Loss on drying and validation

of Moisture Analyzers

S.ZALI
M.Sc.
Dept. of Physico chemistry
Razi vaccine serum research institute
[email protected]
1389/8/12
 WATER DETERMINATION (921)

Many Pharmacopeial articles either are hydrates or contain water

in adsorbed form. As a result, the determination of the water
content is important in demonstrating compliance with the
Pharmacopeial standards. Generally one of the methods is
called for in the individual monograph, depending upon the
nature of the article. In rare cases, a choice is allowed between
two methods.
USP30–NF25 Page 385
 WATER DETERMINATION (921)

When the article contains water of hydration, the Method I

(Titrimetric), the Method II (Azeotropic), or the Method III
(Gravimetric) is employed, as directed in the individual
monograph, and the requirement is given under the heading
Water.

The heading Loss on drying (see Loss on Drying 731 ) is used in

those cases where the loss sustained on heating may be not
entirely water.
USP30–NF25 Page 385
Water and Loss on Drying— Where the water of hydration or
adsorbed water of a Pharmacopeial article is determined by the
titrimetric method, the test is generally given under the
heading Water. Monograph limits expressed as a percentage
are figured on a weight/weight basis unless otherwise
specified. Where the determination is made by drying under
specified conditions, the test is generally given under the
heading Loss on drying.
However, Loss on drying is most often given as the heading
where the loss in weight is known to represent residual volatile
constituents, including organic solvents as well as water.
USP30–NF25 Page 385
 LOSS ON DRYING (731)

The procedure set forth in this chapter determines the amount of

volatile matter of any kind that is driven off under the
conditions specified. For substances appearing to contain
water as the only volatile constituent, the procedure given in
the chapter, Water Determination 921 , is appropriate, and is
specified in the individual monograph.
USP30–NF25 Page 300
 LOSS ON DRYING (731)
¾ Mix and accurately weigh the substance.
¾ If the test specimen is in the form of large crystals, reduce the
particle size to about 2 mm by quickly crushing.
¾ Tare a glass stoppered, shallow weighing bottle that has been
dried for 30 minutes under the same conditions
¾ Put the test specimen in the bottle.
¾ By gentle, sidewise shaking, distribute the test specimen as
evenly as practicable to a depth of about 5 mm generally.
Place the loaded bottle in the drying chamber.
¾ Dry the test specimen at the temperature and for the time
specified.
USP30–NF25 Page 300
 LOSS ON DRYING (731)
¾ If the substance melts at a lower temperature than that
specified for the determination of Loss on drying, maintain the
bottle with its contents for 1 to 2 hours at a temperature 5 to 10
below the melting temperature, then dry at the specified
temperature.

¾ Where the specimen under test is Capsules, use a portion of

the mixed contents of not fewer than 4 capsules.

¾ Where the specimen under test is Tablets, use powder from not
fewer than 4 tablets ground to a fine powder.
USP30–NF25 Page 300
 LOSS ON DRYING (731)
¾ Where the individual monograph directs that loss on drying be
determined by thermogravimetric analysis, a sensitive electro
balance is to be used.
¾ Where drying in vacuum over a desiccant is directed in the
individual monograph, a vacuum desiccator or a vacuum
drying pistol, or other suitable vacuum drying apparatus, is to
be used.
¾ Where drying in a desiccator is specified, exercise particular
care to ensure that the desiccant is kept fully effective by
frequent replacement.
USP30–NF25 Page 300
 LOSS ON DRYING (731)

¾ Where drying in a capillary-stoppered bottle in vacuum is

directed in the individual monograph, use a bottle or tube fitted
with a stopper having a 225 ± 25 μm diameter capillary, and
maintain the heating chamber at a pressure of 5 mm or less of
mercury. At the end of the heating period, admit dry air to the
heating chamber, remove the bottle, and with the capillary
stopper still in place allow it to cool in a desiccator before
weighing.
USP30–NF25 Page 300
 XM120 Moisture Analyzer
¾Developed for users with highest requirements
and a wide range of samples
¾High end instrument, conforming to the most
stringent
¾International
¾ standards
¾Fastest sample
¾optimum precision
¾ analysis
 Introduction
Top quality technology
¾ Weighing technology which meets all international
metrological regulations
¾ Weighing range 124 g / readability of balance 1 mg
¾ High temperature range up to 230 °C, temperature
increments of 1°C, results displayed to 0.01%
¾ 3.4" VGA touch-screen graphic display
¾ Graphic print-out (RS232 interface)
¾ Extended method memory capacity
¾ Choice of radiation heat source: halogen, quartz infra-
red, dark infra-red
 Introduction

Simple controls
¾ Icon driven user guidance
¾ Variety of start-up and end-point control selections
¾ Three-phase drying for total control
¾ Easy access sample holder
¾ Practical construction to enable easy cleaning
 Introduction

Quality Assurance
¾ Results displayed in GLP guideline format.
Numerical and statistical analysis available

¾ Real-time results shown in graphic display

¾ Download latest software through the internet

Technical Data Moisture Analysers
 CLEANING
Procedure:
1) Unplug the unit.
2) Allow the unit to cool for at least thirty (30) minutes.
3) Check that the unit is still unplugged.
4) Use a mild detergent and a soft rag to clean the
external surfaces of the unit.
CAUTION: Do not immerse unit in water or any other
cleaning solution.
5) Carefully remove the weighing pan, draft shield and
sample holder to thoroughly clean them.
 CLEANING
6) Keep all warning labels clean.
7) Clean the chamber and other parts. Use extreme care
in removing the accumulated residue with a clean,
damp cloth.
8) Keep the mechanical part of the printer free from dirt
and dust. Periodically lift up the printer cover to clean
the printer mechanism with a soft brush.
 Calibration

¾ Balance Calibration

¾ Temperature adjustment
 Balance Calibration
¾ Enter a user-definable
weight as a criterion for
calibration in "ext.-
def." mode
 Balance Calibration
The instrument performs a zero point measurement
(-- 0000 g is displayed flashing)
The instrument performs a zero point measurement
(0000 g is displayed flashing
After the zero point measurement, the display
flashes the recommended calibration weight
(100.000 g) or the weight defined by you.
Place the calibration weight on.
The display flashes Once the display stops
flashing, this indicates that the calibration has
ended.
. The measured weight is displayed.
Temperature adjustment
 Temperature adjustment
Temp.-1
. Set,°C:
First target temperature. You can enter other target temperatures
according to your samples. (default 100°C)..
Act,°C:
Temperature which was actually reached. If the temperature
adjustment tool is connected, the temperature is automatically
copied over from the temperature adjustment tool. Otherwise,
it has to be input manually.
. Temp.-2
. Set,°C:
Second target temperature (default 160°C).
. Act,°C:
Temperature which was actually reached. If the temperature
adjustment tool is connected, the temperature is automatically
copied over from the temperature adjustment tool. Otherwise,
it has to be input manually.
 Linearity

A balance is linear when the displayed weight is

equal (within the tolerance specified) to the
actual weight, for weights between minimum
and maximum capacity. To determine if the
unit is linear, the same test mass is weighed at
two pre-loads.
 Repeatability (Balance)
Number Weight=100gr Weight=1gr
1 99.999 0.999
2 100.000 0.999
3 100.001 1.000
4 100.001 1.000
5 100.001 1.001
6 100.001 1.000
7 100.001 1.000
8 100.001 1.001
9 100.001 0.999
10 100.001 0.999
11 100.000 1.000
Average= 100.0006364 0.999818181
Standard deviation= 6.752E-4 7.507E-4
RSD= 6.751E-4 7.508E-2
 Thermogravimetric Analysis
Thermogravimetric analysis involves the determination of the
mass of a specimen as a function of temperature, or time of
heating, or both, and when properly applied, provides more
useful information than does loss on drying at fixed
temperature, often for a fixed time and in what is usually an
ill-defined atmosphere. Usually, loss of surface-absorbed
solvent can be distinguished from solvent in the crystal lattice
and from degradation losses. The measurements can be carried
out in atmospheres having controlled humidity and oxygen
concentration to reveal interactions with the drug substance,
between drug substances, and between active substances and
excipients or packaging materials.
¾ USP30–NF25 Page 377
 Thermogravimetric Analysis
While the details depend on the manufacturer, the essential
features of the equipment are a recording balance and a
programmable heat source. Equipment differs in the ability to
handle specimens of various sizes, the means of sensing
specimen temperature, and the range of atmosphere control.
Calibration is required with all systems, i.e., the mass scale is
calibrated by the use of standard weights; calibration of the
temperature scale, which is more difficult, involving either
variations in positioning of thermocouples and their
calibration; or in other systems, calibration involves the use of
standard materials because it is assumed that the specimen
temperature is the furnace temperature.
USP30–NF25 Page 377
 Thermogravimetric Analysis
Procedural details are specified in order to provide for valid
interlaboratory comparison of results. The specimen weight,
source, and thermal history are noted. The equipment
description covers dimensions and geometry, the materials of
the test specimen holder, and the location of the temperature
transducer. Alternatively, the make and model number of
commercial equipment are specified. In all cases, the
calibration record is specified. Data on the temperature
environment include the initial and final temperatures and the
rate of change or other details if nonlinear. The test
atmosphere is critical; the volume, pressure, composition,
whether static or dynamic, and if the latter, the flow rate and
temperature are specified.
USP30–NF25 Page 377
 Validation of facility systems and
equipment
The validation protocols for equipment and systems are normally
divided into three segments: IQ, OQ, PQ. For systems and
equipment, Performance Qualification is often synonymous
with Validation. Depending on the function and operation of
some equipment, only IQ/OQ are required. For equipment
whose correct operation is a sufficient indicator of its function,
and that are monitored and/or calibrated on a regular schedule
(e.g. pH meter, incubator, centrifuge, freezer), the installation
and operational qualifications are performed. Systems such as
air, water, steam, and major equipment which perform critical
support processes, such as sterilization (autoclave, oven),
depyrogenation (oven or tunnel), or lyophilization, require
installation, operational and performance qualifications.
A WHO guide to good manufacturing practice (GMP) equirements Part 2: Validation
 Validation of facility systems and
equipment
The following table lists the typical categories of systems and equipment
which require performance qualification
Systems Equipment
Air (HVAC) Autoclave
Compressed air Depyrogenation oven or tunnel
Pure Steam Lyophilizer
Raw steam Continuous flow centrifuge
Purified water
WFI
Central vacuum
A WHO guide to good manufacturing practice (GMP) equirements Part 2: Validation
 Installation qualification(IQ)
The IQ should list all the identification information, the
location, utility requirements and any safety features
of the equipment.
The IQ protocol prepared for each piece of equipment
or system lists the name, description, model and
identification numbers, the location, utility
requirements, connections, and any safety features
of the system/equipment which need to be
documented.
It should verify that the item matches the purchase
specifications, and that all drawings, manuals, spare
parts list, vendor address and contact number, and
other pertinent documentation are available.
A WHO guide to good manufacturing practice (GMP) equirements Part 2: Validation
 Operational qualification (OQ)
This document outlines the information required to provide evidence
that all the components of a system or of a piece of equipment
operate as specified. This involves testing of all normal operation
controls, all alarm points, all switches and displays, interacting
controls, and any other indications of operations and functions. The
OQ document should provide a listing of SOPs (or reference to
specific manual instructions) for operation, maintenance and
calibration; information on the training of operators; and instructions
for any static or dynamic tests to show that the equipment operates
as expected under normal conditions. Specifications and acceptance
criteria must be defined for all the operations. The OQ document
should include information on equipment or system calibration, pre-
operational activities, routine operations and their acceptance
criteria.
A WHO guide to good manufacturing practice (GMP) equirements Part 2: Validation
 Performance qualification (PQ)
This part of the validation for systems and equipment is performed
after both Installation and Operational Qualifications have been
completed, reviewed and approved.
The PQ document describes the procedure or procedures for
demonstrating that a system or piece of equipment can consistently
perform and meet required specifications under routine operation
and, where appropriate, under worst case situations.
The PQ should include a description of the preliminary procedures
required, the detailed performance test(s) to be done, and the
acceptance criteria for each test. The PQ also requires that other
supporting equipment used during the qualification have been
validated (e.g. the steam system must be validated before the
autoclave can be validated).
A WHO guide to good manufacturing practice (GMP) equirements Part 2: Validation