Application of a Water-Insoluble Active
Ingredient Using Fluid Bed Processing
Joe Cobb, David Ward, Jeff Williamson, Deanna Williamson, Brian
Woodall
OBJECTIVE
To determine the feasibility of applying (layering) a water-insoluble active
pharmaceutical ingredient (API) onto a novel substrate, Emcompress®, (dibasic calcium
phosphate dihydrate, USP; Penwest) using a fluid bed processor equipped with a
Wurster column. Subsequent application of an enteric coating will also be evaluated.
BACKGROUND
Wurster processing is well known in industry and academia as a means to manufacture
microparticles containing drug substances. Typically, the process involves the
application of a coating that may or may not contain an API to a substrate such as a
commercially available sugar/starch sphere or an spheronized extrudate containing an
API. If desired, modified release agents can be included with the application of the API
or added as a separate layer afterward. With all Wurster processes, the coating
materials are either dissolved or suspended in a solvent and sprayed onto the substrate.
Most often, this solvent is water.
Previous work established that it was possible to apply a water-soluble active ingredient,
Y, onto three different novel substrates. Of these, Emcompress rated best based on the
criteria of ease of processing and the adhesion of the coating materials to the substrate.
One fundamental characteristic of Y was its relatively high solubility in water and the fact
that it could be easily dissolved prior to spraying onto the Emcompress. In contrast, the
active ingredient to be used in this experiment, X, is practically insoluble in water (<0.10
mg/mL) and will be suspended in water along with other process-aiding excipients such
as a binder, surfactant and anti-foaming agent.
METHODOLOGY
Materials
• Active Pharmaceutical Ingredient (API) X, supplied by client
• Emcompress (dibasic calcium phosphate dihydrate, USP), supplied by
Penwest/JRS Pharma, Inc.
• Methocel® E5 (hydroxypropyl methylcellulose, NF), donated by Dow Chemical,
Inc.
• Simethicone, USP, supplied by Spectrum, Inc.
• Polysorbate 80, NF, supplied by Spectrum, Inc.
• FD&C Blue #2 Dye, supplied by Warner-Jenkinson Co., Inc.
• Acryleze® Red, donated by Colorcon, Inc.
• Various analytical reagents required for dissolution/assay
Page 1 Equipment (Manufacturing and Analytical)
• Jet-o-Mizer Jet Mill
• Glatt GPCG-1 Fluid Bed Unit equipped with a standard 6 Wurster insert
• Overhead mixer equipped with standard impeller blade
• Masterflex peristaltic pump equipped with size No. 14 platinum-cured silicone
tubing
• Olympus Model C2020Z digital camera
• Hansen Dissolution Batch SR Plus (USP Apparatus 2)
• Jasco 1500 Series HPLC System with a Phenomenex Luna Phenyl-Hexyl
Column, 3-micron, 100 X 4.6 mm
• Malvern Mastersizer® Particle Size Analyzer
Coating Formulation Rationale
In Wurster processing the substrate being coated should have a particle size
approximately 50 times the size of the coating particles (in this case, the API itself) to
prevent excessive attrition during the process. Prior to suspension preparation, the API
(X) was micronized using a jet mill to a volume mean diameter of 4.91 microns. The
average particle size of Emcompress is approximately 180 microns so the ratio
recommendation above is nearly satisfied. A surfactant (polysorbate 80) was included in
the spray suspension in order to reduce the droplet size out of the Wurster column’s
spray nozzle. The use of the surfactant plus the inherent characteristics of X resulted in
excessive formation of foam in the suspension under constant agitation thus requiring
the use of an anti-foaming agent (simethicone). Simethicone proved successful in
mitigation of foam.
Multiple levels of a single binder (Methocel E5) were examined to determine its effect on
ease of processing and the overall efficiency of the application of the active. No other
binders were examined. A coloring agent, FD&C Blue No. 2 dye, was included as a
means of visually assessing the progress of the layering run.
Application of API (X) to Emcompress
A suspension of purified water, API (X), polysorbate 80 and simethicone was added to a
solution of purified water, Methocel E5 and FD&C Blue #2 dye and mixed using low to
moderate shear until homogeneous. This suspension (5-6.5% solids, depending on
binder level) was sprayed onto Emcompress in a GPCG-1 using the following
processing parameters (see Figure 1 for processing setup):
Inlet Air Temperature: 60-75°C
Suspension Spray Rate: 5-10 g/minute
Partition height: 25mm (maximum)
Atomization Air Pressure: 2.0 bar
Shaker Mode: GPCG (alternate shaking)
Shaker Interval/Duration: 30 seconds/ 2 seconds
Page 2 FIGURE 1 – SETUP OF GPCG-1 LAYERING RUN
Figure 2 below shows the progress every 10 minutes throughout the layering run.
FIGURE 2 – COLOR PROGRESSION DURING API (X) LAYERING PROCESS
Page 3 Application of Modified-Release Coatings
The pellets containing the higher of the two levels of binder were subsequently coated
with a modified release polymer. The coating system applied contained Acryleze, a fully
formulated dry enteric coating system. Below are parameters used for the coating runs:
Inlet Air Temp: 60-75°C
Suspension Spray Rate: 4 -10 g/minute
Partition height: 25mm (maximum)
Atomization Air Pressure: 2.0 bar
Shaker Mode: GPCG (alternate shaking)
Shaker Interval/Duration: 30 - 45 seconds/ 2 seconds
The Acryleze that was donated by Colorcon had a red colorant included in the powder.
Figure 3 shows the color progression as the Acryleze suspension was being added to
the blue pellets containing API (X).
FIGURE 3 – COLOR PROGRESSION DURING THE ACRYLEZE COATING PROCESS
Performance of the pellets coated with the Acryleze was assessed by dissolution using a
modified method based on the USP General Chapter <724> Enteric Dissolution Method
B. The acid phase was essentially unchanged from the compendial method but the
neutral phase included 0.5% sodium dodecyl sulfate in the pH 6.8 sodium phosphate
buffer.
RESULTS
Layering of API (X) onto Emcompress
Although yield (indicated by run efficiency) for the layering run containing 0.6% w/w
Methocel E5 was only slightly lower than the yield for the layering run containing 1.2%
w/w Methocel E5, there was a marked difference in the potency, as found from the
assay value based on label claim. See Table 1 for a summary of the data from the two
layering runs.
TABLE 1 – DATA FROM TWO LAYERING RUNS OF API (X) ONTO EMCOMPRESS
Metrics Lot 03/204- 0 25
Metrics Lot 03/204- 0 33
(0.6% Methocel E5)
(1.2% Methocel E5)
Run Efficiency (%)
93.6
94.7
Potency (% Label Claim)
93.9
97.5
Enteric Coating Applied to Pellets Containing API (X)
Page 4 Figure 4 shows the dissolution profile of the enteric-coated sample demonstrating the
effectiveness of the enteric coat.
FIGURE 4 – DISSOLUTION OF API (X) FROM ENTERIC-COATED PELLETS
Emcompress was used successfully as a substrate in a Wurster layering process of a
water-insoluble API. Modification of the release of this API from the pellets was achieved
using a commercially available fully formulated enteric coating system.
Page 5