Roller Compaction: Invention of an Uncomplex Prediction ...
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In roller compaction, a powder is densified to ribbons of a given strength by applying a chosen force at a chosen gap. This strength is related uniquely to the apparent density of the compact. Too large ribbon densities may impair tablet hardness [1]. Especially, if high priced API’s are contained in a blend, it is reasonable to determine the relationship of the primary ribbon strength and the tablet hardness of the recompacted granulate. The prediction model presented here is a time and money saving method because it enables a useful estimation of the corresponding roll compaction settings based on tabletting data. The basic aspects of this model were presented by Busies [2]. In this study, the implementation of the model includes “in- die” density measurements using an instrumented single-stroke tablet press. The recorded “force- displacement” curves are used to predict the roll compaction force for a desired ribbon density as well as the elastic recovery force of the ribbon that is exerted on the rolls. Roller Compaction: Invention of an Uncomplex Prediction Model on the Basis of Tabletting Experiments S. Peter (1) , R. F. Lammens (2) and K.-J. Steffens (1) (1) Department of Pharmaceutical Technology, Rheinische Friedrich-Wilhelms-University Bonn, Gerhard- Domagk-Str. 3, D-53121 Bonn, Germany (2) Technical Services Consult Lammens, Heymannstr. 50, 51373 Leverkusen, Germany 6 th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology; Barcelona; Spain 7 th – 10 th April 2008 corresponding author: [email protected] Introduction Experimental Methods Results & Discussion Conclusion References MATERIALS Three pharmaceutical excipients were separately tested in the model: powdered cellulose (Elcema ® Type G 250, JRS Pharma), pregelatinized starch (C*PharmGel DC 93000, Cargill Cerestar) and dibasic dicalciumphosphate dihydrate (Emcom- press ® Premium, JRS Pharma). Emcompress had to be blended with 1 % (w/w) magnesium stearate (Pharma Veg ® , Baerlocher) in order to avoid sticking during roller compaction. Furthermore a blend of excipients containing 50 % lactose (Granulac ® 200, Meggle), 25 % MCC (Vivapur ® type 101, JRS Pharma), 12.5 % PVP-PVA co- polymerisate (Kollidon ® VA 64, BASF) and 12.5 % cross-linked PVP (Kollidon ® CL, BASF) was used. EXPERIMENTAL METHODS Tabletting: With the fully instrumented tablet press FlexiTab ® (Röltgen, Solingen, Germany) the “force- displacement curves” at different maximum loads were determined. The aim of this study, to invent a prediction model that is easy to realise and yet effective in facilitating scale-up in roller compaction, is considered to be achieved. A prediction for an unknown powder or blend is possible on the basis of only three single compressions. The error of the predictions is low for the density range of practical relevance. In addition, systematic deviation from prediction can be taken into account. Modelling of the densification phase: An exponential relationship was fitted to a single “pressure-density” curve, whereas the data had been limited to the linear part of the corresponding Heckel plot ensuring the best possible coefficient of determination. The reliability of the fit is crucial because slight differences will cause large variations in the predicted roller compaction force. Additionally, the so-called start value was defined as the density at which the compaction force reached 50 N for the first time, further set as the density of the first layer in the prediction model (Fig.2). Theoretical aspects Assuming that the plug of densified powder between the rolls consists of an infinite large number of thin layers (Fig.1), each having a given but constant density, the pressure exerted on the rolls by each of these layers can be calculated from the “force-displacement“ curves, supposing that during the roll compaction process the amount of powder in a given layer does not change. The total force, applied during roller compaction by the hydraulic system, consists of the compaction force, necessary to achieve a certain densification, as well as the elastic recovery force, that is exerted by the recovering ribbon. Figure 1: Thin layer model of powder densification α SUPPLIED POWDER RELEASED RIBBON β Hydraulic Force Tabletting was performed with a big punch diameter (18 mm), aiming at a tablet height of 2 to 3 mm, whilst lubricating externally. This proceeding was chosen because frictional forces may have a significant influence on the results of tabletting, whereas they are negligible for roller compaction. The “force-displacement” curves were standardized by plotting lower-punch compaction pressure against apparent density, further called “pressure- density” curves. The precision and accuracy of the displacement measurement system has been ± 7 μm. Roller compaction: During roller compaction (Macro- Pactor ® 250/100/3, Gerteis Maschinen + Process- engineering AG, Jona, Switzerland), the ribbon density was measured from the ribbon mass and the ribbon volume over time, the so-called throughput. For every setting, a triple determination was performed and mean ± SD calculated. Figure 2: “Pressure-density“ curves of the powder blend in comparison to the fitted exponential equation Modelling of the recovery phase: A transformation of the “pressure-density” curves was performed: both the densities and the compaction pressures were plotted as the percentage of the maximum density value (Fig.3). [1] F. Freitag, P. Kleinebudde, Eur. J. Pharm. Biopharm. 19 (2003), 281-289 [2] H. Busies, Dichteverteilung in Schülpen, Dissertation 2006, Universität Bonn, Verlag Dr. Hut y = 2.24E-27e 6.60E-01x R 2 = 9.93E-01 0 10 20 30 40 50 60 70 80 90 100 93 94 95 96 97 98 99 100 Percentage of maximum density [%] Percent of pressure at maximum density [%] 165 MPa maximum load 25 MPa maximum load Material Start value [g/cm³] Densification (COD) Recovery y = 1.0357 * e 3.3852x (R² = 0.9962) y = 0.1732 * e 4.8753x (R² = 0.9966) y = 0.0149 * e 4.7275x (R² = 0.9991) y = 0.4971 * e 4.2455x (R² = 0.9976) C*PharmGel DC 93000 Elcema G 250 Emcompress Powder blend 0.59 0.5 1.08 0.46 y = 9.89E-24 * e 5.76E-01x y = 3.13E-24 * e 5.88E-01x y = 7.19E+01x - 7.08E+03 y = 2.24*E-27 * e 6.6*E-01x All results were illustrated in a prediction plot (Fig.4). The best predictions were obtained for Elcema and CPharmGel with predicted density deviations not larger than 4 %, generally smaller than 2 %. The roller compaction behaviour of the powder blend could be calculated successfully for small densities but for densities larger than 1.2 g/cm³ the error increased up to 6 %. The predictions for Emcompress showed the largest deviation, differences of up to 7 % occurred. Because the brittle material has time-independent compression properties with very low elastic recovery, this prediction had been expected to be the best one. Table 1: Summary of the prediction input Powder blend y = 1.232x - 0.205 R 2 = 0.9994 CPharmGel DC 93000 y = 1.0283x - 0.0232 R 2 = 0.979 Elcema G 250 y = 1.071x - 0.0515 R 2 = 0.9882 Emcompress y = 1.2909x - 0.416 R 2 = 0.9857 0.8 1.0 1.2 1.4 1.6 1.8 2.0 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Determined density [g/cm³] Predicted density [g/cm³] Powder blend CPharmGel DC 93000 Elcema G 250 Emcompress Figure 3: Decompression phase of the powder blend Thereby, it became possible to establish an equation for the calculation of the elastic recovery force, independent of the applied maximum load. The prediction input is summarised in Table 1. Figure 4: Prediction plot - determined densities ( mean ± SD) vs. predicted ones For all powders, the elastic recovery force ranged from 20 to 25 % of the total specific compaction force although the elastic recovery of the tablets was established to be 6 % for the starch, 6 - 8 % for the cellulose, 1.5 - 3.8 % for the inorganic salt and 4 - 5 % for the powder blend, depending on the maximum force exerted. Recovery angles calculated in this way agree well to the shape of the predicted roll pressure profiles (see Fig.5). 0 10 20 30 40 50 60 70 -15 -10 -5 0 5 Rolling angle [degree] Compaction pressure [MPa] Powder blend (1.15 g/cm³) CPharmGel DC 93000 (1.15 g/cm³) Elcema G 250 (1.15 g/cm³) Emcompress (1.7 g/cm³) 0 20 40 60 80 100 120 140 160 180 200 0.3 0.5 0.7 0.9 1.1 1.3 1.5 "In-die" density [g/cm³] Compaction pressure [MPa] y = 0.4971e 4.2455x start value: 0.461 g/cm³ Figure 5: Comparison of calculated roll pressure profils
Transcript of Roller Compaction: Invention of an Uncomplex Prediction ...
In roller compaction, a powder is densified to ribbons of a given strength by applying a chosen force at a chosen gap. This strength is related uniquely to the apparent density of the compact. Too large ribbon densities may impair tablet hardness [1]. Especially, if high priced API’s are contained in a blend, it is reasonable to determine the relationship of the primary ribbon strength and the tablet hardness of the recompacted granulate. The prediction model presented here is a time and money saving method because it enables a useful estimation of the corresponding roll compaction settings based on tabletting data. The basic aspects of this model were presented by Busies [2]. In this study, the implementation of the model includes “in-die” density measurements using an instrumented single-stroke tablet press. The recorded “force-displacement” curves are used to predict the roll compaction force for a desired ribbon density as well as the elastic recovery force of the ribbon that is exerted on the rolls.
Roller Compaction: Invention of an Uncomplex Prediction Model on the Basis of Tabletting ExperimentsS. Peter(1), R. F. Lammens(2) and K.-J. Steffens(1)
(1) Department of Pharmaceutical Technology, Rheinische Friedrich-Wilhelms-University Bonn, Gerhard-Domagk-Str. 3, D-53121 Bonn, Germany
(2) Technical Services Consult Lammens, Heymannstr. 50, 51373 Leverkusen, Germany
6th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology; Barcelona; Spain 7th – 10th April 2008 corresponding author: [email protected]
Introduction
Experimental Methods
Results & Discussion
Conclusion
References
MATERIALSThree pharmaceutical excipients were separately tested in the model: powdered cellulose (Elcema®
Type G 250, JRS Pharma), pregelatinized starch (C*PharmGel DC 93000, Cargill Cerestar) and dibasic dicalciumphosphate dihydrate (Emcom-press® Premium, JRS Pharma). Emcompress had to be blended with 1 % (w/w) magnesium stearate (Pharma Veg®, Baerlocher) in order to avoid sticking during roller compaction. Furthermore a blend of excipients containing 50 % lactose (Granulac® 200, Meggle), 25 % MCC (Vivapur®
type 101, JRS Pharma), 12.5 % PVP-PVA co-polymerisate (Kollidon® VA 64, BASF) and 12.5 % cross-linked PVP (Kollidon® CL, BASF) was used.
EXPERIMENTAL METHODSTabletting: With the fully instrumented tablet press FlexiTab® (Röltgen, Solingen, Germany) the “force-displacement curves” at different maximum loads were determined.
The aim of this study, to invent a prediction model that is easy to realise and yet effective in facilitating scale-up in roller compaction, is considered to be achieved. A prediction for an unknown powder or blend is possible on the basis of only three single compressions. The error of the predictions is low for the density range of practical relevance. In addition, systematic deviation from prediction can be taken into account.
Modelling of the densification phase:An exponential relationship was fitted to a single “pressure-density” curve, whereas the data had been limited to the linear part of the corresponding Heckel plot ensuring the best possible coefficient of determination. The reliability of the fit is crucial because slight differences will cause large variations in the predicted roller compaction force. Additionally, the so-called start value was defined as the density at which the compaction force reached 50 N for the first time, further set as the density of the first layer in the prediction model (Fig.2).
Theoretical aspectsAssuming that the plug of densified powder between the rolls consists of an infinite large number of thin layers (Fig.1), each having a given but constant density, the pressure exerted on the rolls by each of these layers can be calculated from the “force-displacement“ curves, supposing that during the roll compaction process the amount of powder in a given layer does not change. The total force, applied during roller compaction by the hydraulic system, consists of the compaction force, necessary to achieve a certain densification, as well as the elastic recovery force, that is exerted by the recovering ribbon.
Figure 1:Thin layer model of powder densification
α
SUPPLIED POWDER
RELEASED RIBBON
β
Hydraulic Force
Tabletting was performed with a big punch diameter (18 mm), aiming at a tablet height of 2 to 3 mm, whilst lubricating externally. This proceeding was chosen because frictional forces may have a significant influence on the results of tabletting, whereas they are negligible for roller compaction. The “force-displacement” curves were standardized by plotting lower-punch compaction pressure against apparent density, further called “pressure-density” curves. The precision and accuracy of the displacement measurement system has been ± 7 µm.
Roller compaction: During roller compaction (Macro-Pactor® 250/100/3, Gerteis Maschinen + Process-engineering AG, Jona, Switzerland), the ribbon density was measured from the ribbon mass and the ribbon volume over time, the so-called throughput. For every setting, a triple determination was performed and mean ± SD calculated.
Figure 2: “Pressure-density“ curves of the powder blend in comparison to the fitted exponential equation
Modelling of the recovery phase:A transformation of the “pressure-density” curves was performed: both the densities and the compaction pressures were plotted as the percentage of the maximum density value (Fig.3).
[1] F. Freitag, P. Kleinebudde, Eur. J. Pharm. Biopharm. 19 (2003), 281-289
[2] H. Busies, Dichteverteilung in Schülpen, Dissertation 2006, Universität Bonn, Verlag Dr. Hut
y = 2.24E-27e6.60E-01x
R2 = 9.93E-01
0
10
20
30
40
50
60
70
80
90
100
93 94 95 96 97 98 99 100Percentage of maximum density [%]
Perc
ent o
f pre
ssur
e at
max
imum
de
nsity
[%]
165 MPa maximum load
25 MPa maximum load
Material Start value[g/cm³]
Densification(COD) Recovery
y = 1.0357 * e3.3852x
(R² = 0.9962)y = 0.1732 * e4.8753x
(R² = 0.9966)y = 0.0149 * e4.7275x
(R² = 0.9991)y = 0.4971 * e4.2455x
(R² = 0.9976)
C*PharmGel DC 93000
Elcema G 250
Emcompress
Powder blend
0.59
0.5
1.08
0.46
y = 9.89E-24 * e5.76E-01x
y = 3.13E-24 * e5.88E-01x
y = 7.19E+01x - 7.08E+03
y = 2.24*E-27 * e6.6*E-01x
All results were illustrated in a prediction plot (Fig.4). The best predictions were obtained for Elcema and CPharmGel with predicted density deviations not larger than 4 %, generally smaller than 2 %. The roller compaction behaviour of the powder blend could be calculated successfully for small densities but for densities larger than 1.2 g/cm³ the error increased up to 6 %. The predictions for Emcompress showed the largest deviation, differences of up to 7 % occurred. Because the brittle material has time-independent compression properties with very low elastic recovery, this prediction had been expected to be the best one.
Table 1: Summary of the prediction input
Powder blendy = 1.232x - 0.205
R2 = 0.9994
CPharmGel DC 93000y = 1.0283x - 0.0232
R2 = 0.979
Elcema G 250y = 1.071x - 0.0515
R2 = 0.9882
Emcompress y = 1.2909x - 0.416
R2 = 0.9857
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0.8 1.0 1.2 1.4 1.6 1.8 2.0Determined density [g/cm³]
Pred
icte
d de
nsity
[g/c
m³]
Powder blendCPharmGel DC 93000Elcema G 250Emcompress
Figure 3: Decompression phase of the powder blend
Thereby, it became possible to establish an equation for the calculation of the elastic recovery force, independent of the applied maximum load. The prediction input is summarised in Table 1.
Figure 4: Prediction plot - determined densities ( mean ± SD) vs. predicted ones
For all powders, the elastic recovery force ranged from 20 to 25 % of the total specific compaction force although the elastic recovery of the tablets was established to be 6 % for the starch, 6 - 8 % for the cellulose, 1.5 - 3.8 % for the inorganic salt and 4 - 5 % for the powder blend, depending on the maximum force exerted. Recovery angles calculated in this way agree well to the shape of the predicted roll pressure profiles (see Fig.5).
0
10
20
30
40
50
60
70
-15 -10 -5 0 5Rolling angle [degree]
Com
pact
ion
pres
sure
[MPa
] Powder blend (1.15 g/cm³)
CPharmGel DC 93000 (1.15 g/cm³)
Elcema G 250 (1.15 g/cm³)
Emcompress (1.7 g/cm³)
0
20
40
60
80
100
120
140
160
180
200
0.3 0.5 0.7 0.9 1.1 1.3 1.5"In-die" density [g/cm³]
Com
pact
ion
pres
sure
[MPa
]
y = 0.4971e4.2455x
start value:0.461 g/cm³
Figure 5: Comparison of calculated roll pressure profils
