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Application Notes
Isolating polymorphs and
detecting form transition in real time
as presented by Paul Fernandez
Merck & Co., Inc.
at Lasentec® Users’ Forum 2002 - Charleston
Because polymorphic forms have different solubilities, dissolution rates,
and drug bio-availabilities, polymorphic changes of an active drug
substance can be a significant problem in the pharmaceutical industry.
Utilizing the in-process monitoring techniques of Raman spectroscopy and
Lasentec® FBRM® and PVM®, the desired polymorph of a specific
compound was isolated and small polymorphic transitions were identified.
FBRM® was used to examine the chord length distribution of a compound
with a number of polymorphs. PVM® was used to validate the FBRM® data
and identify the presence of certain polymorphic forms that exhibited
different crystal habits. Raman spectroscopy was used to track the
polymorph content.
The primary role of FBRM® was to evaluate the seed amount needed for
growth-dominated crystallization of a specific polymorphic form. It was
concluded that 6% seed loading was necessary to ensure growthdominated crystallization without nucleation (Figure 1). While 2% seed
loading seemed to work, FBRM® data showed that there was still a chance
nucleation was occurring (Figure 2).
add 1 eq. nHPT
50°C
add 1 eq. nHPT
50°C
20°C
#/measure, 1/10
Counts (0-14,000)
Counts (0-14,000)
Application Notes
20°C
10-50 microns (#/sec)
0-10 microns (#/sec)
#/measure, 1/10
10-50 microns (#/sec)
0-10 microns (#/sec)
50-200 microns (#/sec)
50-200 microns (#/sec)
Time, minutes (0-300)
Figure 1: FBRM® data shows that 6%
seed loading is necessary to ensure
growth-dominated crystallization
without nucleation
Time, minutes (0-300)
Figure 2: However, nucleation can
occur at 2% seed loading
The use of PVM® confirmed needle growth rather than nucleation (see
Figure 3). PVM® also detected and recorded an unexpected polymorph
that occurred at a level too low for the Raman instrument to detect.
Figure 3: PVM® images confirm needle
growth rather than nucleation. The top
image shows milled Form A seed after
16 minutes. In the next image, 20 minutes
later, needles are beginning to occur. In the
final image, at 55 minutes total age time,
needles are clearly formed.
It was concluded that PVM® is more sensitive than Raman at detecting the
presence of different polymorphs and/or the end of the transition between
the two forms. PVM® can also be used in conjunction with Raman to
increase the potential for early discovery of new polymorphs.
Mettler-Toledo
Mettler-Toledo Xxxxx
AutoChem, Inc.
Address
7075 Samuel Morse Drive
Address
Columbia, MD 21046 USA
Address
Tel: +1 410 910 8500
Address
Fax: +1 410 910 8600
Email: [email protected]
M-2-132 Rev D (03/2006) Printed in USA
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