Evaluate Impact of Spray Drying Process Parameters and Equipment Type on theGranule Characteristic of the Immediate Release Tablets of a BCS(Biopharmaceutical Classification System) Class –IV Drug
Saurabh Shah, Lalji Kathiria, Milan Babusaurabh.shah@thermofisher.com | lalji.kathiria@thermofisher.com | milan.babu@thermofisher.com
Thermo Fisher Scientific

PURPOSEMETHOD(S)Spray drying process for IR product was developed using a Niro Aeromatic S2
fluid bed granulator (FBG) (campaign 1). The process was linearly scaled up
from Aeromatic S2 to S4 FBG (campaign 2). Variation in content uniformity(CU), as evidenced by high Acceptance value (AV), was observed as a result of
increased granule particle size. Particle size reduction through milling study
shown lower AV warranted further development on granule properties. In order
to identify the processing conditions that resulted in unexpected increase in
granule particle size, two granulations study (campaign 3) were evaluated.
Several changes such as bowl fill volume, binder spray rate, airflow were madein campaign 3 to identify the process parameters that could influence thegranule particle size. The bowl fill for both batches was reduced from 74% to37% and as a result, the binder spray rate was reduced to accommodate thesmaller bowl size. In addition, the airflow for both batches was reduced to 650
cfm in order to align the superficial velocity which was used for previous smallscale batches produced on S2 FBG. Based on results from campaign 3,changes were implemented in campaign 4 including the increased spray-shakecycle interval. Three registration stability batches (campaign 5) weremanufactured using parameters identified during campaign 4.
The process was then transferred from S4 FBG to MP4 FBG. A development
batch (campaign 6) was manufactured to demonstrate comparability between
the S4 and MP4 FBG. Given that the S4 and MP4 FBG were of the same
design and operating principles, manufacturing was anticipated to proceed
similarly regardless of which granulator was used. In addition, MP4 granulator
had several merits including recipe driven process equipped with a PID
feedback system to maintain parameter targets versus operator-controlled
process and a dual-chamber filter system that allowed uninterrupted
processing during the filter shake-cycle. The target spray rate for the binder
solution was 300 g/min in campaign 5 and 6. The inlet air volume, which is theinput parameter on both the S4 and MP4 granulators, was further reduced from650 to 450 cfm in order to maintain a constant superficial velocity (CSV) ofapproximately 125 m/s. Maintaining a CSV when transferring processes
between FBGs is a common practice that is used to accommodate fordifferences in equipment geometry. The inlet temperature was reduced from 85
to 75 °C in order to operate within the temperature range that was qualified for
the MP4. The atomization air was selected as 3.5 bar based on the results ofthe process optimization batches.

RESULT(S)The geometric mean particle size (GMS) and % particles retained on the 500 μm
sieve in campaign 3 were similar to campaign 2 despite the changes in blow fill, sprayrate and inlet air volume. Hence, two additional changes were made in campaign 4
including increase in the filter shake interval from 90 to 300 sec and an adjustment inspray nozzle tip position from 1 mm to 3 mm from the air cap. The GMS and %particles retained on the 500 μm sieve in campaign 4 dropped to 204 μm and 4%,respectively. Though all these changes did not facilitate the reduction in the GMS and%particles retained on the 500 μm sieve in campaign 4 and remain inclusive, theincrease in filter bag shake interval was thought to be an important factor. The GMSin campaign 5 was also observed below 175 μm and % particles retained on the 500μm sieve was less than 8%. The AV values in campaign 5 were below 4.5 for all three
registration batches compared to 6.1 and 13.1 from campaign 3. Following transfer ofproduct from S4 to MP4 FBG, the material properties were observed to similar while
comparing campaign 5 and 6. Small reductions in the GMS, quantity of particles ≥500 mm and quantity of particles ≤ 44 mm were noted in campaign 6 suggested anarrowing of the distribution, where greater than 60% of the particles were retainedon the 75 μm sieve for this batch.

Process parameters

Campaign #6,
Batch #2

S2

S4

S4

MP4MP4Batch Size (kg)

10 kg

65 kg

32.5 kg

32.5 kg

32.5 kg

Spray rate (g/min)

100 ± 10650 ± 100300 ± 60300± 30300± 30

1.55553.51515101515

Shake interval (sec)

9090

300

120120

Inlet temperature (ºC)

8585

85

7575

100 - 200

900 - 920

640 – 660

450

450

Atomizing Air pressure(bar)
Shake time (Sec)Air Flow (cfm)

CONCLUSION(S)The S4 FBG has a single filter chamber, as a result the granulation
process is interrupted during the shake cycle. This interruption includes ashut-off of not only the airflow but also the binder-spray rate. Theinterruption of the process was thought to be an important factor in theincreased granule particle size in campaign 3. As a result, MP4 wasdetermined to be suitable for commercial production. The particle size
distribution was noticeably improved from S4 to MP4 granulation FBG.
The data from particle size distribution suggested narrow distribution,
which eventually reduced content uniformity variation, as evident by lowAV.

Campaign #1 Campaign #2 Campaign #4

Campaign #6,
Batch #1

Equipment

Comparison Between S4 and MP4 granules

80706050%

To study the impact of spray drying process parameters and equipment type on
the granule characteristics of immediate release (IR) tablets containing a highdrug load (40%).

40
30
20

10035
S2 (Campaign 1)

45

60100
Mesh #

S4 (Campaign 2)

MP4 (Campaign 6, batch 1) MP4 (Campaign 6, batch 2)

200325

S4 (Campaign 4)pan