Focusing on Pharmacy

The Analysis, Characterization and Identification of Substances

2
Company founder Thomas NETZSCH
(1845 - 1897), born in Selb, Germany
Expertise in Thermal Analysis
The NETZSCH Company was founded in 1873 in
Selb, Germany, by the brothers Thomas and Christian
Netzsch. Today, it is a sound, medium-sized, family-
run company specializing in the manufacturing of
machines and measuring instruments. As a global
innovator, Netzsch continues to grow its three busi-
ness units of 2,100 employees in the manufacturing,
sales and service divisions.
Analyzing & Testing
Grinding & Dispersing
Pumps
Flame Photometer from 1958
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Experts in Thermal Analysis for over 50 years
As early as 1953, the Analyzing & Testing business
unit began developing and manufacturing thermo-
analytical instruments. In 1962, NETZSCH-Gertebau
was registered as an independent limited company.
Its headquarters are still located in Selb, where the
majority of the measuring instruments are manu-
factured, including all instruments for differential
scanning calorimetry (DSC), thermogravimetry (TG)
and simultaneous thermal analysis (STA). NETZSCH
technology is made in Germany and it is
technology you can rely on.
Since its inception, NETZSCH has been continuously
expanding its library of applications and solidifying
its role as an expert in Thermal Analysis. Today,
NETZSCH offers a complete product line of instru-
ments for research, development and quality
assurance. Cutting edge technology, premium
service, and high quality standards make NETZSCH a
leading manufacturer.
NETZSCH Your Partner for Thermal Analysis.
4
Quality and Service Come First
Chemical and pharmaceutical research, development,
and manufacturing all place high demands on the
security, accuracy, dependability and reproducibility
of the analytical methods employed. NETZSCH instru-
ments set high standards in these areas with regard
to precision, flexibility and consistency.
For Thermal Analysis, the Pharmacopoeia of Europe
(Ph. Eur., chapter 2.2.34) and the United States (USP,
chapter 891) describe the methods for differential
scanning calorimetry (DSC) and thermogravimetry
(TG or TGA). These methods can be utilized for the
characterization of both pure substances and mix-
tures. Thermal Analysis yields valuable information
about the physical-chemical properties of such
materials.
The coupling of thermobalances to gas analysis
systems such as mass spectrometers (QMS, quadru-
pole mass spectrometer) or FTIR instruments (Fourier
Transform Infrared Spectroscopy) expands the
spectrum of analysis and allows for conclusions to
be drawn on evaporation processes (release of
solvents, sublimation) or changes in the chemical
composition (water release from hydrates, de-
composition) of active pharmaceutical ingredients,
additives and formulations.
.
Typical application fields for DSC, TG:
Purity testing
Determination of melting of glass transition
temperatures
Polymorphic studies
Investigation of interaction between
components
Determination of thermal stabilities
Analysis of composition
Studies of decomposition kinetics
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Methology:
A DSC measures the change in heat balance (heat
absorption or heat release) of a sample during
heating or cooling as compared to an inert reference.
With a thermobalance (TG), the mass change of a
sample can be determined as a function of temper-
ature or time. Simultaneous thermal analysis (STA)
combines both methods in one instrument.
The customer is our focus!
It is our philosophy to provide you with a complete
solutions packages specially tailored to your
needs for the successful accomplishment of your
tasks. Along with our high-performance instruments,
we offer you measurement and evaluation software
conforming to 21 CFR part 11 (FDA regulation
Electronic Records, electronic signatures), flexible
qualification documents (IQ-OQ), individually
designed service plans, on-site calibration service, a
variety of training options, and expert application
support. Our qualified staff from the applications,
laboratory, technical service and training departments
will be pleased to discuss your requirements from
selecting appropriate measurement parameters to
interpreting the results. Various seminars, users
meetings and individual customer training sessions
can help you tap into the full potential of your
thermoanalytical systems and get optimal results.
We look forward to sharing our decades of hands-on
experience with you. You can find plenty of applica-
tion examples in our book entitled Characterization
of Pharmaceuticals, on our website, or in our
customer magazine (OnSet) published twice a year.
.
Put your faith in us!
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Superior Service
Optimal customer service and worldwide support are
trademarks of NETZSCH.
Our training department offers a wide variety of
events, tailored to the needs of users from research,
education and industry. Our application laboratories
are expert partners for contract testing and our
scientists work out individual solutions to your labs
specific requirements.
In addition, NETZSCH Analyzing & Testing offers a
broad range of instrument-specific services. Trained
NETZSCH employees in more than 45 service centers
worldwide provide fast, reliable customer support for
installation and commissioning, calibration or main-
tenance.
What NETZSCH offers
Installation, commissioning and initial
qualification of your instruments
Installation and commissioning include a com-
plete configuration and parameterization of your
instrument, as well as comprehensive instruction
for your operators. After successful commis-
sioning, our service engineers carry out
the installation qualification (IQ), operation
qualification (OQ) and assist you with the
performance qualification (PQ). The type and
extent of the documentation is designed around
your requirements.
Hotline service
Our experienced service staff is happy to provide
you with assistance by telephone and e-mail.
Inquiries are normally handled within 24 hours.
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Flexible qualification agreements and
calibration service
You decide how often your instrument should be
inspected this guarantees that your mainte-
nance schedule is customized to your needs. Our
clearly structured service price list makes plan-
ning and budgeting straightforward and mini-
mizes your administrative efforts. Your service
history manual gives you an overview of the
instrument configuration and the scheduling
for your next instrument qualification.
To make sure that your Netzsch instrument still
complies with the corresponding specifications
and standards after extended operation, our
service team will coordinate with you system
check-ups. On request, we will also carry out re-
qualifications after a software update is installed.
All members of our expert service staff receive
continuing education in maintenance, repair and
validation on a regular basis. We can guarantee
an efficient and professional service perfor-
mance.
On-site repairs and spare part service
Diagnostic systems implemented within NETZSCH
instruments enable quick and efficient problem
solving. Any problems are immediately localized
and service quickly restored.
For newly installed instruments, we guarantee
spare part availability for at least 10 years.
Almost any spare part can be shipped from our
warehouse within two working days after receipt
of your order. Should on-site repair be impos-
sible, our exchange and loan services will offer
you a suitable component replacement for the
duration of the repair time.
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Ribavirin
DSC is used for studying the melting behavior of
crystalline samples. The standardized DSC evaluation
methods determine the melting point as an extra-
polated onset. The peak area is proportional to the
melting enthalpy. The temperature difference be-
tween the beginning of melting (extrapolated onset)
and the temperature at which the entire sample is
melted (peak maximum) is dependent upon the
sample amount, among other variables. Optical
methods such as the capillary method show the
temperature at which the sample no longer contains
any crystalline (diffusing) portion, which corresponds
to the peak maximum of the DSC curve. The begin-
ning of melting cannot always be clearly determined
by means of the capillary method.
Deoxyribonucleic acid (DNA)
During thermal treatment of deoxyribonucleic acid
(DNA), a structural transition occurs from the helical
structure to isolated single strands. This transition
can be observed as an endothermal effect in the DSC
thermogram (red). By plotting the heat flow versus
time during the transition as an integral (blue), the
temperature at which 50% of the helical structure
has become single strands can be determined. This
temperature is a measure of the stability of the helix
and is also designated as the melting temperature of
DNA.
Applications
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Diclofenac sodium
Many powdery solids tend to adsorb moisture
(deliquescence) or form pseudopolymorphs
(solvates). Diclofenac sodium shows no tendency to
bind water at 40C up to a relative humidity of
50%. At a relative humidity of 75%, however, a
water absorption of 29% occurs. If the moisture
content of the sample atmosphere is then reduced
again to 5%, the release of water can be observed
by means of the TG signal; the reversibility of the
water absorption can thereby be confirmed. The
exposure of active ingredients and formulations at
40C and a relative humidity of 75% serves for
testing storage stability in climates with high humid-
ity.
In both research and production related monitoring, it is important to analyze properties such as melting behavior, purity,
thermal stability, decomposition behavior and the absorption of moisture during storage. The following examples show the
versatile possibilities for employing thermal analysis instrumentation in pharmaceutical applications.
-Lactose monohydrate
By investigating -lactose monohydrate with the STA
449 Jupiter

, simultaneous TG and DSC data can be

obtained with one measurement. By the mass loss of
4.91% along with the endothermal signal at 144C,
dehydration of -lactose mono-hydrate to water-free
-lactose. The energetic effects at 165C and 171C,
however, are not connected with a mass change and
can therefore be interpreted as structural phase
transitions. The decomposition is shown by the mass
loss in the TG curve and already starts at the begin-
ning of the melting process of water-free -lactose.
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Applications
Aminobenzoic acid
The gas-tight design of the DSC 204 F1 Phoenix

allows it to be directly combined with instruments

for Fourier Transform Infrared Spectroscopy (FTIR)
and mass spectrometry (MS). This enables not only
the recording of caloric effects for the sample, but
also the identification of evolving gaseous sub-
stances (like residual solvents or humidity). Amino-
benzoic acid decomposes immediately after melting
(peak temperature: 192C). The mass-to-charge ratio
(amu) detected in the mass spectrometer enables the
identification of the investigated substance and its
fragments.
Maltose monohydrate
The coupling of a DSC 204 F1 Phoenix

to a Fourier
Transform Infrared Spectrometer (FTIR) allows,
among other things, for the monitoring of gas
release during dehydration of hydrates. Even when
using temperature programs providing several
heating and cooling cycles, FTIR data can be recod-
ed continuously. This is implemented during the
measurements as the Gram-Schmidt trace in the
thermoanalytical evaluation software. The example
used here is maltose monohydrate. The sample
dehydrates during the first heating and is present as
an amorphous anhydrate during cooling. In the
second heating, the glass transition and subsequent
decomposition can be observed.
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Melting behavior of biphenyl (C
12
H
10
)
Based on the Vant Hoff approach, impurities in
eutectic mixtures can be quantified in a concentra-
tion of <5 mol%. As the degree of impurity in-
creases, the melting temperature is shifted lower. In
this example, the melting behavior of biphenyl
(C
12
H
10
) was analyzed with the DSC.
Purity determination of biphenyl (C
12
H
10
)
For the evaluation of DSC data, the areas where
melting begins are particularly significant, and are
why these are generally referenced until a conversion
of 20% is reached. The corrected, non-linear form of
the Vant Hoff equation takes into consideration,
among other things, the thermal resistance in the
measuring structure of the DSC and the non-
achievement of a thermodynamic balance under a
dynamic temperature program. The purity deter-
mination of the biphenyl sample yielded 99.27%.
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Proteus

Pharm is an efficient, easy-to-operate

software combining all regulatory requirements
(technical compliance) with a maximum of
flexibility and user friendliness.
One can upgrade to advanced modules, such as
temperature-modulated DSC (TM-DSC*), determina-
tion of specific heat (c
p
), determination of the calcu-
lated DTA signal (c-DTA

), automation of evaluations
with integrated result monitoring (macrorecorder) or
purity determination at any point in time. Some
advanced options are already included in the soft-
ware of the F1 series instruments, specially designed
for research & development.
* TM-DSC not available in North America and Japan
In 1997, the United States Food and Drug Admin-
istration (FDA) published regulations defining re-
quirements for electronic records and criteria for the
use of electronic signatures. The objective of these
guidelines known as 21 CFR Part 11 after the
location of their publication is the complete trace-
ability of processes in the development, approval
and production of drugs and medical products.
Proteus

Pharm
- a Customized Software Solution
All-in-one concept
Even the basic version of the software program
includes all relevant functions for the evaluation and
graphical presentation of DSC or TG measurements.
These include:
Determination of onset, peak, end temper-
atures as well as inflection points
Analysis of peak areas (enthalpies) and partial
peak areas with selectable baseline
Evaluation of glass transitions
Determination of mass-loss steps
Calculation and presentation of 1
st
and 2
nd
derivatives
Extensive graphical choices
Graphic and data export
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Effectice security system independent of the
Windows

operating systems:
The software can be adapted to almost any lab
organization despite its regulated built-in security
systems. Apart from the request to enter a user
name and password when opening the software,
the user will not notice any difference during the
measurement and evaluation as compared to a
program which does not comply with the FDA
regulations.
A combination of user name and password serves
to identify authorized personnel. Unauthorized
access attempts are recorded reliably and result in
a blocking of the corresponding user account. This
blocking can only be cancelled by the authorized
safety administrator.
Audit Trail:
Proteus

Pharm keeps two logs in which all rele-

vant actions are recorded (who has done what when
and why). One audit trail is connected to the safety
system, the second one to the measurement and
evaluation part of the software.
Database orientation with convenient search
possibilities:
Proteus

Pharm supports the two database

systems, Microsoft

SQL Server and Oracle. This

makes it possible to search not only by file name
but also by any entries made during the parameter
definition. For example, a listing of all measurements
of a certain sample carried out during the last two
months can be generated in a matter of only a few
seconds
Electronic signatures:
Electronic signatures can also be activated or
deactivated with one simple click of the mouse.
Best conditions for working in the hybrid mode.
Method editor:
With the method editor, measurement instructions
(SOPs = standard operation procedures) can be
formulated independently from the instrument,
computer or instrument configuration.
For all users bound to conformity with 21 CFR Part
11, Proteus

Pharm is the ideal solution. For areas

independent from this guideline, we recommend our
proven NETZSCH Proteus

software.
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TG 209 F3 Tarsus
Reliable thermobalance for quality assurance
and process optimization
Top-loading balance; fast and easy to operate
Gas-tight construction
Determination of the calculated DTA signal
(c-DTA

)
Automatic sample changer (optional) for up to
20 samples
The Right Instrument for Every Application
DSC 200 F3 Maia

Robust, reliable DSC for routine applications

Easy handling
Great variety of accessories
Low maintenance costs
Automatic sample changer (optional) for up to
20 samples
TG 209 F1 Iris

- FTIR
STA 449 F1 Jupiter

- FTIR
High-resolution, high-performance combina-
tion for the characterization and identification
of gaseous products
Heated transfer line to prevent condensation
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* not available in North America and Japan
TG 209 F1 Iris

Highly precise mirco thermobalance for use in

research & development
Vacuum-tight design
Pre-configured for coupling to gas analysis
systems (FTIR or MS)
High sample throughput by means of fast
heating and cooling rates
Automatic sample changer (optional) for up to
64 different crucibles
DSC 204 F1 Phoenix

Dynamic differential scanning calorimeter to

meet highest requirements
Various sensors, optimized for different appli-
cation fields
Temperature-modulated DSC (TM-DSC)*
Pre-configured for coupling to gas analysis
systems (FTIR or MS)
Automatic samples changer (optional) for up
to 64 different samples
STA 449 F1 Jupiter

Unrivalled flexibility in simultaneous thermal

analysis
Thermo nanobalance with a digital resolution
of 0.025g
Modular concept
A variey of furnaces and samples holders
Automatic sample changer (optional) for up to
20 samples
www.netzsch.com N
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Service at NETZSCH means worldwide competence, professionalism and the highest
level of customer satisfaction.
You can count on us!
Asia:
NETZSCH Instruments Co., Ltd.
Room 2402-05, Unicom International Tower,
547 Tianmu Road (W)
Shanghai 200 070
China
Phone: +86 21 63532705
Fax: +86 21 63532704
E-mail: roshangh@nsi.netzsch.com.cn
Americas:
NETZSCH Instruments, Inc.
37 North Avenue
Burlington, MA 01803
USA
Phone: +1 781 272 5353
Fax: +1 781 272 5225
E-mail: at@nib.netzsch.us
Europe:
NETZSCH-Gertebau GmbH
Wittelsbacherstrae 42
95100 Selb
Germany
Phone: +49 9287 881-110
Fax: +49 9287 881-505
E-mail: at@netzsch.com
NETZSCH Korea Co. Ltd.
5F, Jaeneung Bldg., #1294-3, Beaksuk-Dong
Ilsan-Gu, Koyang
Korea
Phone +82 31 907-3193
Fax: +82 31 908-3198
E-mail: info@netzsch.kr