esomeprazole magnesium Tartrate Monomethylamine, tetrabutyl- Terbinafine hydrochloride Febuxostat Hydroxylamine ammonium Felodipine Silicate, sodium Topiramate Carbohydrates, sulfate and sulfamate Fenofibrate Sodium lauryl sulfate (SLS) Triclosan Potassium Ferumoxide (contrast enhancer) Citrate Timolol maleate Chlorite Fluorouracil (also fluoruracil) Fluoride Varenicline tartrate salt Trifluormethanesulfonic acid Gabapentin Chloride Voriconazole Camphorsulfonic acid Gadopentetate dimeglumine Gadolinium Zingisol Potassium and zinc Gentamicin sulfate (see page 17) Gentamicin Zoledronic acid Phosphite, phosphate Detection method: conductivity detection with suppression; direct conductivity detection; conductivity detection with and without suppression; amperometric detection; spectrophotometric detection Voltammetry Voltammetric trace analysis determines electrochemically 22 sensitivity. In addition, unlike spectroscopic methods, active substances. In many cases, these are traces of voltammetry can distinguish between different oxidation heavy metals. Voltammetry is frequently employed to states of metal ions as well as between free and bound complement and validate spectroscopic methods. It metal ions. This is referred to as speciation analysis. features modest equipment requirements, relatively low Voltammetric results provide important information investment and operating costs, simple sample regarding the bio availability and toxicity of heavy metals. preparation, short analysis times, and high accuracy and Detection limits (1 ppt = 1 ng/kg) Element Detection limit Element Detection limit [ppt] [ppt] Antimony SbIII/SbV 200 Molybdenum Mo 50 Arsenic AsIII/AsV 100 Nickel Ni 50 Bismuth Bi 500 Platinum Pt 0.1 Lead Pb 50 Rhodium Rh 0.1 Cadmium Cd 50 Mercury Hg 100 Chromium CrIII/CrVI 25 Selenium SeIV/SeVI 300 Cobalt Co 50 Thallium Tl 50 Iron FeII/FeIII 50 Uranium U 25 Copper Cu 50 Tungsten W 200 Zinc Zn 50 Voltammetry also enables organic compounds to be 884 Professional VA determined with a high degree of sensitivity. This makes The 884 Professional VA is a flexible measuring instru-it possible to analyze many active pharmaceutical ment for accurate and sensitive polarographic voltam-ingredients in accordance with USP<801>. metric analyses. The accompanying viva software enables individual optimization of methods, for example, the Voltammetry is particularly well-suited to laboratories in automatic calculation of results according to special for-which only a few parameters need to be monitored in mulas prescribed by the USP. combination with a moderate sample throughput. It is frequently used for special applications which cannot be performed using other techniques or only with a great deal of effort. 23 Application examples Fe(II) in iron sucrose injection solution in Thimerosal in accordance with USP-NF accordance with USP-NF Mercury-containing thimerosal (or thiomersal) is used as Polarography makes it possible to determine, directly and a preservative for pharmaceuticals and cosmetics to pro-selectively, the proportion of iron(II) within the total tect them from microbial contamination. Examples of the concentration of iron in a preparation. No prior sample use of thimerosal are: cleaning and storage solutions for preparation and chemical separation of the iron species contact lenses; eye, nose, and ear drops; and tattoo inks. is required. The separated signals of the iron(II) and Injectable medicinal products − for example, immuno-iron(III) complex are measured during determination. The globulins and many vaccines (flu, hepatitis B, etc.) – can iron(II) content is derived from the ratio of the signals. also be preserved with thimerosal. Direct determination in the finished preparation is possible in many cases. Heavy metal impurities For more than a century now, international pharma- copoeias have relied on sulfide precipitation for a semiquantitative determination of the heavy metal content in pharmaceutical products. As of 2018, this is no longer the case: USP regulations USP<232> and USP<233> then require individual determinations of selected heavy metals in place of sum parameters. The USP leaves it up to the user to select the analysis method, requiring only its validation. Stripping voltammetry is particularly suitable here, and a simple sample digestion is sufficient for sample preparation. Other active pharmaceutical ingredients that can be determined by polarography in accordance with USP-NF Electrochemically active pharmaceutical ingredients, such as azathioprine, cefamandole, cysteine hydrochloride, diclofenamide, iodine, or procarbazine, can be determined Polarographic determination of iron(II) content directly with polarography in accordance with USP<801>. Electrochemistry for electroactive pharmaceuticals 24 Electrochemistry in pharmaceuticals Research and development Many of the active pharmaceutical ingredients are elec- Electrochemical methods help to develop and character- troactive, which makes them easy to determine using ize new materials for use in biosensors and electroanaly-electrochemical methods. Electrochemistry is both highly sis. In combination with proven electroanalytical meth-sensitive and selective, and also has an outstanding ods, these new, specially designed composite materials dynamic range with very rapid response times. – mostly based on metal nanoparticles, carbon nano-Furthermore, there are numerous possibilities for record-tubes, or graphene – improve the sensitivity, specificity, ing signals. Potentiometric, amperometric, impedimetric, and detection limits of measurements. and electrogravimetric analyses are numbered among these. High-end instruments from Metrohm Autolab Metrohm Autolab offers a range of high-end instruments Real-time blood sugar monitoring for electrochemical research. A broad array of modules With the development of amperometric glucose sensors enables individual adaptation of the instruments to every – at the heart of every blood glucose meter – electro- desired application. Electrochemical impedance spectros- chemistry has significantly improved the quality of life of copy measurements can be performed with the FRA32M, diabetes patients. Basic research efforts are constantly and the EQCM enables electrochemical quartz crystal being directed towards further improvements of these microbalance measurements. types of sensors. The goal is to develop an implantable sensor for real-time monitoring. For sensitive electrochemical impedance measurements in pharmacy: the Autolab PGSTAT204 with the FRA32M module www.metrohm-autolab.com 25 «Why did I choose Metrohm? I have Sandrine Caristan and her team been working with Metrohm for 25 provide analytical support at years. When a new lab was to be built Sanofi-aventis’ R&D center in here in Montpellier, we naturally chose Montpellier, France. Determination Metrohm.» of the water content by Karl Fischer titration is one of their most Sandrine Caristan, Sanofi-aventis frequent analyses. A Metrohm USB Oven Sample Processor is their solution of choice for higher throughput and reliable results. And thanks to the client-server version of Metrohm’s tiamo software, Sandrine doesn’t have to leave her office to manage data from workplaces all over the site. Metrohm. People you can trust. testimonials.metrohm.com www.metrohm-autolab.com Near-infrared spectroscopy 26 NIRS – interaction of light and physical matter Many parameters in a single analysis Near-infrared spectroscopy (NIRS) is an analytical tech- NIRS offers numerous advantages over many wet-chem- nique based on the absorption of radiation by matter. ical analytical methods. A diverse range of parameters Molecular vibrations are induced in the near-infrared can be determined simultaneously with just one analysis. region of the magnetic spectrum (800–2500 nm) – i.e., NIRS is economical and fast, enabling qualitative and from the end of the visible to the mid-infrared (MIR) quantitative analyses that are noninvasive and nonde-range. The main absorption bands of the functional structive. groups of chemical substances are located in the MIR range and are very strong. The absorption bands of the NIRS is an indispensable analysis technique that can be harmonics, however, and the combination of the funda-used along the entire production chain – from incoming mental molecular vibrations are in the NIR spectral materials to processing to the quality control of finished region. They are significantly weaker and enable direct products. NIRS meets the requirements of numerous measurement without sample preparation, while at the international pharmacopoeias, e.g., USP, Ph. Eur., and JP. same time offering deep insights into the chemical and physical properties of the sample. The strongest overtone How absorptions in the NIR range are displayed by com- pounds with OH, CH, NH, and SH bonds. Because the Atline/offline NIR spectrum represents the result of numerous overlap- • Warehouse ping absorption bands, it is normally evaluated with • QC laboratory multivariate chemometric methods. Lactose monohydrate Lactose anhydride Inline/online • Production Absorbance [Log 1/R] Wavelength [nm] NIR spectra of lactose monohydrate and lactose anhydride for Atline/offline identifying excipients • Process control (IPC) laboratory ] Atline/offline • IPC laboratory CPM content NIRS [mg • QC laboratory CPM content HPLC [mg] Calibration model for the quantitative determination of the active ingredient content of tablets; in this case, chlorpheniramine maleate (CPM). NIR analysis establishes a connection between Offline the target value of a determination – in this case, CPM content • QA/QC – and the measured data in the spectrum. laboratory NIRS – the fast solution for every sample matrix NIRS – screening through packaged materials 27 Near-infrared spectroscopy requires no sample prepara- NIRS can even perform determinations on contents tion and can handle any sample matrix, no matter if it is: sealed in transparent packaging such as glass and films. This is particularly appealing for incoming goods inspec- • powders or granulates tions and packaged end products. Handling could not be • tablets or capsules easier; in fact, it is so easy that NIRS can be used directly • creams or gels in pharmacies and customs offices. • solutions or suspensions • polymer films • freeze-dried samples. Where What Incoming goods inspection of raw materials starting from step one Incoming • Identity tests directly in the warehouse for active pharmaceutical ingredients, excipients, materials and packaging • Quality control (purity, chemical and physical properties) Real-time monitoring, optimizing the drying process • Inline determination of water and solvents in powders and granulates (page 33) Drying • Determination of the endpoint of drying processes • Determination of residual water content in freeze-dried products Monitoring blending processes Blending and granulation • Determination of blend homogeneity • Setting required granulation time by tracking blend quality Faster analytical results and minimization of rejected products Tablet pressing • Content uniformity test in solid dosage forms (tablets and capsules) and capsule filling • Determination of tablet characteristics (hardness, stability, etc.) • Identification of tablets and products before they are packaged Less expended effort compared to reference methods (e.g., HPLC) Final product control and • Content determination in finished products (creams, gels, solutions, tablets, capsules) packaging • Final product inspection 28 Nondestructive analysis technique NIRS has long been one of the most important and ver- This prevents charges related to rejected products and satile analytical techniques in the pharmaceutical indus-reduces overall costs. try – and not just because everybody in the pharma industry is talking about PAT and QbD. The decisive In accordance with international pharmacopoeias benefit of NIRS is the possibility of obtaining reliable As a secondary test method, NIRS is recommended in all analysis results in just seconds without any sample prepa-of the key pharmacopoeias – from the European ration or reagents whatsoever. (Ph. Eur. 2.2.40) to the American (USP<1119>) to the Japanese pharmacopoeia. All of Metrohm's NIRSystems PAT and QbD – with NIRS in search of the best of instruments meet the standards for wavelength preci-all methods sion, reproducibility, and photometric noise. Numerous Drug manufacturing is undergoing a transformation. The reference standards and user-friendly software make it FDA's stated goal is to cut development time for new easy to check the instrument requirements specified in drugs while at the same time significantly improving qual-the pharmacopoeias. The pharmaceutical version of the ity. This requirement can only be fulfilled with analytical Vision software is fully validated and compliant with 21 techniques which monitor the entire process – from CFR Part 11. incoming raw materials to the final inspection. To achieve that, perfect PAT sensors are needed that enable "live" Metrohm NIRSystems also offers complete IQ/OQ docu-tracking of the manufacturing process. NIRS is the tech- mentation and instrument performance certification nique that makes this possible. An inline sensor monitors (IPC). Documented parameters guarantee that the instru-product quality in real time (see also pages 32 and 33). ment performs properly. Atline, online, and inline analysis systems from Metrohm Process Analytics Atline, online, and inline analysis systems from Metrohm specialist with more than 40 years' experience in the 29 Process Analytics are the preferred solution for process field. We offer a broad program of process analyzers and monitoring in a wide range of industries. Reliable analysis sample preparation systems for a large array of applications results are determined directly in-process with the latest in a wide number of industries. methods of ion analysis and spectroscopy: Measurement of pH value, conductivity, and redox potential, as well as Metrohm Applikon – globally present titration, Karl Fischer titration, photometry, ion-selective Metrohm Applikon is part of the Metrohm Group sup-electrode measurement (dynamic standard addition), ion porting you globally with offices in 45 countries. Our chromatography, voltammetry, and near-infrared specialists offer you advice during the planning and spectroscopy. development of your own custom-designed analysis sys- tem, commission the system, and provide professional Metrohm Applikon, with the brand name Metrohm maintenance and service during routine operations. Process Analytics, is an inline, online, and atline analysis Atline process analysis 30 More efficient production with PAT and QbD Drugs are manufactured in accordance with very strict meets the requirements of the FDA Regulation 21 CFR directives and must meet high standards with respect to Part 11. ProcessLab features a modular design and is quality, effectiveness, and safety. Every process step is configured to meet specific analytical requirements. It thoroughly monitored during the manufacture of various can be optimally integrated into process communications active ingredients and excipients. Added to that are through inputs and outputs (typically 4–20 mA). Sample exhaustive approval analyses at the end of the manufac-identification is further simplified through the use of a turing process: pharmaceutical producers often spend barcode reader. Just minutes after the sample is collect-more time on final checks than on the production itself. ed, the relevant process information is available to a LIMS Stringent regulatory requirements also make it more dif- or the master display. ficult to optimize pharmaceutical manufacturing pro- cesses. With its Process Analytical Technology (PAT) initia-Atline analyzer ADI 2045PL ProcessLab tive and the principle of Quality-by-Design (QbD), the The ADI 2045PL ProcessLab atline analyzer is ideally FDA is striving to increase the efficiency of drug produc-suited to rapid and independent process monitoring in tion. The approach involves a departure from final in - the production environment. A ProcessLab analysis sys- spections toward real-time process analysis and checks. tem consists of a TFT touch screen operating unit and an analysis module that is tailored to the specific applica-Rapid process monitoring tion. Thanks to its splashproof housing (housing protec- Metrohm Process Analytics offers a robust analysis sys- tion class IP66/NEMA 4), ProcessLab is ideally suited to tem that is easy to operate and can be set up directly on harsh production environments. The pharmaceutical the production floor. The sample is brought to the industry is held to high standards of hygiene, which is ProcessLab and the analysis started at the push of a sin-why most equipment is made with a stainless steel hous- gle button. ProcessLab is based on the proven Titrando ing. system, which in combination with tiamo software ADI 2045PL ProcessLab: each system is configured with the relevant modules according to user preferences. 31 Analysis of acidic and basic components Determination of redox-sensitive components Numerous pharmaceutical intermediates and end pro- Oxidizable and reducible components and active ingredi-ducts contain acidic and basic components. These are ents are determined with redox titrations. Methods fre-determined with a suitable acid-base titration method. quently used include iodometry, cerimetry, bromato-Depending on the sample matrix, either aqueous or non- metry, and/or permanganometry. The modular structure aqueous titrations are carried out. The latter are done of ProcessLab enables easy adaptation to the specific with a titrant and solvent suitable for the particular appli-requirements of the application. Because of its proximity cation – for example, with perchloric acid in glacial acetic to the process, the relevant analytical values are available acid or with tetrabutylammonium hydroxide (TBAH) in within just a few minutes. 2-propanol or acetone. Online and inline process analysis 32 Customized online process control Robust design in stainless steel Production processes in the pharmaceuticals industry must Metrohm Process Analytics analyzers are constructed for be continuously monitored. Online and inline analyzers the demands of the harsh production environment. The from Metrohm Process Analytics optimally fulfill this housings meet NEMA 4 and protection class IP66 speci-requirement. Engineered for continuous operation, these fications. In environments that demand the highest stan-instruments enable fully automatic checks of production dards of hygiene and durability, Metrohm Process processes – around the clock, seven days a week. Analytics offers its ADI 2045TI and ADI 201Y Process Moreover, it does not make a difference whether a single Analyzers equipped with stainless steel housings. parameter is to be determined in a single sample stream or several different parameters are to be determined Inline process analysis with NIRS simultaneously in complex, multiple sample streams – The goal of the FDA's PAT/QbD approach is process opti-Metrohm Process Analytics provides you with a suitable mization through improved process controls. Instead of system for all applications. time-consuming final inspections, PAT calls for monitor- ing product quality in real time. Near-infrared spectros-Proven wet chemistry methods copy offers meaningful help toward achieving this objec- Metrohm Process Analytics online analyzers are based on tive: NIR always has the process in view, it is not destruc-wet chemistry processes such as titration, colorimetry, tive, requires no sample preparation, and delivers precise and measurements with ion-selective electrodes; near-results in just seconds. The software uses multivariate infrared spectroscopy is used for inline monitoring. data analysis to extract the data required for the analysis Sampling and sample preparation are at least as impor-at hand from the comprehensive NIR data. Physical tant as the analysis itself. Metrohm Process Analytics has parameters, such as density and particle size distribution, great expertise in this field and configures the sampling in addition to water or solvent content, can also be con-system to fit your application precisely, including features veniently determined. such as filtration, the removal of samples from pressur- ized containers, and degassing. Straightforward network integration All Metrohm Process Analytics online and inline analyzers are equipped with digital and analog data outputs. Results can be transmitted via analog 4–20 mA signals and alarms can be triggered by digital outputs. Digital inputs can be employed for remote start/stop com- mands. The robust NIRS Analyzer PRO for inline analysis with interfaces for reflection or transmission technology. 33 Eye on the process: granulation and drying A key manufacturing process in the pharmaceutical industry is the granulation and drying process for pow- ders that precedes tablet manufacturing and makes it possible to press powders into tablets in the first place. NIRS is the method of choice for determining the reac- tion endpoint when pressability is at the optimal point. Probes in the drier or granulator make it possible to track the process in real time. That reduces the process dura-tion and thus increases the drying and granulation capacity of the system. At the same time, it minimizes the Calibration model for quantitative determination of water con-deviation from the required setpoint values. tent in powders. Karl Fischer titration is the reference method for the determination of the water content. 5:20 5:30 5:40 5:50 6:00 6:10 6:20 Reduction of water content in a pharmaceutical powder over time. Rapid and nondestructive NIR analysis makes it possible to determine the optimal moment for further processing in real time. The sensor is installed directly in the granulator. 34 Metrohm Quality Service – Service you can rely on Reliable results – for the lifetime of the analyzer Metrohm Compliance Service Particularly in the pharmaceutical industry, measurement You can trust Metrohm Compliance Service when it is errors can have serious consequences and must there-time for the professional qualification of your analyzers. fore be avoided at all cost. The name Metrohm stands The wide range of different laboratory instruments and throughout the world for high-quality laboratory analyz-analyzers makes it very complicated for pharmaceutical ers for ion analysis. They are designed to deliver excep-companies to keep in step with legal requirements. As an tionally precise results. Leading international pharmaceu-experienced and reliable partner, Metrohm provides its tical companies also value Metrohm for our comprehen- customers with technical advice and expertise, with sive service, which ensures that the users can rely on respect not only to instruments and applications, but their results for the entire lifetime of their instruments. also to the latest regulatory requirements. With Metrohm Quality Service you are on the safe side Analyzers used in laboratories must satisfy the latest from day one. From installation and start-up, to regular requirements of FDA regulations, GLP/GMP standards, maintenance and fast repair – if problems arise – we and the GAMP directives. This is achieved through instru-guarantee that you can rely on your instrument and gain ment qualification and system validation. Metrohm maximum uptime from your investment. offers documents for analytical instrument quali- fication (AIQ) as well as services that meet or exceed the requirements of the FDA and other regulatory authorities. Metrohm Quality Service 35 Metrohm’s global Quality Service, and regularly sched- particular need. With a Total Care Contract, for example, uled preventive maintenance in particular, extends your you can rely on the optimum performance of your instrument’s lifetime and ensures trouble-free operation. Metrohm instruments at all times, incurring no additional Maintenance work is carried out by qualified and certi-costs whatsoever and benefit from complete and com- fied service engineers. You have the option of selecting pliant documentation. different types of service contracts depending on your Metrohm Quality Service Customer benefits • Minimizes downtime through preventive maintenance • Cost control and savings through free or discounted replacement materials Metrohm Care Contracts and consumables • Guaranteed reaction times and rapid on-site repair • Documented instrument certification as an ideal preparation for audits • High data security and maximum system performance through regular, Metrohm Software Care professional software maintenance • Customized services and documentation for analytical instrument qualification (AIQ) Metrohm Compliance Service • Professional start-up (IQ/OQ or Certified Installation) and requalification or recertification by specifically trained employees Metrohm Remote Support • Quick resolution of software and application issues directly at the workplace • Calibration of burettes (e.g., dosing and exchange units) with certification Metrohm Dosing Test • Accurate measurement results • Verification documentation for compliance with regulations and efficient audits • Rapid availability of repaired instruments thanks to decentralized repair workshops around the world and a central workshop at the manufacturer site Metrohm Repair Service • Highly qualified service technicians ensure sustainable repair success • Rapid resolution of problems and minimized downtimes through on-site emergency services and express repairs • Original spare parts, made in Switzerland and available worldwide • Short delivery times through warehousing from local distributors Metrohm Spare Parts • Investment security through ten-year spare parts guarantee after discontinuation • Free access to the Metrohm Application Finder (www.metrohm.com/en/ applications/) with more than 1800 applications (Application Bulletins, Application Notes, monographs, technical posters, and technical articles) Metrohm Application Support • Rapid and professional resolution of any application issues through personal consultations with our specialists by e-mail, telephone, or remote support • Support for the solution of complex analytical problems, as well as method optimization on-site or at our application laboratories • Basic and advanced training with local representatives, at the Metrohm Academy or directly on-site Metrohm Training Programs • Efficient and proper use of all analytical methods, as well as results reliability through competently trained users • Training documentation and certificates for trouble-free audits Ordering information 36 pH value and conductivity measurement pH value measurement 2.867.0110 867 pH Module with Touch Control 2.867.0210 867 pH Module with tiamo light Conductivity measurement 2.856.0120 856 Conductivity Module with Touch Control and stainless steel measuring cell 2.856.0220 856 Conductivity Module with tiamo light and stainless steel measuring cell 6.0916.040 Conductivity measuring cell made of stainless steel, c = 0.1 cm–1, with Pt1000 Titration 2.907.1020 Pharm Titrando 2.902.0010 902 Stat Titrando 6.6056.2X2 tiamo 2.X full Water determination according to Karl Fischer Coulometric KF Titration 2.756.0010 756 KF Coulometer with generator electrode with diaphragm 2.756.0110* 756 KF Coulometer with generator electrode without diaphragm 2.831.0010 831 KF Coulometer with generator electrode with diaphragm 2.831.0110* 831 KF Coulometer with generator electrode without diaphragm 2.851.0010 851 Titrando with generator electrode with diaphragm 2.851.0110* 851 Titrando with generator electrode without diaphragm 2.852.0050 852 Titrando with generator electrode with diaphragm and volumetric titration cell 2.852.0150* 852 Titrando with generator electrode without diaphragm and volumetric titration cell * The magnetic stirrer has to be ordered separately. Volumetric KF Titration 2.890.0110 890 Titrando with Touch Control 2.890.0210 890 Titrando with tiamo light 2.901.0010 901 Titrando including titration cell MATi 11 Automated volumetric Karl Fischer titration including sample preparation KF oven 2.860.0010 860 KF Thermoprep 2.874.0010 874 Oven Sample Processor Automation MATi 03 Automatic titration system for nonaqueous titrations in the pharmaceutical industry in series of up to 59 samples 2.815.1110 815 Robotic Titration Soliprep 2.815.2110 815 Robotic Flexible Soliprep 2.815.3110 815 Robotic Filtration Soliprep 2.815.4110 815 Robotic Soliprep for LC Oxidation stability 2.892.0010 892 Professional Rancimat including accessories, without StabNet software 6.6068.102 StabNet 1.0 Full 6.6068.103 StabNet 1.0 Multi 37 Ion chromatography 2.940.2500 940 Professional IC Vario TWO/SeS/PP for anion and cation determination 2.940.1520 940 Professional IC Vario ONE/SeS/PP/Prep2 2.850.9010 IC Conductivity Detector 2.850.9110 IC Amperometric Detector 2.858.0020 858 Professional Sample Processor for the automation of determinations 6.5337.010 IC Equipment Wall-Jet cell for carbohydrate determination 6.1090.420 Metrosep Carb 2 - 150/4.0 for carbohydrate determination 6.1050.410 Metrosep C 4 - 100/4.0 for cation determination 6.1020.030 Metrosep A Supp 10 - 250/4.0 for anion determination Voltammetry 2.884.0110 884 Professional VA manual for Multi-Mode Electrode (MME) 2.884.1110 884 Professional VA semiautomated for MME consisting of 884 Professional VA, measuring head for MME and two 800 Dosinos. MVA-22 Fully automated Professional VA system consisting of 884 Professional VA, measuring head for MME, 919 IC Autosampler plus for VA and two 800 Dosinos for automatic addition of auxiliary solutions. Allows the automatic processing of up to 28 samples. This system is the optimum solution for automatic analysis of small sample series. Required Accessories 6.5339.030 VA-Elektrodenkit with Multi-Mode Electrode 6.6065.202 viva 2.0 Full 38 Near-infrared spectroscopy – laboratory, atline 2.922.0010 NIRS DS2500 Analyzer 2.921.1110 NIRS XDS RapidContent Analyzer 2.921.1120 NIRS XDS RapidContent Analyzer – Solids 2.921.1210 NIRS XDS MultiVial Analyzer 2.921.1310 NIRS XDS MasterLab Analyzer 2.921.1410 NIRS XDS RapidLiquid Analyzer 2.921.1510 NIRS XDS Interactance Optiprobe Analyzer 2.921.1520 NIRS XDS Transmission Optiprobe Analyzer 2.291.1530 NIRS XDS Transmission Optiprobe Analyzer – Heated Vials 2.291.1610 NIRS XDS SmartProbe Analyzer – 2 m fiber 2.291.1620 NIRS XDS SmartProbe Analyzer – 3 m fiber Process analysis We offer online and atline Analyzers that meet any requirement in the process industry, from single-parameter to the most advanced multiparameter analyzers. Every analyzer is custom-tailored to the specific task at hand. Wet chemistry ADI 2045PL ProcessLab system for atline determination of various parameters using titration, colorimetry, and ISE ADI 201Y Series Single method Process Analyzers, available with titration, colorimetry, or ISE ADI 204Y Series Multifunctional Process Analyzers, available with titration, ISE, colorimetry, and voltammetry 2035 Series Analyzer family designed in 3 configurations: potentiometric, photometric, and thermometric titration Furthermore, we offer the Plug and Analyze Series – ICON and Alert for single method, single component water analysis. Near-infrared spectroscopy 2.928.0210 NIRS XDS Process Analyzer – SingleFiber SinglePoint 2.928.0220 NIRS XDS Process Analyzer – SingleFiber 4 Channels 2.928.0230 NIRS XDS Process Analyzer – SingleFiber 9 Channels 2.928.0110 NIRS XDS Process Analyzer – Microbundle SinglePoint 2.928.0120 NIRS XDS Process Analyzer – Microbundle 4 Channels 2.928.0130 NIRS XDS Process Analyzer – Microbundle 9 Channels 2.928.0310 NIRS XDS Process Analyzer – DirectLight/NonContact 2.928.1110 NIRS Analyzer PRO – ContactReflection 2.928.1120 NIRS Analyzer PRO – FiberSystem 2.928.1130 NIRS Analyzer PRO – DirectLight/NonContact Please contact your Metrohm supplier for further information. Please also consult www.metrohm.com 39 pharma.metrohm.com witzerland G, CH-9100 Herisau, S ohm A ; printed by Metr SW Subject to modifications Layout by Ecknauer+Schoch A 8.000.5139EN – 2015-09