Written by Kitti Csordas, early stage researcher in the IPROCOM project
Heat or moisture sensitive active pharmaceutical ingredients requires a processing chain, which does not require water or organic solvents. Roll compaction/dry granulation is a suitable process for this purpose that provides additional advantages, e.g. increase of bulk density, improvement of flowability and reduction of manufacturing cost . Due to the growing interest of the understanding of this granulation process, the IPROCOM project ‘The development of in silico process models for roll compaction’ brought together several research groups, e.g. Heinrich Heine University, Duesseldorf and Research Center of Pharmaceutical Engineering, Graz that are also members of PSSRC. The purpose of the project is the deeper understanding of fundamental mechanisms of particulate manufacturing processes involving roll compaction. In this work introduced below, results are exhibited obtained in one of the 15 main topics in the IPROCOM project .
Process parameters, e.g. specific compaction force (SCF) / hydraulic pressure (HP), gap width (GW), screw speed and roll speed (RS) are found to be critical to obtain ribbons and granules providing the aimed quality [3, 4]. Thus, the maintenance of these parameters during production is required .
In the framework of IPROCOM, different types of roll compactors were used in order to compare their control performance. Mannitol ribbons were produced using an AlexanderWerk BT120, an L.B. Bohle BRC 25 and a Gerteis Mini-Pactor roll compactor. The accuracy and precision of the specific compaction force or hydraulic pressure and gap width were examined. The best results for accuracy, precision and adaptation time of the process data was found in case of the tested Mini-Pactor, while the investigated BRC 25 roll compactor provided slightly less accurate and precise control in the actual test setting. In case of both roll compactors the gap width was controlled by a PI-control loop. Due to the lack of any gap control system, the least accurate process data were obtained compacting with the tested AlexanderWerk BT120.
Materials and methods
Spray-dried mannitol (Pearlitol 200 SD, Roquette, France) as brittle model substance was roll compacted. The bulk powder was compacted by different types of roll compactors without using any type of lubricant in order to avoid its effect on the roll compaction process. An AlexanderWerk BT120 (AlexanderWerk, Germany, year 2008), a L.B. Bohle BRC 25 (L.B. Bohle, Germany, year 2015) and a Gerteis Mini-Pactor (Gerteis Maschinen+Prozessengineering, Switzerland, year 1999) were used to investigate the process control performance thereof. Knurled roll surface was used during all roll compaction runs. The roll compactor configurations are presented in Figure 1.
The AlexanderWerk roll compactor does not have any control system, thus the gap width was dependent on the screw speed and roll speed. The hydraulic pressure was adjusted by the hydraulic system. The BRC 25 set the specific compaction force through a spindle motor , while the gap size was controlled by a PI control system. The PI parameters of the gap width control loop were set at P: 10 and I: 20 s. In case of Mini-Pactor, the specific compaction force was adjusted by the hydraulic system and the gap width was controlled by a PI control loop (automatic mode) that was set at P: 12 s and at I: 15. The mean and the standard deviation of the process parameters were calculated, when the process parameters achieved the specifications described below, thus steady-state process condition was realized. The effect of specific compaction force and hydraulic pressure were tested at five settings, while the gap size was adjusted to 1.5 mm or 3.0 mm. The feeding screw speed was changed between 10 – 70 rpm, thus the tamping screw speed was set between 20-140 rpm. The experiments were conducted according to the principles of design of experiment following multilevel full factorial experimental plan in case of each roll compactor. The data recording frequency was set at 0.1 Hz, when AlexanderWerk BT120 was used, while in case of BRC 25 a frequency of 7-9 Hz was adjusted. The data obtained using Mini-Pactor showed a recording frequency of 1 Hz.
Results and discussion
The defined specification of the hydraulic pressure is set at the setpoint HP ± 2 bar and at the setpoint GW ± 0.1 mm, when AlexanderWerk BT120 is used. According to these terms, the accuracy and precision of the hydraulic pressure and gap width adjustment are inappropriate to produce ribbons with proper quality, presented in Table 1. In case of 18 bar and 60 bar hydraulic pressure setting 3.0 mm gap width, the actual values (20.43 ± 0.50 bar and 58.07 ± 0.33 bar) of the hydraulic pressure are out of specification. The gap width is least accurate and precise, when 18 bar hydraulic pressure and 1.5 mm gap width are set, as exhibited in Figure 2. 0 s settling times regarding 18 bar hydraulic pressure are obtained, while 10 s is needed to increase the hydraulic pressure from 36 bar to 60 bar independently of the set gap width. 0.1 Hz data recording frequency does not allow to have more detailed information about the settling time. Immediately, after setting 18 bar hydraulic pressure, 18 bar as actual value is observed, when 1.5 mm gap is set. Since the previous set hydraulic pressure is 18 bar, 0 s adaptation time of the hydraulic pressure is determined, when 3.0 mm gap width is set. The settling time of the gap width is observed between 30-70 s.
Table 1. Process parameters using AlexanderWerk BT120 compacting mannitol.
|Batch||HP [bar]||GW [mm]|
|HP [bar]||GW [mm]||RS [rpm]||time [s]||mean ± s||CV [%]||time [s]||mean ± s||CV [%]|
|24 → 18||3 → 1.5||3||0||18.37 ± 0.61||3.31||40||1.55 ± 0.29||18.67|
|18 → 18||1.5 → 3.0||3||0||20.43 ± 0.50||2.45||50||3.01 ± 0.02||0.75|
|36 → 60||2.2 → 1.5||3||10||59.02 ± 0.22||0.37||70||1.47 ± 0.03||2.48|
|36 → 60||2.2 → 3.0||3||10||58.07 ± 0.33||0.57||30||2.99 ± 0.03||0.96|
Figure 2. Change of the hydraulic pressure from 24 bar to 18 bar and gap width from 3.0 mm to 1.5 mm for AlexanderWerk BT 120.
Compacting with BRC 25, the adjustment of the specific compaction force has priority to the gap width control. Thus, the obtained periods of time needed to change the gap width are longer compared to the time required to set the specific compaction force. The specification of the specific compaction force is the set value SCF ± 0.1 kN/cm and for the gap width set value ± 0.1 mm. The specific compaction force is adjusted precise but not perfectly accurate, presented in Table 2. The specific compaction force is found to be within the specification, when 2 kN/cm specific compaction force and 3.0 mm gap width are set. The gap width adjustment is observed accurate and precise, except setting 3.0 mm gap width and 10 kN/cm specific compaction force. The mean of the gap size is calculated to be 3.05 ± 0.11 mm, which is above the defined threshold. The smaller the difference between the previous and the new gap width, the less adaptation time is necessary to achieve steady-state process conditions. Increasing the gap width from 2.3 mm to 3.0 mm takes 24 s, while the increase or decrease of gap width with 1.5 mm requires 42-48 s. The settling time of the specific compaction force is obtained between 15-38 s. In Figure 3, the increase of the hydraulic pressure from 6 kN/cm to 10 kN/cm and the decrease of the gap width from 3.0 mm to 1.5 mm is plotted. To decrease the gap width, first the speed of the feeding and tamping augers are decreased and then increased by the PI control loop till the set gap width is achieved as actual value. The specific compaction force shows an increasing-decreasing trend, before the constant value is achieved.
Table 2. Process parameters of L.B. Bohle BRC 25 roll compactor.
|Batch||HP [bar]||GW [mm]|
|SCF [kN/cm]||GW [mm]||RS [rpm]||time [s]||mean ± s||CV [%]||time [s]||mean ± s||CV [%]|
|8 → 2||3.0 → 1.5||2||31||2.09 ± 0.05||2.38||46||1.49 ± 0.04||2.38|
|10 → 2||1.5 → 3.0||2||28||2.00 ± 0.02||1.07||48||2.98 ± 0.06||1.86|
|6 → 10||3.0 → 1.5||2||38||10.07 ± 0.05||0.47||42||1.48 ± 0.04||2.67|
|6 → 10||2.3 → 3.0||2||15||10.07 ± 0.07||0.65||24||3.05 ± 0.11||3.63|
Figure 3. Change of the specific compaction force from 6 kN/cm to 10 kN/cm and gap width from 3.0 mm to 1.5 mm for L.B. Bohle BRC 25.
For the Gerteis Mini-Pactor the specification of the specific compaction force is the set value SCF ± 0.1 kN/cm and for the gap width set value ± 0.1 mm. The obtained gap widths and the time required to achieve the steady-state processing condition are listed in Table 3. The actual values of specific compaction force and gap width are found to be the most precise and accurate. The adaptation times are obtained under 16 s regarding specific compaction force, while the longest settling time of gap width is 8 s. In Figure 4 the roll compaction process in automatic mode is introduced showing smooth specific compaction force and gap width trends.
Table 3. Process parameters of Gerteis Mini-Pactor compacting in automatic mode.
|Batch||SCF [kN/cm]||GW [mm]|
|SCF [kN/cm]||GW [mm]||RS [rpm]||time [s]||SCF kN/cm]||CV [%]||time [s]||GW [mm]||CV [%]|
|15 → 2||1.5 → 1.5||2||16||1.98 ± 0.04||4.61||0||1.51 ± 0.07||2.26|
|6 → 2||3.0 → 3.0||2||9||1.99 ± 0.03||1.48||0||3.01 ± 0.03||0.89|
|6 → 10||2.3 → 1.5||2||3||10.00 ± 0.02||0.23||8||1.49 ± 0.03||1.91|
|2 → 10||3.0 → 3.0||2||7||10.02 ± 0.04||0.44||7||2.99 ± 0.04||1.20|
Figure 4. Change of specific compaction force and gap width for Gerteis Mini-Pactor using automatic mode.
It is difficult to obtain a desired gap width without a gap control during roll compaction. Thus, the process has poor accuracy and precision, when AlexanderWerk BT120 roll compactor is used. When the process is tested using BRC 25, it is not always possible to obtain the desired specific compaction force, however appropriate precision of the specific compaction force is achieved due to the spindle motor configuration. The observed deviation of the specific compaction force is marginal compared to the determined deviations of hydraulic pressure provided by AlexanderWerk BT120. The most accurate and precise process is determined, when Mini-Pactor is used in automatic mode. The settling time of the gap width is found to be shorter compared to the BRC 25 roll compactor, which is explained through the PI control loop adjustments of the Mini-Pactor. Compared to BRC 25, the Mini-Pactor reacts stronger to gap width changes due to the higher P-portion and the more frequent control steps and distinctive response of the gap width values due to the lower I-portion, a more consistent process and faster process adaptation are obtained in case of Mini-Pactor operating in automatic mode.
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Beside extrusion and coating processes, the working group of Professor Peter Kleinebudde does research on roll compaction/dry granulation. The understanding of the roll compaction process is of main interest, considering the effect of material properties, process parameters, control systems and scale on roll compaction. A further aim of research is the development of PAT tools measuring the ribbon relative density and granule size distribution as critical quality attributes of roll compaction.
This work was supported by the IPROCOM Marie Curie initial training network (www.iprocom.org), funded through the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/ under REA grant agreement No. 316555.