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
03
You 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 specications
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 tiamo
TM
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. FDAs
regulation 21 CFR Part 11 must be satisfied. The 856
Conductivity Module, together with the 840 Touch
Control, PC Control or tiamo
TM
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 S/cm, and thus for
measuring water for pharmaceutical use.
.
07
Because 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 HClO
4
In glacial acetic acid/acetic anhydride, with HClO
4
In glacial acetic acid plus mercury acetate, with HClO
4
In glacial acetic acid/methyl ethyl ketone, with HClO
4
In formic acid/glacial acetic acid or acetic anhydride,
with HClO
4
In other solvents or solvent mixtures
Iodine/thiosulfate (Iodometry)
Iodine/arsenite (Iodometry)
Diazotization with NaNO
2
Redox titrations
Cer(IV) (cerimetry)
KBrO
3
(bromatometry)
KMnO
4
(permanganometry)
KIO
3
Reducing sugars
Precipitation titrations
AgNO
3
(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 tiamo
TM
.
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.
09
tiamo
TM
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 tiamo
TM
stands for titration and more
tiamo
TM
can do much more than just titrate. tiamo
TM

is a titration network (NTDS = Networked Titration Data
System).
tiamo
TM
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 FDAs regulation 21 CFR
Part 11 tiamo
TM
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.
tiamo
TM
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 companys security policy. tiamo
TM
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.
tiamo
TM
titration and more
Data export
tiamo
TM
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. tiamo
TM
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
tiamo
TM
supports you in safeguarding your data. Acti-
vate the automatic backup function; tiamo
TM
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. tiamo
TM
will grow together with
your requirements. As soon as data security and cen-
tral data management make it necessary, you can con-
figure tiamo
TM
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
tiamo
TM
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
12
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
13
Fully automatic ltration: The 815 Robotic Filtration Soliprep
lters remaining solids out of the homogenized sample. What
remains is a clear 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 Net
TM
. Complete documentation
on the state of the analyzers and user activities pro vides
complete traceability of the analysis results. MagIC Net
TM

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 Ringers lactate; column: Metrosep C
4 100 (6.1050.410); eluent: 1.7 mmol/L HNO
3
, 0.7 mmol/L
dipicolinic acid, 0.9 mL/min; sample volume: 10 L; 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 g/L azide; column:
Metrosep A Supp 10 250 (6.1020.030); eluent: 5 mmol/L
Na
2
CO
3
, 5 mmol/L NaHCO
3
, 1.0 mL/min; column temperature:
60C; sample volume: 1000 L; 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
Na
2
SO
4
, 1.75 g/L sodium octane sulfonate, 1.34 g/L NaH
2
PO
4
,
8 mL/L THF (pH = 3, H
3
PO
4
), 1.0 mL/min; column temperature:
55 C; sample volume: 20 L; post-column addition:
300 mmol/L NaOH (0.4 mL/min)
Precision and recovery of the azide
Peak area
Mean value RSD Recovery
[Ss/cm] [%] [%]
5 g/L spike 0.4223 1.96 101.71
30 g/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 Sb
III
/Sb
V
200
Arsenic As
III
/As
V
100
Bismuth Bi 500
Cadmium Cd 50
Chromium Cr
III
/Cr
VI
25
Cobalt Co 50
Copper Cu 50
Iron Fe
II
/Fe
III
50
Lead Pb 50
Mercury Hg 100
Element Detection limit
[ppt]
Molybdenum Mo
IV
/Mo
VI
50
Nickel Ni 50
Platinum Pt 0.1
Rhodium Rh 0.1
Selenium Se
IV
/Se
VI
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 tiamo
TM
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 (I
2
/S
2
O
4
2-
), cerimetry
(Ce(IV)), bromatometry (KBr0
3
) and permanganometry
(KMnO
4
). 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 tiamo
TM
light
Conductivity measurement
2.856.0110 856 Conductivity Module with Touch Control
2.856.0210 856 Conductivity Module with tiamo
TM
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 tiamo
TM
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 tiamo
TM
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
25
26
27
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