Addressing handling challenges of chemicals by dry granulation
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Dry granulation of biopharmaceutical raw materials like urea and glycine significantly reduces caking and improves handling efficiency compared to bulk materials, even under challenging storage conditions. The granulated products demonstrated enhanced mechanical stability and flowability, despite slightly longer dissolution times. These improvements facilitate manufacturing processes, reduce disruptions, and enhance operator safety.
![Introduction
Buffers, salts and stabilizing chemicals are used in multi-ton quantities during biopharmaceutical
manufacturing. The handling of such quantities in a
pharmaceutical production environment can
be challenging: Caking and clumping of chemicals, dust formation and laborious weighing have a
negative impact on manufacturing efficiency and may even lead to process interruptions, quality
deviations and operator safety risks.
Figure 1: Potential effects of poor material characteristics.
Dry granulation was assessed as a potential means to overcome caking issues and improve handling.
As it uses compression force only without water or other additives, it is ideal for highly sensitive
materials and offers the benefit of ensuring that characteristics of the raw materials are preserved.
Materials and Methods
Bulk powders were dry-granulated as shown in Figure 2 using an RC120 roller compactor (Powtec
GmbH, Remscheid, Germany). To assess the potential of dry granulation to reduce caking,
flowability and dissolution kinetics of granulated glycine and urea were compared to the respective
bulk material before and after storage at ambient (25 °C / 60 % rH) and accelerated conditions
(40 °C / 75 % rH). At specified time points the bottles were inverted and the material was sieved to
assess the extent of clumping. Flowability of material after storage was assessed via measurement
of the avalanche angle using a Revolution Powder Analyzer (PS Prozesstechnik, Basel, Switzerland).
Dissolution studies were performed by dissolving 80 g of the respective material in 800 mL of
purified water. Samples were stirred in a 1.2 L bioreactor with Rushton impellors at 250 rpm
and at room temperature. Undissolved particles were determined by focused beam reflectance
measurement and visual inspection. Material integrity was tested using an abrasion drum with
added ceramic balls. The drum was rotated at 20 rpm for 10 min and the percentage of fine particles
mass <500 μm was determined.
Bulk
material
Compression
to plates
Milling to
granules
1
2
3
8
4
5
6
7
Figure 2:
Schematic depiction of dry-granulation process.
The powder is filled in the funnel (1), conveyed
to the rolls by a mixer and tamp auger (2), and
compressed between temperature-controlled rolls
using hydraulic pressure (3). The resulting plate
(4) is milled to granules using a rotor sieve mill
(5). A vibrating sieve separates non-compacted
fines from granules (6) which are then recirculat-
ed back into the funnel to increase final yield (7).
Final granules are collected (8).
Results
Stability Studies and Caking Behavior
After 7 weeks under accelerated conditions at 40 °C / 75 % rH, granulated materials showed
significantly less caking compared to the “standard” bulk material (powder): The bulk material needed
de-caking efforts to be removed from the container while granules were still free-flowing and could
be poured out easily (Figure 3). The same effect was observed during long-term stability studies
at ambient conditions (25 °C / 60 % rH). Here granulated material showed significantly less clumping
compared to bulk material (Figure 4).
Heavily caked
powder after
storage
Free flowing
powder at start
of experiment
Powder
t = 0 t = 7 weeks
40 °C / 75 % rH
Free flowing
granules after
storage
Free flowing
granules at start
of experiment
Granules
t = 0 t = 7 weeks
40 °C / 75 % rH
Figure 3:
Comparison of caking behavior of bulk and granulated material before and after storage under accelerated conditions:
example glycine.
Bulk
Granules
t = 0
t = 12 months
25 °C / 60 % rH
12 % clumps
3.15 mm
68 % clumps
3.15 mm
Figure 4:
Comparison of caking behavior of bulk and granulated material before and after storage under ambient conditions:
example urea.
Flowability
Flowability measurements revealed
an improvement of flowability of
the granules in comparison to bulk
materials. An improvement from
non-satisfactory to good and from
good to excellent was observed
for granulated urea and granulated
glycine, respectively.
Mechanical Stability
Sustained integrity of granules
during transport and storage is key
to preserve the material’s positive
characteristics. Abrasion tests
confirmed an excellent integrity for
both granulated glycine and urea
with abrasion rates of only 3.8 %
and 1.8 %, respectively.
Dissolution
Dissolution experiments showed slightly prolonged dissolution times for granules compared to
bulk material. However, if de-caking steps for the bulk material are taken into consideration (1 h
for larger volumes), overall process time is improved for granulated material despite the observed
difference in dissolution time.
Glycine Urea
Normalized
particle
count
Time [min]
100 g/L
1.33 mol/L
Addition
of
Glycine
0.0
0.5
1.0
0 2 4 6 8 10
Powder
Granules
Normalized
particle
count
Time [min]
100 g/L
1.67 mol/L
Addition
of
Urea
0.0
0.5
1.0
0 2 4 6 8 10
Powder
Granules
Figure 7:
Comparison of dissolution behavior of bulk and granulated material showing results for glycine (left) and urea (right).
Addressing Handling Challenges
of Chemicals by Dry Granulation
Thomas Briel, Raphael Guebeli, Rupa Bhattarai, Anke Simon, Corinna Merkel, Moritz Beck-Broichsitter
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
MilliporeSigma, the Vibrant M, Emprove and SAFC are trademarks of Merck KGaA, Darmstadt, Germany or its
affiliates.
All other trademarks are the property of their respective owners. Detailed information on trademarks is available
via publicly accessible resources.
Lit. No. MS_PS6722EN 12/2020
The Life Science business of Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma in the U.S. and Canada.
Summary
Dry granulation of raw materials such as urea and glycine resulted in greatly reduced caking,
even under accelerated storage conditions. In addition, the granules showed good mechani-
cal stability and improved flowability as compared to bulk material. Although the dissolution
kinetics of granules can be slightly longer, their better handling characteristics more than
outweigh the additional time needed for dissolution.
In summary, granulated raw materials show great promise to facilitate processability, avoid
disruptions and speed up handling in a manufacturing environment while at the same time
increasing the safety of operators.
Granulated MilliporeSigma Products
Raw materials currently commercially available in granulated form:
Product Name Art. Number
Urea Granulated EMPROVE®
EXPERT Ph Eur, BP, JP, USP, ACS 104166
Glycine Granulated EMPROVE®
EXPERT Ph Eur, BP, ChP, JP, USP 103669
Potassium Chloride Granulated EMPROVE®
EXPERT Ph Eur, BP, JP, USP 104165
Diverse pack sizes available. Additional products are currently under development.
0
10
20
30
40
50
60
70
80
Granules
Bulk
Urea
Glycine
Average
Non-satisfactory
Good
Excellent
Avalanche
Angle
[°]
Figure 5: Comparison of material flowability.
0
2
4
6
8
10
Granules
Urea
Glycine
Abrasion
[%]
Figure 6:
Abrasion rates of granulated glycine
and granulated urea.
Visually
clear
Visually
clear
Visually
clear
Visually
clear
Implications Speed
Quality
Flexibility
Cost
Process delay
Process interruption
Operator safety risks
Extensive cleaning
Quality deviations
Risk of bioburden
Additional floor space](https://image.slidesharecdn.com/addressing-handling-challenges-of-chemicals-by-dry-granulation-milliporesigma-210610054838/85/Addressing-handling-challenges-of-chemicals-by-dry-granulation-1-320.jpg)
Addressing handling challenges of chemicals by dry granulation
- 1. Introduction Buffers, salts and stabilizing chemicals are used in multi-ton quantities during biopharmaceutical manufacturing. The handling of such quantities in a pharmaceutical production environment can be challenging: Caking and clumping of chemicals, dust formation and laborious weighing have a negative impact on manufacturing efficiency and may even lead to process interruptions, quality deviations and operator safety risks. Figure 1: Potential effects of poor material characteristics. Dry granulation was assessed as a potential means to overcome caking issues and improve handling. As it uses compression force only without water or other additives, it is ideal for highly sensitive materials and offers the benefit of ensuring that characteristics of the raw materials are preserved. Materials and Methods Bulk powders were dry-granulated as shown in Figure 2 using an RC120 roller compactor (Powtec GmbH, Remscheid, Germany). To assess the potential of dry granulation to reduce caking, flowability and dissolution kinetics of granulated glycine and urea were compared to the respective bulk material before and after storage at ambient (25 °C / 60 % rH) and accelerated conditions (40 °C / 75 % rH). At specified time points the bottles were inverted and the material was sieved to assess the extent of clumping. Flowability of material after storage was assessed via measurement of the avalanche angle using a Revolution Powder Analyzer (PS Prozesstechnik, Basel, Switzerland). Dissolution studies were performed by dissolving 80 g of the respective material in 800 mL of purified water. Samples were stirred in a 1.2 L bioreactor with Rushton impellors at 250 rpm and at room temperature. Undissolved particles were determined by focused beam reflectance measurement and visual inspection. Material integrity was tested using an abrasion drum with added ceramic balls. The drum was rotated at 20 rpm for 10 min and the percentage of fine particles mass <500 μm was determined. Bulk material Compression to plates Milling to granules 1 2 3 8 4 5 6 7 Figure 2: Schematic depiction of dry-granulation process. The powder is filled in the funnel (1), conveyed to the rolls by a mixer and tamp auger (2), and compressed between temperature-controlled rolls using hydraulic pressure (3). The resulting plate (4) is milled to granules using a rotor sieve mill (5). A vibrating sieve separates non-compacted fines from granules (6) which are then recirculat- ed back into the funnel to increase final yield (7). Final granules are collected (8). Results Stability Studies and Caking Behavior After 7 weeks under accelerated conditions at 40 °C / 75 % rH, granulated materials showed significantly less caking compared to the “standard” bulk material (powder): The bulk material needed de-caking efforts to be removed from the container while granules were still free-flowing and could be poured out easily (Figure 3). The same effect was observed during long-term stability studies at ambient conditions (25 °C / 60 % rH). Here granulated material showed significantly less clumping compared to bulk material (Figure 4). Heavily caked powder after storage Free flowing powder at start of experiment Powder t = 0 t = 7 weeks 40 °C / 75 % rH Free flowing granules after storage Free flowing granules at start of experiment Granules t = 0 t = 7 weeks 40 °C / 75 % rH Figure 3: Comparison of caking behavior of bulk and granulated material before and after storage under accelerated conditions: example glycine. Bulk Granules t = 0 t = 12 months 25 °C / 60 % rH 12 % clumps 3.15 mm 68 % clumps 3.15 mm Figure 4: Comparison of caking behavior of bulk and granulated material before and after storage under ambient conditions: example urea. Flowability Flowability measurements revealed an improvement of flowability of the granules in comparison to bulk materials. An improvement from non-satisfactory to good and from good to excellent was observed for granulated urea and granulated glycine, respectively. Mechanical Stability Sustained integrity of granules during transport and storage is key to preserve the material’s positive characteristics. Abrasion tests confirmed an excellent integrity for both granulated glycine and urea with abrasion rates of only 3.8 % and 1.8 %, respectively. Dissolution Dissolution experiments showed slightly prolonged dissolution times for granules compared to bulk material. However, if de-caking steps for the bulk material are taken into consideration (1 h for larger volumes), overall process time is improved for granulated material despite the observed difference in dissolution time. Glycine Urea Normalized particle count Time [min] 100 g/L 1.33 mol/L Addition of Glycine 0.0 0.5 1.0 0 2 4 6 8 10 Powder Granules Normalized particle count Time [min] 100 g/L 1.67 mol/L Addition of Urea 0.0 0.5 1.0 0 2 4 6 8 10 Powder Granules Figure 7: Comparison of dissolution behavior of bulk and granulated material showing results for glycine (left) and urea (right). Addressing Handling Challenges of Chemicals by Dry Granulation Thomas Briel, Raphael Guebeli, Rupa Bhattarai, Anke Simon, Corinna Merkel, Moritz Beck-Broichsitter © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. MilliporeSigma, the Vibrant M, Emprove and SAFC are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. Lit. No. MS_PS6722EN 12/2020 The Life Science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Summary Dry granulation of raw materials such as urea and glycine resulted in greatly reduced caking, even under accelerated storage conditions. In addition, the granules showed good mechani- cal stability and improved flowability as compared to bulk material. Although the dissolution kinetics of granules can be slightly longer, their better handling characteristics more than outweigh the additional time needed for dissolution. In summary, granulated raw materials show great promise to facilitate processability, avoid disruptions and speed up handling in a manufacturing environment while at the same time increasing the safety of operators. Granulated MilliporeSigma Products Raw materials currently commercially available in granulated form: Product Name Art. Number Urea Granulated EMPROVE® EXPERT Ph Eur, BP, JP, USP, ACS 104166 Glycine Granulated EMPROVE® EXPERT Ph Eur, BP, ChP, JP, USP 103669 Potassium Chloride Granulated EMPROVE® EXPERT Ph Eur, BP, JP, USP 104165 Diverse pack sizes available. Additional products are currently under development. 0 10 20 30 40 50 60 70 80 Granules Bulk Urea Glycine Average Non-satisfactory Good Excellent Avalanche Angle [°] Figure 5: Comparison of material flowability. 0 2 4 6 8 10 Granules Urea Glycine Abrasion [%] Figure 6: Abrasion rates of granulated glycine and granulated urea. Visually clear Visually clear Visually clear Visually clear Implications Speed Quality Flexibility Cost Process delay Process interruption Operator safety risks Extensive cleaning Quality deviations Risk of bioburden Additional floor space