Robert Mattes, application scientist, FOSS NIRSystems. Stephen Hoag, professor, and Ravikanth Kona, PhD candidate, both in
the Department of Pharmaceutical Sciences, University of Maryland
Top-spray granulation in a fluid-bed dryer is a common method of increasing particle size to increase flow characteristics
and API content homogeneity. After spraying the liquid into the formulation and forming the granule, the product must be dried
to the proper moisture level. If the granules are overdried or underdried, damage to the formulation may occur, thereby causing
problems with subsequent processing and problems with product stability during storage (1). Samples are typically withdrawn
from the fluid bed with a thief during processing and analyzed off line in a laboratory for moisture content. Commonly, there
is a delay before analysis results are available to the operator, which results in processing decisions being made without
optimal product-moisture information. Top-spray granulation end point is often based on time or product temperature and not
actual moisture content.
Near-infrared spectroscopy (NIRS) is a rapid, nondestructive technique for in-process analysis of moisture in a manufacturing
environment (2). Real-time measurements are made with no sample preparation, and data can be analyzed and stored automatically.
NIRS fits in well with FDA's process analytical technology initiative (3). Using NIRS, the process can be monitored for
low levels of residual moisture and other process constituents to yield better process control and end-point determination
(4). Laboratory-scale fluid-bed dryers are often used in research at the university level and in process development to better
understand formulation processing. This study shows the use of NIRS for monitoring residual moisture in laboratory-scale equipment.
Methods and materials.
The NIR instrument used to collect spectra was the ProFoss Diode Array (FOSS NIRSystems). Spectra were collected in the reflectance
mode from 1100 nm to 1650 nm with 0.5-nm data intervals, and 32 scans were co-added to produce a single spectrum. A fluid-bed
probe, specifically for fluid-bed dryer applications, was inserted into a fluid-air granulator at a 45 ° angle to the central
axis of the product container as seen in Figure 1 (NIRS). The collection "spoon" and purge vents are located on the probe tip (see Figure 2 [NIRS]). After each NIR spectrum was collected, the software sent a "data complete" signal that energized an air purge exiting through
the ports in the probe, thereby clearing the "spoon" for a new sample. The insert in Figure 2 (NIRS) shows the probe with the sample collected.
Figure 1 (NIRS): The fluid-bed dryer with the near infrared probe inserted at a 45° angle. Also shown is the black purge
line on the left and the sample thief on the right. (FIGURES 1–5 (NIRS) ARE COURTESY OF THE AUTHORS (MATTES ET AL.))
A charge of lactose monohydrate (Pharmatose 110M, DMV-Fonterra Excipients) and microcrystalline cellulose (Avicel PH 102,
FMC) was prepared and loaded into the product container. The product was fluidized for 5 min to blend and dry the mixture
to homogeneity. An aqueous solution of 10% polyvinyl pyrrolidone (Kollidon K30, BASF) was added by top spray. NIR spectra
were collected every 50 s during the blending operation. Samples for loss on drying (LOD) analysis were withdrawn with the
sample thief at approximately 5-min intervals to be later correlated with spectra acquired at the same time.
Figure 2 (NIRS): The specially designed spoon probe with purge ports. The insert shows sample collected on the probe. (FIGURES
1–5 (NIRS) ARE COURTESY OF THE AUTHORS (MATTES ET AL.))
Results and discussion. Figure 3 (NIRS) shows the second derivative of the sample spectra. The second-derivative mathematical treatment is commonly used in NIR spectroscopy
to minimize baseline offset caused by scattering and to enhance absorbance peaks. Due to the second derivative treatment,
the moisture increases downward in this region. Water absorbs strongly in the NIR between 1400 and 1450 nm as evidenced by
the peaks in that region.
Figure 3 (NIRS): Second derivative mathematically treated dryer spectra. (FIGURES 1–5 (NIRS) ARE COURTESY OF THE AUTHORS (MATTES
A two-factor partial-least-squares regression model was developed with spectra from a calibration run and LOD reference values.
The second derivative intensity over the range 1100–1650 nm was used to develop a prediction model with an R2 value of 0.9519 and a standard error of calibration of 0.7358%. Figure 4 (NIRS) shows a calibration plot of NIR predicted versus LOD % moisture.
Figure 4 (NIRS): Scatter plot of the near infrared (NIR) predicted values versus the loss-on-drying (LOD) values. (FIGURES
1–5 (NIRS) ARE COURTESY OF THE AUTHORS (MATTES ET AL.))
Figure 5 (NIRS) is a typical analysis output trend chart showing the moisture decrease during the drying cycle. The operator is aided with
real-time graphical output such as this in making the decision to end the drying operation before the product is damaged or
degraded. The delay caused by waiting for laboratory results before the product can be released for subsequent processing
can be minimized or eliminated. Output from the NIR computer is used by the fluid-bed dryer's programmable logic controller
for closed-loop process-control decisions. The correct NIR probe must be placed in the product container in a manner that
provides sufficient sample contact with the probe-tip window. Correct probe design and proper placement in process equipment
is of high importance (4).
Figure 5 (NIRS): Trend plot of moisture on subsequent run. (FIGURES 1–5 (NIRS) ARE COURTESY OF THE AUTHORS (MATTES ET AL.))
1. A.G. Rogers, "Granulation and Drying Principles," Hands-on Postgraduate Course in Tablet Technology, Univ. Tennessee (Memphis, 2003).
2. R.A. Mattes et al., "Process Analytical Technology" supplement to Pharm. Technol. 28 (9), s17–s20 (2004).
3. A.M. Afnan, J. Proc. Anal. Technol.
1 (1), 8–9 (2004).
4. R.A. Mattes, D.E. Root, and A.P. Birkmire, "The Role of Spectroscopy in Process Analytical Technologies" special issue
to Spectrosc. 20 (1), 14–17 (2005).