Pharmaceutical analysis

Quality assurance of pharmaceuticals

Metrohm...

02

• is the global market leader in titration

• is the only company to offer a complete range of ion analysis equipment – 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 ion chromatography

• provides you with unparalleled application expertise

• offers you more than 1300 applications free of charge

• supports you with expert service through local representatives and regional support centers

• is not listed on the stock exchange, but is owned by a foundation

• gives the interest of customers and employees priority over maximizing profit

The regulatory authorities set high standards

With regard to the quality and safety of drugs, authori-

ties worldwide set high standards for the pharmaceutical

industry. These are documented in pharmacopoeias in

the form of official collections of recognized pharmaceu-

tical rules. As legal tools of consumer protection, they

ensure that drugs are used safely. It is only the measuring

and test procedures used within the framework of drug

testing that identify a drug and determine whether it is

approved or not.

To ensure these high quality and safety standards, reliable

instruments and methods are needed.

Metrohm − customized analysis for the pharmaceutical industry

03You can count on our support

As a leading manufacturer of instruments for chemical

analysis, we are aware of these challenges. For this rea-

son, Metrohm offers you not only the latest instruments,

but complete solutions for very specific analytical issues.

Your Metrohm contacts are competent specialists, who

will develop customized applications and provide you

with professional support in all matters of regulatory

compliance.

Discover on the following pages what solutions Metrohm

is able to offer the pharmaceutical sector in general and

you in particular, to ensure the quality and safety of your

products. Challenge us!

The history of pharmacy

The search for remedies is as old as humanity itself. There

is evidence that the first advanced civilizations (China,

India, Mesopotamia, Egypt) were already using drugs of

plant, mineral and animal origin for medicinal purposes.

Systematic descriptions of remedies have been handed

down to us from Greek antiquity (Hippocrates, Theo-

phras tus) and from the Roman Empire (Dioscorides,

Galen). This knowledge was adopted by Arabian scholars

(e.g., Avicenna) and was developed further. It served for

a long time as an important basis of medicine. It was not

until the 16th century that this began to detach itself

from the ancient models. A typical representative of the

new direction was Paracelsus, who, in 1537, coined the

famous phrase: «Only the dose makes the poison»

(«dosis sola facit venenum»).

The way to organic synthetic drugs

The emergence of organic chemistry at the start of the

19th century brought progress, the importance of which

can hardly be overestimated. Whereas previously treat-

ment with drugs had been restricted largely to natural

substances and inorganic chemicals, people now started

specifically to produce organic synthetic drugs, using

substances isolated from medicinal plants as the basis.

An unprecedented advance in pharmaceutical synthesis

led within a very short time to a vast number of synthe-

sized active ingredients. In this context, researchers in -

crea singly succeeded in establishing a relationship be-

t ween the action of these substances and their chemical

structure.

Chemical pharmaceutical analysis

04 Determination of active ingredients, excipients

and impurities

Pharmaceutical analysis provides information on the

identity, purity, content and stability of starting materials,

excipients and active pharmaceutical ingredients (APIs). A

distinction is made between analysis of the pure active

ingredients used to cure, alleviate, prevent or identify ill-

nesses and diseases (active ingredient analysis) and

analysis of medicinal preparations. The latter can exist in

various forms (ointments, tinctures, pills, lotions, suppo-

s itories, infusions, drops, etc.) and consists of the phar-

maceutically active substance and at least one pharma-

ceutical excipient. Impurities usually stem from the syn-

thesis of the active ingredient; they are usually monitored

according to the guidelines of the ICH (International

Conference on Harmonisation of Technical Requirements

for Registration of Pharmaceuticals for Human Use) and

the pharmacopoeias.

Pharmacopoeias to ensure the safety of drugs

Specifications and test methods for the commonly used

active ingredients and excipients are monographed in

detail in national pharmacopoeias in more than 38 states

according to the World Health Organization (WHO). They

include the United States Pharmacopeia (USP), the

European Pharmacopoeia (Ph.Eur.), which emerged from

the harmonization of the regulations of a number of

individual states, and the Japanese Pharmacopoeia (JP),

to name but a few. The pharmacopoeias are official com-

pendia and contain the statutory requirements regarding

the identity, content, quality, purity, packaging, storage

and labeling for active pharmaceutical ingredients and

other products used for therapeutic purposes, and are

essential for anyone who wants to produce, test or mar-

ket medicinal products.

Metrohm is the competent contact for all matters con-

cerning chemical-pharmaceutical analysis and the valida-

tion of analytical methods. Apart from complying with

numerous official guidelines, Metrohm instruments and

applications satisfy the test methods for quality control

and product release that are listed in the most important

pharmacopoeias.

In accordance with the harmonization efforts of the Phar-

macopoeial Discussion Group (PDG), the present bro-

chure, taking the place of the pharmacopeias not men-

tioned here, relates primarily to selected test methods

Selected test methods and USP-NF monographs

05

and monographs of the USP. The National Formulary (NF)

is the official compendium of standards for excipients

and plant-based drugs.

Structure of the USP-NF

Apart from the description of numerous analytical meth-

ods in the general section of the USP-NF, the main section

contains generally applicable standards for active ingredi-

ents (USP) and excipients (NF) in the form of monographs.

More recent texts (since 1997) also contain a list of pos-

sible impurities (transparency list) that can be determined

with the test methods described.

Parameter USP monograph Number of citations in the monographs Test method Page

pH value USP<791> In 1328 USP monographs

pH measurement 6 In 68 NF monographs Conductivity USP<645> Ultrapure water for pharmaceutical use Conductivity measurement 6 Various active ingredients

USP<541> In 127 USP monographs

Titration

7-9

Various excipients In 51 NF monographs

Water content USP<921> In 616 USP monographs

Karl Fischer Titration 10-11 Method I In 98 NF monographs Various active ingredients

In 27 USP monographs

16-17 Various excipients

USP<621>/USP<1065> In 3 NF monographs

Ion chromatography

Various active ingredients USP<801> In 8 USP monographs Polarography 18-19

Thimerosal USP<341> Determination of

Polarography 19 antimicrobiotics pH value, conductivity and parameters that can be Process-dependent

Various Process analysis 20-21 determined by titration specifi cations and voltammetry

Test methods referenced in USP-NF monographs (USP 32-NF 27)

Water for pharmaceutical use (water for injection)

pH value

The 867 pH Module provides all that is needed for meas-

uring the pH value according to USP<791>. With 840

Touch Control, PC Control or tiamoTM full, intelligent

sensors and five-point calibration it meets the require-

ments of FDA regulation 21 CFR Part 11. In conjunction

with PC Control and 840 Touch Control it is possible to

carry out an electrode test. Conductivity and pH value

can be measured in the same vessel if the 856 Conductivity

Module is combined with the 867 pH Module.

Conductivity

Particularly strict rules apply to the measurement of the

conductivity of water for pharmaceutical use (water for

injection) according to USP<645>. Apart from the highest

level of precision, all the requirements of the U.S. FDA’s

regulation 21 CFR Part 11 must be satisfied. The 856

Conductivity Module, together with the 840 Touch

Control, PC Control or tiamoTM full, guarantees this.

06

Conductivity measuring cell (stainless steel) with

Pt 1000

This measuring cell was developed especially for measure-

ment in waters with very low conductivity. The robust

and easy-to-clean stainless steel construction is ideally

suited for conductivity values <300 μS/cm, and thus for

measuring water for pharmaceutical use.

.

07Because of the simplicity and the accuracy of the proce-

dure, a large proportion of the content determinations

described in the monographs are carried out using titra-

tion methods, for example, according to USP<541>.

Taking into account the latest methodological knowl-

edge, Metrohm has developed hundreds of titration

methods with Metrosensors based on the U.S. Phar ma-

copeia (USP) and European Pharmacopoeia (Ph.Eur.).

Some older USP methods are still frequently based on

high sample weights, which require a titrant consump-

tion of up to 50 mL. Following Ph.Eur., Metrohm has

re duced the sample weights considerably and thus cut

titrant consumption to at most 10 mL.

All the methods have been worked out in such a way

that you can adopt them as SOPs (Standard Operating

Procedures) in your titration laboratory.

Aqueous acid-base titrations

Titrations with bases or acids

Indirect titrations (back-titrations)

Alkaline titrants

In ethanol with the addition of HCl

In dimethylformamide (DMF)

In acetone

In pyridine

In ethanol or methanol

In special solvents

Non-aqueous 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

Redox titrations Cer(IV) (cerimetry)

KBrO3 (bromatometry)

KMnO4 (permanganometry)

KIO3

Reducing sugars

Precipitation titrations AgNO3 (argentometry)

Surfactant titrations

Photometric titrations Photometric EDTA titrations

(chelatometry/complexometry)

Acid number and free fatty acids (FFA)

Hydroxyl number

Characteristic fat and oil values Iodine value

Peroxide value

Saponification value

PharmPAC – application know-how from experts

08 Thanks to its modular concept, the Titrando system can

easily be adapted to any application. It meets the require-

ments of FDA regulation 21 CFR Part 11, irrespective of

its use as stand-alone titrator in combination with 840

Touch Control, PC Control or tiamoTM.

Brainy dosing elements with certification

Metrohm dosing elements set new standards with regard

to reliability. An inconspicuous data chip contains all the

data that the Titrando needs to carry out the titration

properly, i.e. serial number, cylinder number, type of rea-

gent, titer, last titer determination, shelf-life data and

much more. In addition, the Titrando compares the data

it has obtained with those of the selected method. If they

do not agree, a clear error message appears.

The iTrodes – intelligent electrodes

The electrode used for the titration is the most important

component of any titration system. The Titrando with

iConnect and iTrodes ensures complete traceability of the

analysis result to any component involved in the analysis.

The built-in memory chip allows the storage of such

important sensor data as article and serial numbers, cali-

bration data, calibration history and calibration intervals.

All the sensor data are read in automatically when the

iTrode is connected to the Titrando. If the type of elec-

trode is not the same as that defined in the method then

the user is informed.

STAT titration with tandem dosing

The determination of enzyme activity (lipase, trypsin,

etc.) or the release kinetics of antacid tablets requires a

titrator that rapidly adjusts to a preset pH value and

keeps it constant for a long period. Tandem dosing is a

feature that prevents dosing interruptions when the

buret is refilled during the titration – a second buret im -

mediately takes over. In this way rapid reactions with a

high reagent consumption can be monitored with maxi-

mum accuracy.

The Titrando – the intelligent titrator without reliability gaps

Flexibility – from the individual instrument to the

fully automated system

Increasing sample numbers, time-consuming sample

preparation steps and unattended overnight operation

are good reasons for using sample changers. Together

with the 814 USB Sample Processor and 815 Robotic USB

Sample Processor XL the Titrando offers a high degree of

automation at low investment costs. The 855 Robotic

Sample Processor combines a top-class Robotic Sample

Processor with a Titrando and takes up minimum space.

Sample preparation at the touch of a button

Metrohm instruments not only cope with the analysis

itself, but also, as the example of the 815 Robotic Soli-

prep shows, perform the most frequent sample prepara-

tion steps.

• Homogenizing

The Polytron® PT 1300D made by Kinematica ensures

reproducible particle size reduction and homogeniza-

tion of all samples.

• Filtering

Commercially available syringe filters with standard

Luer connector can be used directly with the Robotic

Soliprep.

• Liquid handling

From dilution series to sample transfer into a sealed

vessel, liquid handling with Metrohm automation knows

almost no limits.

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tiamoTM is the leading control and database software for

titrators and dosing devices as well as for complete labo-

ratory automation up to a client-server system. This is

why the name tiamoTM stands for «titration and more»

– tiamoTM can do much more than just titrate. tiamoTM

is a titration network (NTDS = Networked Titration Data

System).

• tiamoTM guarantees data security

It does not matter whether the need is to satisfy the

GMP or GLP rules, regulations on the security of elec-

tronic data or the requirement for the traceability of

results in accordance with the FDA’s regulation 21 CFR

Part 11 – tiamoTM has been developed from the very

start to meet all these requirements and thus sets new

standards.

• Signatures

Digital signatures can be added to determinations.

tiamoTM offers two signature levels. As soon as a level-

2 signature is appended to a determination, the data

are protected from any further changes.

• User administration

Arrange the access rights of each user according to

your company’s security policy. tiamoTM sets no limits,

but will convince you with its unique flexibility.

• Complete audit trail

Each action performed by a user is stored automati-

cally in the audit trail. Data for an audit can be pre-

pa red by pressing a button.

• Traceability

Be absolutely certain and place your confidence in the

traceability of Metrohm software and hardware for

your titrations. Each data record contains all the raw

data necessary to ensure traceability.

tiamoTM – titration and more

• Data export

tiamoTM offers you different export formats, including

the modern XML format. Your data are available to all

conceivable Office applications, databases and long-

term archiving programs.

• Determination reprocessing

Wrong sample weight? No problem. With the reproc-

essing function you do not have to worry about your

documentation. tiamoTM automatically records all alter-

ations and thereby gives you a complete overview.

• Report generator

The unique report generator allows you to arrange

your analytical report layout as you want. You can

adapt one of the many report templates to suit your

particular requirements and then send the report com-

fortably by e-mail.

• Data security

tiamoTM supports you in safeguarding your data. Acti-

vate the automatic backup function; tiamoTM will then

automatically make complete copies of all determina-

tions and configurations.

• Client-server functionality

In the simplest case you just install the databases on

your local computer. tiamoTM will grow together with

your requirements. As soon as data security and cen-

tral data management make it necessary, you can con-

figure tiamoTM as client/server.

• Plug and play

Our modern USB devices ensure that all connected

devices appear in the devices window. Monitoring op-

t ions rule out the use of system components that are

wrong or have expired.

• Parallel titration

tiamoTM and the Titrando form a powerful team. Pa r-

al lel titrations − if necessary, carried out by different

users − increase efficiency.

10 The quality, effectiveness and shelf life of pharmaceutical

products depends to a very large extent on their water

content. For this reason a great deal of importance is

attached to water determination in pharmaceutical

ana lysis. Thanks to the specific and selective reaction

with water, Karl Fischer titration (KFT) is one of the most

accurate and most reproducible water determination

methods. That is why, for many years, it has been pre-

scribed in numerous pharmacopoeias as a standard

method for fast and automatable water determination.

If the test substance is completely soluble in the Karl

Fischer reagent and does not enter into any secondary

reactions with the solvent, the sample can be put

directly into the titration cell and the water content

determined directly using volumetry or coulometry.

Not all substances dissolve completely in methanol. This

is, however, an important requirement for the correct

determination of the sample`s water content. Some tech-

niques for improving the solubility of samples are set out

below. These techniques can also be combined with one

another.

Solubilizers

Depending on the test substance, solubilizers can be

added. In the case of samples containing fat or oil, for

example, ointments or creams, the KF reagent is treated

with chloroform, to ensure that the sample dissolves

completely.

High-frequency homogenizers

Tablets must be comminuted prior to titration. This can

be done either manually with a mortar or, more conven-

iently and above all more reproducibly, with the help of

a high-frequency homogenizer directly in the closed titra-

tion cell. In this way one prevents the water content of

the sample from changing during preparation. In addi-

tion, in some cases, it is possible to dispense with the use

of toxic solubilizers.

Higher temperature in the titration cell

Another possibility is titration of the water at a higher

temperature (e.g., at 50 °C).

Karl Fischer water determination

901 Titrando with 840 Touch Control

870 KF Titrino plus

901 Titrando with 803 Ti Stand and Polytron PT 1300D

Titration cell

11

Karl Fischer oven method

Many substances release their water only very slowly or

only at high temperatures. Some react with KF reagents,

forming water or consuming iodine, so the determined

water content is incorrect. Such samples are unsuitable

for direct Karl Fischer titration. For such substances both

the U.S. Pharmacopeia and the European Pharmacopoeia

stipulate determination of the loss on drying in the drying

oven or desiccator. However, this method suffers from

the drawback that it determines not only the water con-

tent, but also other volatile constituents in the sample.

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 transported into the titration cell with

the help of a stream of dry carrier gas; there it is deter-

mined, usually by means of coulometric Karl Fischer titra-

tion. Because the sample itself remains in the vessel and

only the water enters the titration cell, secondary reac-

tions and matrix effects can be ruled out.

The 874 Oven Sample Processor with 852 Titrando

860 KF Thermoprep with 756 Coulometer

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Laboratory automation

Fully automatic sample preparation and analysis of tablets: After the addition of solvent the Polytron high-frequency homogenizer grinds the tablets directly in the sample beaker. Each sample is treated exactly in the same way.

The entire range of automatic sample

preparation from one supplier

Normally, accurate pipetting and dilution of the sample is

enough to determine liquid forms of drugs (tinctures,

infusions, drops, etc.). Metrohm offers you a wide range

of products with which the preparation of liquid samples

can be automated precisely and with time savings.

If, however, solid or semisolid samples are involved, for

example, tablets, suppositories and ointments, the

sample preparation is more demanding. As a specialist in

the field of laboratory automation, we offer you a wide

range of so lutions for the preparation of solid samples –

customized to your needs, if necessary.

Automation = time savings and higher accuracy

In pharmacopoeia analysis, apart from direct titration,

the reliance is mainly on chromatographic methods such

as IC, HPLC and GC. These techniques require that the

sample is present in a liquid and filtered form before it

can be injected onto the column. The preceding sample

preparation steps, still often carried out manually, such as

• grinding/homogenizing

• filtering

• pipetting/diluting

are laborious and time-consuming. Furthermore, manual

sample preparation bears the risk of erroneous results.

Especially where high sample volumes are involved and

when several persons work on the samples, it is hardly

possible to ensure consistent quality in sample prepara-

tion.

The 815 Robotic Filtration Soliprep

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Fully automatic fi ltration: The 815 Robotic Filtration Soliprep fi lters remaining solids out of the homogenized sample. What remains is a clear fi ltrate, that can either be injected directly into the analyzer or diluted further.

Robotic Soliprep – automatic sample preparation

tailored to your needs

With instruments of the Robotic Soliprep family, neither

deviant results nor time-consuming manual routines are

an issue. The solid substance is simply weighed out and

placed in the sample rack – all the rest is done fully auto-

matically. Depending on the model 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 + + + + Titration + Filtration + + + Transfer to + HPLC/GC vials Connection to

+ an LC system

14 Ointments, lotions, cosmetics

Natural fats and oils have a limited shelf life, because

they slowly become oxidized by atmospheric oxygen.

The oxidation stability of fats and oils has been a stand-

ard parameter in quality assurance for many years. To

determine oxidation stability with the Rancimat method,

air is passed through the test sample at a high tempera-

ture to cause artificial aging. During this process the fatty

acids are oxidized by oxygen, forming volatile organic

compounds and other products. These are driven off by

the stream of air, absorbed in water and detected there

by means of conductivity measurement. The time until

these degradation products form is known as induction

time and characterizes the resistance of the sample to

oxidative aging processes, i.e. the oxidation stability.

The method is used to monitor natural fats and oils

which are used in the manufacture of fat-containing

phar maceutical products such as ointments, creams and

lotions. In many cases it is, however, also possible to exa m-

ine the oxidation stability of the finished formulations.

The requirement here is that the proportion of fat in the

sample is significantly higher than the proportion of water.

743 Rancimat

The 743 Rancimat enables the oxidation stability of

natural fats and oils to be determined easily and reliably

in up to eight samples. The instrument is controlled

by PC; the PC software plots the measurement curves,

eva l uates them automatically and calculates the result.

Oxidation stability

15

Rancimat control: up to eight samples can be analyzed for their oxidation stability at the same time

Ion chromatography

Ion chromatography (IC) is the method of choice to de -

term ine active ingredients, excipients and traces of impu-

rities and metabolites in the form of organic and in -

organic ions or polar substances in a number of pharma-

ceuticals, pharmaceutical solutions or even body fluids.

Ion chromatography can determine chemically similar

substances within a very short time in a single analysis.

The concentration of the analytes can vary from ng/L up

to the percent range. Another advantage is the large

selection of separation columns and elution systems

available. Interfering matrix effects can be avoided by

using a suitable inline sample preparation method or

through the choice of the detection method:

• conductivity detection with and without suppression

• electrochemical detection

• spectrophotometric detection with and without

post-column derivatization (UV/VIS)

• coupled detection methods such as IC-MS and

IC-ICP/MS.

16 The intelligent ion chromatographs, automation devices

and peripheral equipment are controlled by the user-

friendly software MagIC NetTM. Complete documentation

on the state of the analyzers and user activities pro vides

complete traceability of the analysis results. MagIC NetTM

fully supports FDA regulation 21 CFR Part 11 and offers

a large number of tools for compliance with the GLP

guidelines.

Pharmaceutical solutions

The term pharmaceutical solutions denotes isotonic solu-

tions, hemodialysis solutions or infusion solutions. They

contain anions, cations, carbohydrates and organic acids,

the concentrations of which frequently differ from one

another by several orders of magnitude. Within the con-

text of production monitoring and final quality control

these ingredients need to be determined easily, quickly

and with a high degree of precision. Ion chromatogra-

phy, with its intelligent analytical procedure and auto-

matic inline sample preparation, fully accomplishes this

task.

Analysis of a solution of Ringer’s lactate; column: Metrosep C 4 – 100 (6.1050.410); eluent: 1.7 mmol/L HNO3, 0.7 mmol/L dipicolinic acid, 0.9 mL/min; sample volume: 10 μL; 1:20 (v/v) inline dilution

850 Professional IC with 858 Professional Sample Processor: an intelligent ion chromatography system for parallel determination of anions and cations in pharmaceutical products

17

Active pharmaceutical ingredients

Active pharmaceutical ingredients in tablets such as gen-

tamicin, neomycin, cefadroxil or bethanechol chloride

can be determined by ion chromatography in accordance

with the regulations of the U.S. Phar ma copeia and

European Pharmacopoeia. The requirements regarding

precision, separation and recovery of the analytes are

described in detail in the pharmacopoeias.

Irbesartan sample spiked with 5...80 μg/L azide; column: Metrosep A Supp 10 – 250 (6.1020.030); eluent: 5 mmol/L Na2CO3, 5 mmol/L NaHCO3, 1.0 mL/min; column temperature: 60°C; sample volume: 1000 μL; inline matrix elimination with 70:30 (v/v) methanol/water

IC determination of the antibiotic gentamicin by means of pulsed amperometric detection using the 871 Advanced Bioscan; column: Polymer Laboratories RP-S; eluent: 60 g/L Na2SO4, 1.75 g/L sodium octane sulfonate, 1.34 g/L NaH2PO4, 8 mL/L THF (pH = 3, H3PO4), 1.0 mL/min; column temperature: 55 °C; sample volume: 20 μL; post-column addition: 300 mmol/L NaOH (0.4 mL/min)

Precision and recovery of the azide

Peak area

Mean value RSD Recovery

[μS·s/cm] [%] [%]

5 μg/L spike 0.4223 1.96 101.71

30 μg/L spike 2.5754 0.14 103.38

n = 3 measurements

Impurities in pharmaceuticals

Apart from active ingredient analysis, it is also possible to

determine impurities in pharmaceutical products by

means of ion chromatography. Even small concentrations

of an impurity can cause significant side effects. The azide

used in the synthesis of antihypertensive Irbesartan can

be detected in traces as an impurity in the product.

The U.S. Pharmacopeia recommends ion chromatogra-

phic azide determination after direct injection according

to USP<621>. Azide determination is more selective,

more sensitive and, above all, quicker with the use of

inline matrix elimination, where the interfering pharma-

ceutical matrix is separated from the target analyte in the

course of sample preparation.

Voltammetric trace analysis determines electrochemically

active substances. In many cases these are traces of

heavy metals. Voltammetry is frequently employed to

complement and validate spectroscopic methods. Its

features are: compact equipment, relatively low invest-

ment and running costs, simple sample preparation,

short analysis times and high accuracy and sensitivity. In

18

Voltammetry

addition, unlike the spectroscopic methods, voltammetry

can distinguish between different oxidation states of

metal ions as well as between free and bound metal ions.

This is referred to as speciation analysis. Voltammetric

results provide important information regarding the bio-

availability and toxicity of heavy metals.

Voltammetry also enables organic compounds to be de -

ter mined with a high degree of sensitivity. This makes it

possible to analyze many active pharmaceutical ingredi-

ents according to USP<801>.

Voltammetry is especially suitable for laboratories in

which only a few parameters have to be monitored with

a moderate sample throughput. It is frequently used for

special applications which cannot be performed with

other techniques or, if they can, require a lot of work.

797 VA Computrace

The 797 VA Computrace is a modern measuring stand

that allows voltammetric and polarographic determina-

tions to be performed. By adding Dosinos and a sample

changer to the stand, analysis can easily be automated.

Detection limits (1 ppt = 1 ng/kg)

Element Detection limit

[ppt]

Antimony SbIII/SbV 200

Arsenic AsIII/AsV 100

Bismuth Bi 500

Cadmium Cd 50

Chromium CrIII/CrVI 25

Cobalt Co 50

Copper Cu 50

Iron FeII/FeIII 50

Lead Pb 50

Mercury Hg 100

Element Detection limit

[ppt]

Molybdenum MoIV/MoVI 50

Nickel Ni 50

Platinum Pt 0.1

Rhodium Rh 0.1

Selenium SeIV/SeVI 300

Thallium Tl 50

Tungsten W 200

Uranium U 25

Zinc Zn 50

Application examples

Fe(II) in iron sucrose injection solution

according to USP-NF

Polarography makes it possible to determine, directly and

selectively, the proportion of iron(II) within the total con-

centration of iron in the preparation. No prior sample

preparation and chemical separation of the iron species

is required. During determination the separate signals of

the iron(II) and iron(III) complex are measured. The iron(II)

content is derived from the signal ratio.

19

Thimerosal in eye or nose drops, vaccines and

cleaning solutions for contact lenses according to

USP-NF

Mercury-containing thimerosal (or thiomersal) is used as

a preservative for pharmaceuticals and cosmetics, to

protect them from microbial contamination. Examples of

the use of thiomersal are: cleaning and storage solutions

for contact lenses, eye, nose and ear drops and tattoo

inks. Injectable medicinal products − for example, immu-

noglobulins or many vaccines (flu, hepatitis B, etc.) – can

also be preserved with thimerosal.

In many cases direct determination in the finished prepa-

ration is possible.

Heavy metal impurities in pharmaceutical

products

Besides the main constituents, inorganic impurities, espe-

cially heavy metals, can also be determined. For this, the

pharmaceutical preparation is digested and the relevant

metal ions are then determined by means of stripping

voltammetry.

Other active ingredients that can be determined

by polarography according to USP-NF

Electrochemically reducible and oxidizable active pharma-

ceutical ingredients, for example, azathioprine, cefaman-

dole, cyst eine hydrochloride, diclofenamide, iodine or

procarba zine, can be determined directly with the help of

po la ro graphy in accordance with USP<801>.Polarographic determination of iron(II) content

Atline process analysis

20 PAT and QbD

Medicinal products are produced according to very strict

guidelines and must satisfy the highest standards with

regard to quality, effectiveness and safety. During the

production of the various active ingredients and excipi-

ents every step of the process is closely monitored. In

addition, there are extensive release analyses at the end

of the production process, which often lead to the situa-

tion where pharmaceutical producers spend more time

on final checks than on production. Furthermore, strict

regulatory requirements make optimization of the phar-

maceutical production processes more difficult. With the

PAT (Process Analytical Technology) and QbD (Quality by

Design) initiatives, the FDA aims to bring about an in -

crease in efficiency in pharmaceutical production, in clud-

ing a trend away from final checks towards real-time

process analysis and control.

Fast process monitoring

ProcessLab, a robust and easy-to-use system that is

installed directly within the process, makes it possible to

carry out not only the release analyses, but also the

analysis of intermediate products. The sample is brought

to the ProcessLab and the analysis is started with a single

push of a button. ProcessLab is based on the proven

Titrando system, which, combined with the tiamoTM soft-

ware, meets the requirements of FDA regulation 21 CFR

Part 11.

ProcessLab features a modular design and it is configured

according to analytical requirements and can be ideally

integrated into the process communication system via

inputs/outputs (typically 4...20 mA). Through the use of

a barcode reader, sample identification can be made

even easier. Just a few minutes after sampling, the rele-

vant process information is available to a LIMS or the

master display. The process conditions can be rapidly and

efficiently altered according to the preset conditions.

ProcessLab is therefore ideally suited for rapid and inde-

pendent process monitoring in an industrial environment.

A ProcessLab analysis system consists of a TFT operating

panel and a customized analysis module. For even easier

and more comfortable operation, the operating panel is

also available with a touch-sensitive screen. With its

splash-proof housings (protection class IP54), ProcessLab

is ideally suited for use in the production environment.

ProcessLab analysis system with touch monitor and analysis module

Determination of acidic and basic components

Numerous pharmaceutical intermediate and end prod-

ucts contain acidic and basic components. These are

determined by means of an appropriate acid-base titra-

tion. Depending on the sample matrix, either aqueous or

non-aqueous titrations are carried out. The latter are

done with a titrant and solvent suitable for the particular

application, for example, with perchloric acid in glacial

acetic acid or with tetrabutylammonium hydroxide (TBAH)

in acetone.

21

Determination of redox-sensitive components

Oxidizable and reducible components and active ingre-

dients are determined with redox titrations. Methods

frequently used include iodometry (I2/S2O42-), cerimetry

(Ce(IV)), bromatometry (KBr03) and permanganometry

(KMnO4). The modular structure of ProcessLab enables

easy adaptation to the specific requirements of the appli-

cation. Because of its closeness to the process, the relevant

analytical values are available within just a few minutes.

Security of results – for the lifetime of the analyzer

Particularly in the pharmaceutical industry, measurement

errors can have serious consequences and must there-

fore be avoided at all costs. Throughout the world the

name Metrohm stands for high-quality laboratory ana-

lyzers in ion analysis. They are designed to deliver high-

pre cision results. Leading international pharmaceutical

com panies also value Metrohm for its comprehensive

services, which ensure that the responsible people in the

laboratories can absolutely rely on their results through-

out the lifetime of their analyzers.

Regulatory Compliance

With the Metrohm Compliance Service®, Metrohm guar-

antees compliance with statutory requirements for phar-

maceutical companies. Owing to the large number of

different laboratory instruments and analyzers, that has

become very complicated. As an experienced and trusted

partner, Metrohm makes its regulatory expertise available

to its customers.

22

Analyzers used in laboratories must satisfy the latest re -

quirements of FDA regulations, GLP/GMP standards and

the GAMP guidelines. This is achieved through ins tru-

ment qualification and system validation. Metrohm offers

qualification and validation documents as well as ser-

vices, which meet the requirements of the FDA and other

regulatory authorities.

These include:

• competent assistance with Design Qualification (DQ)

• documented installation and fast professional setup of

new instruments with Installation Qualification (IQ)

• Operational Qualification (OQ), guaranteeing that

Metrohm instruments meet the stated equipment

speci fication. This ensures full performance capability.

• all qualification and validation work, which is per-

for med only by professionally trained and certified

service technicians

• user training taught by experts

• efficient audit processes

• competent requalification and revalidation

Metrohm Quality Service®

ween different types of service contracts. A full service

contract, for example, offers you optimum security for

work without any worries, whilst giving you complete

control of costs and providing fully compliant documen-

tation.

Metrohm Quality Service®

The worldwide Metrohm Quality Service®, especially the

scheduled and preventive maintenance, extends the

trouble-free life and operating time of your analysis sys-

tems. Qualified service technicians with proof of training

carry out the maintenance work. You can choose bet-

Metrohm Quality Service® at a glance

Metrohm Quality Service® Customer benefits

Application support by means of our vast selection of

Application Bulletins, Application Notes, monographs, Fast and professional solution to all arising application

validation brochures, technical posters and articles issues and complex analytical challenges

Personal advice from our specialists by e-mail or

telephone

Training courses Competent users contribute substantially to results

Accurate results

Certified calibrations, e.g. of dosing and exchange units

Documentary evidence to comply with regulations

and for efficient audits

Remote maintenance Fast resolution of software issues

Back-up support High data security

Emergency services, e.g. express repairs on-site Short response time and thus rapid resolution of

problems and minimization of downtimes

Spare parts, made in Switzerland by Metrohm and Sustainable repair success, short delivery times,

available worldwide, with guarantee of availability of minimization of downtimes

spare parts ten years after the end of production

Regional repair workshops available worldwide and Instruments soon available for use again

a central workshop in Switzerland

23

Thanks to Metrohm Quality Service® you can rely

on your results for the lifetime of the analytical

instrument.

We look forward to working with you.

Ordering information

24 pH and conductivity measurement

pH measurement

2.867.0110 867 pH Module with Touch Control

2.867.0210 867 pH Module with tiamoTM light

Conductivity measurement

2.856.0110 856 Conductivity Module with Touch Control

2.856.0210 856 Conductivity Module with tiamoTM light

6.0916.040 Conductivity measuring cell c = 0.1 cm–1 with Pt 1000

Titration

2.907.1020 Pharm Titrando

2.902.0010 902 Stat Titrando

6.6056.2X2 tiamoTM 2.X full

Water determination according to Karl Fischer

Coulometric KF titration

2.756.0010 756 KF Coulometer with generator cell with diaphragm

2.756.0110 756 KF Coulometer with generator cell without diaphragm

2.831.0010 831 KF Coulometer with generator cell with diaphragm

2.831.0110 831 KF Coulometer with generator cell without diaphragm

2.851.0010 851 Titrando with generator cell with diaphragm

2.851.0110 851 Titrando with generator cell without diaphragm

2.852.0050 852 Titrando with generator cell with diaphragm and volumetric titration cell

2.852.0150 852 Titrando with generator cell without diaphragm and volumetric titration cell

Volumetric KF titration

2.890.0110 890 Titrando with Touch Control

2.890.0210 890 Titrando with tiamoTM light

2.870.1010 870 KF Titrino plus complete

2.901.0010 901 Titrando including titration cell

KF oven

2.860.0010 860 KF Thermoprep

2.874.0010 874 Oven Sample Processor

Automation

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

2.743.0014 743 Rancimat (230 V) including software and accessories

2.743.0015 743 Rancimat (115 V) including software and accessories

Ion chromatography

2.850.3030 850 Professional IC AnCat – MCS for anion and cation determination

2.850.2150 850 Professional IC – MCS – Prep 2 for the determination of anions after inline matrix elimination

2.871.0010 871 Advanced Bioscan for pulsed amperometric detection

2.858.0020 858 Professional Sample Processor for the automation of determinations

6.5331.010 Equipment set for Au flow cell

6.1050.410 Metrosep C 4 – 100 for cation determination

6.1020.030 Metrosep A Supp 10 – 250 for anion determination

Voltammetry

2.797.0010 797 VA Computrace for manual operation

MVA-2 VA Computrace system with automatic standard addition. Consisting of 797 VA Computrace

with two 800 Dosinos.

MVA-3 Fully automated VA Computrace system. Consisting of 797 VA Computrace with 863 Compact

VA Autosampler and two 800 Dosinos for automatic addition of auxiliary solutions. Allows the

automatic processing of up to 18 samples possible. This system is the optimum solution for

automatic analysis of small sample series.

Process analysis

2.875.0010 875 ProcessLab Base Unit, left-hinged door

2.875.0020 875 ProcessLab Base Unit, right-hinged door

2.875.0510 875 ProcessLab Base Unit with TFT operating panel incl. touch function, left-hinged door

2.875.0520 875 ProcessLab Base Unit with TFT operating panel incl. touch function, right-hinged door

2.875.0210 875 ProcessLab Base Unit VA with TFT operating panel incl. touch function, right-hinged door

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