Chemical Engineering September 2010 - 58

Pristine Processing
dispersion can be achieved in a liquid
cell with the addition of appropriate surface-active
agents. Dispersion can also
be achieved by controlled agitation or
by the application of ultrasound. Here,
there is always a possibility of changing
the particle-size distribution due to the
thermodynamic Ostwald ripening or recrystallization
effects. In addition, the
blender is stopped at fixed intervals for
sampling. This process of interruption of
the blend cycle and repeated sampling
may change the state of blend.
NIR spectroscopy is a fast and nondestructive
method to determine blend
homogeneity of all the compounds and
endpoints in blending. Online Raman
spectroscopy can evaluate the effect of
parameters such as blend time, blender
speed, API placement in the blender,
filler particle size and density, multiple
tablet components, and sample homogeneity.
The tool is feasible due to large
number of samples across the run
(sampling every 20 s) and the availability
of spectral information on all blend
components throughout the process.
Controlled granulation
The purpose of granulation is to convert
light, small powders into highdensity
free-flowing granulates. A
number of phase changes or processinduced
transformations can occur
due to the different process steps of
wet granulation, which include wetting,
mechanical stress and drying.
Granulation or the manufacture of
pellets using the extrusion-spheronization
technique includes several process
stages (blending of the dry mass,
wet granulation of the mass, extrusion
of the moist mass, rotation of the extrudate
by spheronization, and dryReferences
1.
FDA PAT page. URL: http://www.fda.gov/
cder/OPS/PAT.htm.
2. Manning, H. and Sue, D., " Application of Process
Analytical Technology to Pharmaceutical
Processes, " Ph.D. Thesis, University of
Cincinnati (2004).
3. Mettler Toledo, " Gain Insights into your
Chemistry with ReactIR In situ Reaction
Analysis " Application Note: URL: http://
us.mt.com.
4. Industrial Tomography Systems, ITS Process
Tomography page, URL: http://www.
itoms.com.
5. Bruker Optics, " In-Line Solvent Recovery
Using FT-NIR " (AF # 511 E) URL: http://
www.brukeroptics.com.
6. Yu, L., and others. Applications of process analytical
technology to crystallization processes,
Adv. Drug Deliv. Rev., 56, pp. 349-369 (2004).
ing). Consequently, depending on the
drug substance and excipients processed,
solution-mediated polymorphic
transformations probably take place.
A lack of particle size measurement in
granulator processes denies cost savings
and product consistency.
In granulation, particle size is critically
dependent on the amount of liquid.
Using inline particle-size analyzers,
variables such as moisture content
and liquid saturation of the agglomerate
can be controlled for desired particle
size [7]. An image-processing system
with particle vision management
(PVM) can be used as a PAT tool to
accurately control granule growth in
high-shear granulation processes.
Tableting
Conventional tableting presses are
multistage cycling processes that employ
punches and dies. These machines
are more expensive to operate and less
efficient to use than systems based on
acoustic-resonance spectrometry (ARS),
which measures sample compaction,
axial strain, deformation, hydration,
drying endpoint, elasticity, molecular
stacking, and homogeneity [8]. ARS
identifies and quantifies an analyte online,
providing a simple and continuous
method of process control for tableting
operations.
Perfect coatings
To be coated, tablets are loaded in
large rotating pans and vented for hot
air drying with coating-material-filled
intagliations. Intagliations are impressions
typically achieved by engraving
or impressing an identifying mark or
logo onto a tablet or other solid dosage
form. Because edges and corners can7.
Vaisman, A., and Pugh, D., " The importance
of on-line particle size analysis for the pharmaceutical
industry, " Insitec technical note:
MRK960-01, pp 1-5, URL: www.malvern.com.
8. Medendorp, J., and Lodder, R., Acoustic-Resonance
Spectrometry as a Process Analytical
Technology for Rapid and Accurate Tablet
Identification, AAPS Pharm Sci Tech., 7(1)
A25 (2006).
9. Hagrasy, A., Chang, S., and Desai, D., Raman
Spectroscopy for the determination of coating
uniformity of tablets: assessment of
product quality and coating pan mixing efficiency
during scaleup, J Pharma. Inno., pp.
37-42, (Oct 2006).
10. David, E., Characterization of the solid-state:
spectroscopic techniques, Adv Drug Del Rev,
pp 43 65, 48 (2001).
11. Gregory, A., Robert, A., Susan, M., Characterization
of the solid state: quantitative issues,
Adv Drug Del Rev, pp. 67-90, 48, (2001).
50 CHEMICAL ENGINEERING WWW.CHE.COM SEPTEMBER 2010
not be coated to the same thickness as
the tablet face, the final product may
appear to be nonhomogenous, imperfect
and not finished at all.
NIR spectroscopy is used as an atline
technique for monitoring tablet
film coating in a Wuster column. The
is also useful for analysis of the active
layer of film-coated tablets, for inline
analysis of film coating of pharmaceuticals
pellets in a fluidized-bed apparatus
and for inline monitoring of tablet
film coating in a pan coater.
Raman spectrometry is used as
a tool to examine the variability of
tablet coatings by a spectral changes
correlation with coating thickness [9].
Here, a probe operates with a revolving
laser focus to average content and
coating nonuniformity.
PAT potential
PAT usage encourages the application
of process engineering in pharmaceutical
manufacturing and regulatory
assessment. PAT, therefore, holds the
great promise of improving productivity,
efficiency and quality of pharmaceutical
intermediates, active ingredients
and finished drug products. ■
Edited by Deborah Hairston
Acknowledgment
Thank you to the management of Ranbaxy Research
Laboratories Ltd. for its cooperation and
permission to publish this work. Thank you also
to Vasdev Singh, adjunct professor and head,
University of Petroleum and Energy Studies
(Uttarakhand, India), for his critical remarks
and support.
Authors
Sanjay Gade was formerly
associate director of technology
development and transfer
at Ranbaxy Laboratories Ltd.
(R&D Center II, Plot No. 20,
Sector 18, Udyogvihar Industrial
Area, Gurgaon 122 015,
Haryana, India.) He is now
director of technology and
scaleup for pharmaceutical sciences
at Pfizer Pharmaceutical
India Pvt. Ltd. (Thane Belpur
Road, Navi Mumbai 400 705; Phone: 91-22-6793
2425; Email: sanjay.gade@pfizer.com). Gade has
B.S.Ch.E. and M.S.Ch.E. degrees from the University
Institute of Chemical Technology (Mumbai)
and is a senior member of AIChE and ISPE.
Deepak Jain was senior research
scientist for technology
and transfer at Ranbaxy
Laboratories Ltd., and is now
is manager of technology and
scaleup for pharmaceutical
sciences at Pfizer Pharmaceutical
Sciences India Pvt.
Ltd. (Phone: 91-22-6793 2469;
Email: deepak.jain@pfizer.
com) With 13 years of academic
and industrial experience,
he has M.S.Ch.E. and Ph.D.Ch.E. degrees
from The M.S. University of Baroda.
http://www.fda.gov/ http://www.malvern.com http://http:// http://us.mt.com http://www http://www.itoms.com http://http:// http://www.brukeroptics.com http://WWW.CHE.COM
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