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Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties
Accepted Manuscript Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties Tinne Monteyne, Jochem Vancoillie, Jean-Paul Remon, Chris Vervaet, Thomas De Beer PII: DOI: Reference:
S0939-6411(16)30327-7 http://dx.doi.org/10.1016/j.ejpb.2016.07.021 EJPB 12259
To appear in:
European Journal of Pharmaceutics and Biopharmaceutics
Please cite this article as: T. Monteyne, J. Vancoillie, J-P. Remon, C. Vervaet, T. De Beer, Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties, European Journal of Pharmaceutics and Biopharmaceutics (2016), doi: http://dx.doi.org/10.1016/j.ejpb.2016.07.021
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Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties Tinne Monteynea,1 , Jochem Vancoilliea , Jean-Paul Remonb , Chris Vervaetb , Thomas De Beera a Laboratory
of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium b Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
Abstract The pharmaceutical industry has a growing interest in alternative manufacturing models allowing automation and continuous production in order to improve process efficiency and reduce costs. Implementing a switch from batch to continuous processing requires fundamental process understanding and the implementation of quality-by-design (QbD) principles. The aim of this study was to examine the relationship between formulation-parameters (type binder, binder concentration, drug-binder miscibility), process-parameters (screw speed, powder feed rate and granulation temperature), granule properties (size, size distribution, shape, friability, true density, flowability) and tablet properties (tensile strength, friability, dissolution rate) of four different drug-binder formulations using Design of experiments (DOE). Two binders (polyethylene glycol (PEG) and Soluplusr ) with a different solid state, semi-crystalline vs amorphous respectively, were combined with two model-drugs, metoprolol tartrate (MPT) and caffeine anhydrous (CAF), both having a contrasting miscibility with the binders. This research revealed that the granule properties of miscible drug-binder systems depended on the powder feed rate and barrel filling degree of the granulator whereas the granule properties of immiscible systems were mainly influenced by binder concentration. Using an amorphous binder, the tablet tensile strength depended on the granule size. In contrast, granule friability was more important for tablet quality using a brittle binder. However, this was not the case for caffeinecontaining blends, since these phenomena were dominated by the enhanced compression properties of caffeine Form I, which was formed during granulation. Hence, it is important to gain knowledge about formulation behavior during processing since this influences the effect of process parameters onto the granule and tablet properties. Keywords: Continuous hot melt granulation (HMG), granule and tablet properties, DOE, solid state binder, drug binder interaction
Preprint submitted to x
July 19, 2016
1
1. Introduction
2
Granulation is an important process step to improve processability, flowability, compactability and con-
3
tent uniformity of the raw materials to be formulated into a final solid dosage form (e.g., tablets). This
4
particle size enlargement process is often done via wet granulation using a solvent (mostly water) to initiate
5
binding between powder particles, followed by a drying step. However, some pharmaceutical actives are not
6
suitable for wet processing and drying because of stability and degradation problems. In this case, HMG
7
or thermoplastic granulation is a valuable alternative to overcome that problem [1][2]. HMG uses a molten
8
binder instead of a granulation liquid to agglomerate the pharmaceutical powder particles and, hence, no
9
drying step is needed, reducing process time and energy consumption.
10
11
The pharmaceutical industry has traditionally relied on batch processing to manufacture their drug
12
products. However, to improve process efficiency and reduce manufacturing costs, there is a growing inter-
13
est in alternative manufacturing models which allow automation and continuous production. Continuous
14
manufacturing processes are based on the one-in-one-out principle, avoid scale-up issues, ensure faster prod-
15
uct release, reduce production time/costs, reduce variability, increase flexibility and efficiency, and might
16
improve product quality [3][4]. Twin-screw wet granulation has already been examined extensively as con-
17
tinuous granulation technology, allowing fully continuous from-powder-to-tablet-manufacturing [5][6][7][8].
18
However, the research of twin-screw hot melt granulation is still in its infancy.
19
20
Implementing a switch from batch to continuous processing could be perceived as a challenge since this
21
requires fundamental process understanding. The Food and Drug Administration (FDA) published the pro-
22
cess analytical technology (PAT) and QbD concept in the 2004 guidance which were more broadly described
23
in the ICH guidelines Q8, Q9, and Q10 [9][10][11]. The initiative emphasizes the need to understand all
24
critical sources of variability (i.e. critical quality attributes (CQAs), critical material attributes (CMAs) and
25
critical process parameters (CPPs)) affecting a pharmaceutical process to ensure that drug products with
26
predefined quality attributes are consistently obtained. The implementation of QbD principles ultimately
27
aims at designing and developing formulations and processes to build quality into the end product (instead ∗ Corresponding
author Email addresses: [email protected] (Tinne Monteyne ), [email protected] (Jochem Vancoillie), [email protected] (Jean-Paul Remon), [email protected] (Chris Vervaet), [email protected] (Thomas De Beer) 1 Phone number: +32(0)9 264 80 68 2 Fax number: +32(0)9 264 82 36
2
28
of testing quality of the end product). Furthermore, this will enable stable operation, help to support feed-
29
back/feed forward controls, and resulting in fewer compliance problems since a manufacturer anticipates
30
these issues and addresses them more systematically if they occur [12].
31
32
The critical sources of variability are still not fully understood for the continuous melt granulation pro-
33
cess. It is known that the melt granule properties depend on the combination of several process and material
34
parameters and can affect subsequent processing steps, such as milling and tableting. For example, changes
35
in screw speed and configuration (number and location of transport and kneading elements), powder feed
36
rate, temperature, and formulation (type binder, concentration binder, drug-binder interaction) can induce
37
changes in granulation mechanism yielding different granule characteristics which will alter the tablet proper-
38
ties. Ultimately, this can affect the drug dissolution profiles and therefore the bioavailability of the final drug
39
product in a patient [13][14]. This emphasizes the need to define influencing parameters such as CMAs and
40
CPPs on CQAs and can be derived using an experimental design, which after optimization assists in creating
41
a design space for the product [15][16]. However, this has proven to be challenging due to the complex rela-
42
tionships between the granule properties (size, size distribution, shape, solid state, granule friability/strength
43
etc.), and the properties of the final product (tablet tensile strength, tablet friability, dissolution rate) [17][7].
44
45
Literature demonstrated that both the interaction between the initial materials and the type of meltable
46
binder (hydrophilic, hydrophobic, (semi)-crystalline, amorphous) used during the melt granulation process
47
are determining factors for the granulation mechanism [18][19]. Hence, these might have an impact on the
48
process and the final product quality [20]. The aim of this study was to examine the relationship between
49
the formulation parameters (type binder, binder concentration, drug-binder interaction), process-parameters
50
(screw speed, powder feed rate and temperature), granule properties (size, size distribution, shape, friabil-
51
ity, true density, flowability) and tablet properties (tensile strength, friability, dissolution) of four different
52
drug-binder formulations by using DOE. Two binders (PEG4000 and Soluplusr ) with a different solid state
53
(semi-crystalline vs. amorphous) were combined with two model-drugs, MPT and CAF, both having another
54
miscibility with both binders. Four screening DOEs were performed to enhance process understanding and
55
to define the critical material attributes and potential critical process parameters that impact intermediate
56
and final product quality attributes.
57
3
58
2. Materials and methods
59
2.1. Materials
60
PEG and Soluplusr (SLP) were used as hydrophilic meltable binders to develop immediate release for-
61
mulations. PEG4000 (BUFA, Uitgeest, Holland) is a semi-crystalline polymer with a melting temperature
62
(Tm ) of 53 ◦ C. Soluplusr (BASF, Ludwigshafen, Germany) is an amorphous polymer with a glass transi-
63
tion temperature (Tg ) of 70 ◦ C. The binders were used to agglomerate two model drugs, being MPT and
64
caffeine anhydrous. MPT (UTAG, Almere, The Netherlands)(Tm =120 ◦ C) was used as miscible model drug
65
in both binders. MPT has a solubility of 0.53 g per gram PEG4000 whereas it has a solubility of 0.72 g per
66
gram Soluplusr . MPT is a micronized powder having a particle size below 10 µm (X10=1 µm, X50=2.2 µm,
67
X90=7 µm). Caffeine anhydrous (BASF, Ludwigshafen, Germany)(Tm =236 ◦ C), on the other hand, was
68
used as a non-miscible model drug in both binders. CAF is insoluble in PEG4000 whereas it has a solubility
69
of 0.03 g per gram Soluplusr . The solubility parameters of both drugs were obtained from BASF and were
70
based on the Hansen solubility parameter and the Flory-Huggins solubility parameter estimation [21]. Caf-
71
feine has a particle size distribution below 150 µm (X10=1.4 µm, X50=11.1 µm, X90=106.6 µm) and appears
72
in two polymorphs, namely Form I and Form II, the latter being the commercially available polymorph [22].
73
Four different formulations were made: MPT/PEG, MPT/SLP, CAF/PEG, and CAF/SLP. Aerosilr 200
74
(Evonik Degussa Corp., Essen, Germany) was added to the initial powder blend (0.2% (w/w)) to increase
75
the flow properties and hence supporting the feeding into the twin-screw granulator. Before tablet compres-
76
sion, the granules in the size range 150-1400 µm were isolated and both magnesium stearate (0.5% (w/w))
77
and Explotabr (5% (w/w)) were added.
78
79
2.2. Continuous hot melt granulation
80
Melt granulation was performed using a co-rotating intermeshing twin-screw granulator (Prism Eurolab
81
16) (Thermofischer Scientific, Karlsruhe, Germany) with a barrel length of 25 L/D, where L is the axial
82
screw length of the machine and D is the inner bore diameter. The screw design was identical for all
83
experiments containing one kneading zone located in the fifth segment and consisting of 6 kneading discs
84
positioned at a 60 ◦ stagger angle in reversed direction. At the end of the screws, a screw mixing element
85
was placed in order to break up large lumps [23]. The premixed samples were fed into the granulator using
86
a DD Flexwallr 18 gravimetric feeder (Brabender Technologie, Germany), which was set in the gravimetric
87
feeding mode. The barrel was divided into 6 barrel zones. Barrel temperature from segment 2 to 5 was 4
88
varied according to the design. Segment 6, which is located at the end of the barrel, had a lower temperature
89
of 40 ◦ C during all runs in order to cool down the granules and hence avoiding them to stick together when
90
leaving the granulator. Granule samples were collected after melt granulation of each run. The sample
91
collection was started after 15 minutes, which is the time needed to reach a steady state process and a stable
92
torque and barrel wall temperature which were unstable at the beginning of each process due to layering of
93
the screws and the screw chamber walls with material. Sample collection was executed until 150 g sample
94
was collected. Afterwards, samples were stored at room temperature. The granulator was equipped with
95
a data logging system allowing monitoring of the screw torque and actual barrel wall temperature during
96
granulation. The torque (expressed as a percentage, which reflects on the fraction of the maximum torque
97
(12 Nm) that can be generated by the screw motor to rotate the screws) was recorded directly from the
98
twin-screw granulator panel every 30 s. The torque at steady state was averaged to give a single value.
99
2.2.1. Differential scanning calorimetry
100
Differential scanning calorimetry (DSC) was used to measure the melt enthalpy of the pure components,
101
physical mixtures and the corresponding granule samples obtained after melt granulation of the caffeine-
102
containing blends. The data were used to determine the remaining amount of caffeine polymorphic Form II
103
after melt granulation according the equation described by Hubert [24]:
% of caffeine Form II = 104
∆trans Hm(II→I) .100 ∆trans Hm(II→I) of pure Form II
(1)
where ∆trans Hm(II→I) is the enthalpy of transition of the sample.
105
106
A DSC Q2000 calorimeter (TA Instruments, Zellik, Belgium) was used. Samples were hermetically sealed
107
in aluminium pans and a heating rate of 10 ◦ C/min was applied. Analysis was performed in triplicate.
108
2.3. Design of experiments
109
Preliminary experiments were carried out for each formulation to determine the experimental ranges for
110
the DOE factors throughput, screw speed, temperature and binder concentration. The extreme parameter
111
settings where only powder was produced or where an excessive amount of lumps were created after twin-
112
screw hot melt granulation (TS HMG), were eliminated. Four two-level full factorial screening designs (24 )
113
were created (one for each formulation) and executed in order to evaluate the influence of the tested parame-
114
ters on granule and tablet properties. Four factors (powder feed rate, screw speed, binder concentration and 5
115
temperature) were used in each design. Three center points were executed to evaluate the reproducibility.
116
The different factor settings for each design are listed in table 1. The responses were regressed against the
117
factors via multiple linear regression (MLR) (using MODDE 10.0 software by Umetrics, Umea, Sweden). Table 1: Factor settings of the four experimental designs
Settings MPT/PEG MPT/SLP CAF/PEG CAF/SLP
throughput (kg/h) −1 0 +1 0.35 0.625 0.9 0.4 0.6 0.8 0.5 0.8 1.1 0.4 0.7 1
screw −1 100 200 150 200
speed (rpm) 0 +1 225 350 312.5 425 225 300 312.5 425
temperature −1 0 30 44 30 50 55 67.5 50 90
( ◦ C) +1 58 70 80 130
−1 5 5 7.5 5
% binder 0 +1 12.5 20 10 15 15 22.5 12.5 20
118
The influence of the factors is measured on both granule properties (granule friability, true density,
119
compressability index, size (fines, yield, oversized, X50), shape (A50), and span distribution) process torque,
120
and tablet properties (tensile strength, tablet friability, and dissolution rate in 5 minutes).
121
2.3.1. Effect and interactions of factors
122
For each design, the effects were calculated representing the response deviation when a factor is varied
123
from its low level (-1) to its high level (+1) keeping the other factors at their center points. The effects
124
were calculated with their respective 95% confidence interval. Insignificant effects are those where their
125
confidence intervals includes zero. Interaction plots has been calculated to study the predicted change in
126
the response when one factor varies, while a second factor is set at both its low (-1) and high (+1) level,
127
while all other factors being set at their center point.
128
2.4. Granule size distribution and granule shape
129
Size and shape of the final granules were determined (n=3) using an off-line image analysis tool (QicPic,
130
Sympatec, Germany). This high speed imaging tool is based on shadow projection and exists of a VIBRI
131
vibrational conveyor, which is a controlled feeding system, allowing the granules to fall through a shaft where
132
the granules are accelerated and finally pass a laser beam and camera, which records images of shadows of
133
the granules. In this configuration, the system is capable of capturing particles in the range of 10 µm to
134
10.2 mm. Size analysis was based on the equivalent projection of a circle (EQPC). The entire size distri-
135
bution was studied where the size values were classified into 39 classes between 0 and 3400 µm and 1 class
136
>3400 µm. The X10, X50 and X90 values represent the particle size at respectively, 10, 50, and 90% of
137
the cumulative distribution. The X50 values were used as a response in the designs to show the influence
138
of the factors on the granule size. The granule shape was represented by evaluating the aspect ratio which 6
139
measures the elongation of the granule. It is the ratio of the length of the minor and the major diameter of
140
the granule. The granule shape is expressed as A50, representing the aspect ratio at 50% of the cumulative
141
distribution. The width of the size distribution was incorporated as a response in the designs using the span
142
values ((X90-X10)/X50).
143
144
2.5. Granule density
145
The true density (TD) (g/m3 ) of the granules was determined (n=3) using an AccuPyc 1330 helium
146
pycnometer (Micromeritics Instruments Inc, Norcross, United States). A precisely measured amount of
147
sample was placed in the test cell, filling at least 65% of the cell. The pycnometer determined the volume
148
occupied by the sample via pressure changes.
149
2.6. Granule flow properties
150
The compressibility index (CI) describes the powder flow characteristics and can be determined by
151
measuring the bulk and tapped volume of the sample (n=3). The bulk volume (V0 ) of 30 g granules was
152
recorded in a 100 ml measuring cylinder, as well as the volume after 10 (V10 ), 500 (V500 ) and 1250 (V1250 )
153
taps in a tapping machine (J. Englesman, Ludwigshafen, Germany). If the difference between V500 and
154
V1250 was larger than 2 ml, the powder was subjected to another 1250 taps (V2500 ). The compressibility
155
index (%) was calculated from the bulk and tapped density using the following equation:
CI = ((ρi − ρf )/ρi )100 156
157
(2)
where ρi is the bulk density and ρf is the tapped density. 2.7. Friability of granules
158
The granule friability was determined (n=3) using a friabilator (PTF E Pharma Test, Hainburg, Ger-
159
many) at a speed of 25 rpm for 10 min, by subjecting 10 g of granules (Iwt ) together with 200 glass beads
160
(mean diameter of 4 mm) to falling shocks. Prior to determination, the granule fraction <250 µm was re-
161
moved to assure the same starting conditions for all evaluated granules. Afterwards, the glass beads were
162
removed and the weight (g) retained on a 250 µm sieve (Fwt ) was determined. The friability (%) was then
163
calculated as:
F riability = ((Iwt − Fwt )/Iwt )100 7
(3)
164
2.8. Tablet production
165
The granule fraction between 150 and 1400 µm was blended with 0.5% (w/w) magnesium stearate and
166
5% Explotabr in a tumbling mixer (W.A. Bachshofen, Basel, Switzerland). The tablets (115±5 mg) were
167
produced automatically using an eccentric tablet press (Korsch EKO, Berlin, Germany) equipped with a
168
concave punch of 7 mm diameter. The displacement of the upper punch into the die was controlled, resulting
169
in a compression force of 14.7 kN per tablet.
170
2.9. Tablet evaluation
171
The tablet friability was determined (n=3) by subjecting 20 dust free tablets (weight=Iwt ) to falling
172
shocks in a drum rotating at 25 rpm for 4 minutes. The tablets were dedusted and weighed (Fwt ). The per-
173
centage weight loss calculated with equation 3 is expressed as tablet friability and ideally does not exceed
174
1.0%.
175
176
177
The hardness, thickness and diameter of tablets (n=10) were determined (Sotax HT 10, Basel, Switzerland). The tablet tensile strength (TS) (Pa) was calculated using the equation [25]:
T S = 2F/π.dt 178
179
(4)
where F, d and t denote the diametrical crushing force or hardness, the tablet diameter and the tablet thickness, respectively.
180
181
Dissolution tests were performed (n=3) in 900 ml demineralised water using the paddle method (VK
182
7010, Vankel, Cary, NC, USA). The temperature of the dissolution medium was maintained at 37±0.5 ◦ C,
183
while the rotation speed was set at 100 rpm. 5 ml samples were withdrawn at 5, 10, 15, 20, 30, 45, 60, and
184
90 min after starting the dissolution. The drug content was determined at 222 nm for MPT and 273 nm for
185
CAF using an UV-1650PC double beam spectrophotometer (Shimadzu Benelux, Antwerp, Belgium).
186
187
3. Results
188
3.1. Factor ranges
189
The results revealed that the required granulation temperature range was shifted to lower temperatures
190
when the binder and active pharmaceutical ingredient (API) were miscible. This can be related to the 8
191
plasticizing effect of the drug on the binder lowering the temperature at which deformability is initiated.
192
Furthermore, an improved blend deformability during processing enlarged the bonding or contact area of
193
the nuclei when colliding, resulting in plastic deformation which resisted the breakup forces [26][27]. Hence,
194
deformability stimulated granule growth and as a result, the maximum process temperature was lower to
195
avoid overgranulation. On the other hand, when binder and API were immiscible, the maximum granulation
196
temperature exceeded the Tm or Tg of the binder as there was no plasticizing effect of the drug on the binder
197
which resulted in low-deformable granules. In this situation, granule coalescence could only occur if there
198
was a binder layer established at the surface of the particles or granules to bind them [27]. Hence, higher
199
temperatures were required to initiate binder distribution and large lumps were only formed at elevated
200
process temperature.
201
202
3.2. Responses
203
3.2.1. Granule properties
204
The comparison of the granule properties obtained after executing the four designs revealed differences
205
caused by the type of binder, type of API and extent of drug-binder miscibility. The SLP granules were
206
larger compared to the particle size of the PEG granules (table 2). PEG is a semi-crystalline polymer
207
having more elastic properties which can result in more brittle agglomerates compared to SLP, which is an
208
amorphous binder. These brittle agglomerates were not able to withstand the impact of the screw mixing
209
elements at the end of the barrel. The temperature in the last barrel segment was lowered allowing granules
210
already to solidify. Hence, the brittle granules break up more easily resulting into smaller granules. The
211
amorphous binder SLP, on the other hand, produced larger granules, even though when a lower % of binder
212
was used. This implies a larger binding capacity of SLP compared to PEG [28].
213
214
Besides this, the maximum size of the caffeine granules was larger than the size of the granules made
215
with MPT. Several explanations can be found. On the one hand, this might be due to the deviating initial
216
particle size of both APIs. The primary particle size of caffeine reached to 106 µm whereas MPT had an
217
initial size less than 10 microns. Smaller starting material results in smaller particles of the end product
218
as also reported by El Hagrasy and coworkers [29][30]. On the other hand, this might be due to the poly-
219
morph transition from the commercial available caffeine Form II to the metastable Form I, which can occur
220
during twin-screw melt granulation [31]. The metastable Form I has a higher deformability and improved
221
compaction properties favoring the compaction behavior during processing and, hence, stimulating granule 9
Table 2: Absolute values of min, mean and max particle size ( µm), true density (g/m3 ) and granule friability (%) in the four designs
Property Size (X50)
True density
Friability
Value Min. Mean Max. Min. Mean Max. Min. Mean Max.
MPT/PEG 282 675 956 1.213 1.217 1.222 15.6 29.7 43.3
MPT/SLP 363 1137 1700 1.170 1.193 1.214 5.1 13.3 31.6
CAF/PEG/ 478 832 1464 1.399 1.422 1.451 13.1 25.8 43.3
CAF/SLP 299 1092 2128 1.382 1.417 1.458 4.0 34.5 90.7
222
growth. The polymorphic transition to caffeine Form I could also be observed in this research and was more
223
expressed at higher binder concentrations (See below in Figure 11). Furthermore, the conversion was more
224
expressed when Soluplusr was used as a binder. Besides the initial drug particle size and the polymorphic
225
transition, also the granulation mechanism can attribute to the difference in granule size of the caffeine-
226
containing blends in comparison with the MPT-containing blends. During granulation of an immiscible
227
drug-binder blend, the binder behaves as a separate phase which distributes over the drug particles when
228
softened/molten [32]. This distinct binder distribution results in successful coalescence and hence to large
229
granules. Note that process parameters inducing a good binder distribution are necessary to reach successful
230
coalescence. In contrast, interaction (hydrogen bond formation) between drug and binder was discovered
231
during granulation of a miscible drug-binder formulation (MPT/SLP) which impeded proper binder distri-
232
bution making coalescence less evident [20]. In figure 1, a visualization of the granulation mechanism is
233
given based on the observations in previous work.
234
Immersion Drug Binder (ini+al step)
Immiscible drug-binder blend
0 0
0 0 0 0 4 Miscible drug-binder blend
Figure 1: Visualization of granule growth mechanism for a miscible and immiscible binder formulation during twinscrew hot melt granulation.
10
235
The true density measurements (Table 2) revealed that the caffeine-containing granules were more dense
236
(1.4) compared to MPT-containing agglomerates (1.2). Table 4 demonstrates that the granule density was
237
negatively influenced by binder concentration in the two caffeine-containing blends. Therefore, there can be
238
assumed that the higher true density is attributed to the different material properties of caffeine compared
239
to MPT. Furthermore, the conversion of caffeine anhydrous into the more deformable and compactable
240
Form I during granulation could have increased the true density of the granules (Figure 11). On the other
241
hand, it has already been demonstrated that drug-binder miscibility produced more porous granules [33].
242
PEG-containing granules were more fragile which can be related to the brittle properties of the binder. If
243
PEG was used as a binder, the friability was in all cases above 13.1% (CAF/PEG) or 15.6% (MPT/PEG)
244
compared to 4% for CAF/SLP and 5.1% for MPT/SLP. It has to be highlighted that a high temperature
245
or shear was required in order to induce granule growth of the CAF/SLP blend [32]. If not, a high fraction
246
of fines and high friability values were obtained which can be seen in table 2.
247
248
3.2.2. Tablet properties
249
The tablet properties revealed that tablets made with Soluplusr have the highest maximum tablet tensile
250
strength, with values of 3.73 MPa for CAF/SLP and 3.33 MPa for MPT/SLP. In comparison, CAF/PEG
251
and MPT/PEG have a maximum tablet tensile strength of 2.44 and 2.66 MPa, respectively. The more
252
ductile behavior of Soluplusr allowed plastic deformation of the granules during tableting, yielding stronger
253
tablets [34]. Besides tensile strength, also dissolution rate is different for both binders. When the API
254
is granulated at the same granulation conditions with both PEG and Soluplusr , the dissolution rate will
255
be 10% faster after granulation with PEG (for both MPT and CAF). Furthermore, when PEG is used to
256
agglomerate caffeine, the entire drug content is dissolved in 30 minutes, whereas only 70% caffeine is released
257
from Soluplusr mixtures. Earlier research on melt granulation already showed PEG to be a suitable binder
258
to enhance the dissolution rate of poorly water-soluble drugs [35][36]. The higher hydrophilicity of PEG
259
might be a possible explanation.
260
261
262
A list of significant effects of the factors and their interactions is given in tables 4 (granule properties) and 5 (tablet properties).
11
Table 3: Absolute values of min, mean and max tensile strength (MPa) and amount API (%) released in 5 minutes for the four designs
Property Tensile strength
API (%) released in 5 min
263
3.3. Influence of powder feed rate
264
3.3.1. Granule properties
Value Minimum Mean Maximum Minimum Mean Maximum
MPT/PEG 1.18 1.93 2.66 61.4 72.4 84.2
MPT/SLP 1.41 2.59 3.33 33.3 63.2 78.9
CAF/PEG 1.19 2.15 2.44 17.3 27.7 52.7
CAF/SLP 1.11 2.02 3.73 8.3 18.3 28.5
265
The influence of powder feed rate on the granule properties depended on the API. In general, throughput
266
had a large influence on the MPT-containing granules, whereas it had a minor effect on the caffeine-containing
267
granules (Table 4). Powder feed rate had even no influence on the granule properties of the CAF/SLP blend.
268
This is in accordance with the miscibility parameters of the APIs with the polymers, except for CAF/PEG.
269
It has to be highlighted that every run in the design of CAF/PEG was performed using a barrel temperature
270
exceeding the melting temperature of PEG and hence it can be stated that PEG was molten throughout
271
the whole design. Therefore, it is obvious that the enhanced compressive forces obtained at high powder
272
feed rate affected the granulation process of CAF/PEG, regardless the miscibility of both materials. The
273
importance of powder feed rate for the granulation properties of miscible systems could be found in the
274
specific granulation mechanism. In miscible drug-binder formulations, granule growth occurs when nuclei
275
deform after they collided. The nuclei are rather ‘kneaded’ instead of sticking together as was seen for
276
immiscible binder blends (Figure 1).
277
278
Performing granulation with a higher throughput resulted in larger and stronger granules with improved
279
flow properties. These effects were negligible for the CAF/SLP blend and less pronounced for CAF/PEG
280
blend (Table 4). These observations might be attributed to the higher screw fill in the barrel appearing
281
at increasing powder feed rate and constant screw speed. The degree of channel fill refers to the volume
282
occupied by the powder blend with respect to the total available volume in the conveying zones of the screw.
283
A higher powder feed rate induces superior screw filling, generating a high throughput force which conveys
284
the powder more quickly through the barrel [37][38]. As a result, the residence time of the material inside
285
the barrel is shortened, but the material packing and compressive forces in the material between the screws
286
is enhanced. The latter induce more interactions between the powder particles or the yet developed gran12
13
T*%bi
Scr*T
Scr*%bi
Thr*T
Thr*%bi
Thr*Scr
Temperature
Binder %
Screw speed
Throughput
Factor
Friability
-5.09 (±3.84) -8.08 (±3.47) -7.6 (±4.39) 24.15 (±18.5) -15.87 (±3.84) -5.07 (±3.47) -15.90(±4.39) -39.46 (±18.5) 4.3 (±3.47) -28.15 (18.5) -9.28 (±3.47) 5.13 (±4.39) 3.47 (±3.47) 5.07 (±3.84) -5.4 (±3.47) -6.69 (±4.39) 6.68 (±3.47) 6.79 (±3.84) 7.90 (±3.47) -
Design
MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP
-0.0175 (±0.01) -0.042 (±0.0043) -0.056 (±0.006) -
Density -3.61 (±2.85) -6.7 (±5.38) 8.70 (±6.40) -3.68 (±2.85) -5.91 (±5.38) -5.35 (±2.92) 2.95 (±2.92) -7.30 (±6.40)
Comp. index -5.59 (±2.2) -9.75 (±4.34) 9.76 (±4.34) 17.25 (±12.5) -10.17 (±2.2) -8.99 (±6.33) -16.51 (±12.50) -2.89 (±2.2) -9.97 (±4.34) 4.11 (±2.2) -
Fines 5.63 (±4.05) -15.12 (±6.85) -7.56 (±5.11) 13.75 (±5.11) 17.51 (±4.05) 4.45 (±4.05) -15.64 (±6.85) -
24.86 (±10.23) 11.6 (±10.7) -13.95 (±10.23) -16.70 (±10.7) 12.09 (±10.7) 32.07 (±17.40) 10.94 (±10.35) 25.61 (±10.23) -
Granule properties Yield Oversized 276.97 (±146.43) 578.92 (±228.77) 270.1 (±226.96) -256.96 (±228.77) -257.71 (±226.96) 348.299 (±226.96) 627.57 (±575) 630.117 (±575) 577.58 (±228.77) -
X50
-0.0422 (±0.022) -0.017 (±0.0127) 0.026 (±0.022) 0.0275 (±0.018) 0.045 (±0.043) -0.0175 (±0.0127) -0.054 (±0.022) 0.015 (±0.0127) -
A50
Table 4: List of significant effects of the factors and their interactions on granule properties of the four designs: granule friability (%), true density (g/m3 ), compressability index (CI)(%), fines (%), yield (%), oversized (%), X50 (µm), A50 (-) and SPAN (-). SPAN -0.44 (±0.39) -0.28 (±0.19) 0.20 (±0.19) -0.51 (±0.39) -2.54 (±0.92) -0.34 (±0.19) -1.14 (±0.92) -
Table 5: List of significant effects of the factors and their interactions on process and tablet properties of the four designs: torque (%), tensile strength (MPa), tablet friability (%) and % drug released after 5 minutes.
Factor Throughput
Screw speed
Binder %
Temperature
Thr*Scr
Thr*%bi
Thr*T
Scr*%bi
Scr*T
T*%bi
Design
Process property Torque
Tensile strength
MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP
9.06 (±2.05) 4.375 (±2.41) -14.19 (±2.05) -10.125 (±2.41) -22.29 (±7.73) 10.29 (±7.73) -3.062 (±2.05) -4.06 (±2.05) 2.88 (±2.41) -2.06 (±2.05) -
0.58 (±0.36) -0.483 (±0.24) -0.56 (±0.36) -0.51 (±0.24) 0.4 (±0.20) 0.93 (±0.74) -0.36 (±0.24) 0.5 (±0.36) -0.27 (±0.24) 0.39 (±0.36) -0.36 (±0.24) 0.536 (±0.24) 0.83 (±0.74) 0.78 (±0.74)
14
Tablet properties Friability -3.24 (±2.61) -1.0 (±0.84) -2.16 (±1.4) -4.79 (±2.61) -1.41 (±1.4) -0.89 (±0.84) 3.36 (±2.61) -
Release -11.86 (±8.29) -9.40 (±3.96) -11.7 (±3.73) -20.37 (±8.29) 5.44 (±3.73) 9.6 (±8.29) 10.75 (±8.29) -
287
ules and the ungranulated powder, causing the powder to efficiently attach on the surface of the granules
288
or around each other which stimulates granule growth. The higher the powder feed rate, the better the
289
interlocking of the primary particles onto the structure of the granules, the stronger the granules become.
290
As a consequence, lower friability rates were obtained when a high powder feed rate was used (Table 4).
291
Furthermore, it is evidenced that the high material packing facilitated interaction between drug and binder
292
explaining the higher influence of throughput on the granule properties for blends having the possibility of
293
interacting (MPT/PEG and MPT/SLP) [39]. Additionally, the superior screw filling reduced the amount of
294
fines since binding of ungranulated powder particles took place at enhanced compression forces [38]. These
295
outcomes were similar to these obtained in continuous wet granulation [40][41].
296
297
The flow properties of the granules obtained from the miscible blends depended on the amount of fines
298
and the span distribution and therefore they are influenced by powder feed rate (Figure 2). The granules
299
have an improved flowability when the amount of fines is sparse, or/and when the span distribution is narrow
300
which is achieved at elevated powder feed rate. However, the throughput can not be too high in order to
301
limit the amount of oversized granules[42].
302
4
20
3
10
1.5
0
1
-10
0
Y=1.3088x-8.066 R2= 0.55349
10
15
20
25
20
2
Compressability index (%)
10 Y=0.600x-10.02 R2= 0.70549
10
15
20
25
SPAN Fines Fines (%)
2.0
1.0
30
SPAN Y=0.0365x+1.3033 Fines R2= 0.65576 Fines (%)
SPAN (-)
2.5
30 Y=5.79x+0.2055 R2= 0.3934
SPAN (-)
3.0
0
Compressability index (%)
Figure 2: Correlation plots for MPT/SLP (left) and MPT/PEG (right) between compressability index (%) and span distribution (◦) and between compressability index (%) and fines (%)(N).
303
3.3.2. Tablet properties
304
The powder feed rate had almost no influence on the tablet properties of the caffeine-containing gran-
305
ules, which is in accordance with its effect on the granule properties (Table 5). MPT/SLP tablets had a
306
sufficient strength with a friability lower than 1% in all cases. For MPT/PEG containing tablets, on the
307
other hand, capping was observed at parameter settings where adhesion was impeded and is demonstrated
308
in figure 3. When the binder concentration or granulation temperature were low, an increase in powder feed 15
4
Temp high Temp low
3
Tablet friability (%)
Tablet friability (%)
4
2 1 0 0.3
0.6
Binder % high Binder % low
3 2 1 0 0.3
0.9
Powder feed rate (kg/h)
0.6
0.9
Powder feed rate (kg/h)
Figure 3: Interaction plot for tablet friability between (left) powder feed rate and granulation temperature and (right) powder feed rate and binder concentration of the MPT/PEG blend.
309
rate affected tablet friability. Increasing the powder feed rate shortened the material residence time inside
310
the barrel which impeded the binder to melt and, hence, to distribute/bind drug particles. Compressing
311
these granules into tablets led to capping of the tablets [43]. If the binder concentration and/or process
312
temperature was higher, the binding capacity was better making the material residence time inside the
313
granulator or the material throughput less important since under these conditions, tablet friability values
314
remained constant below 0.5% and a good tablet strength was obtained.
315
316
3.4. Influence of screw speed
317
3.4.1. Granule properties
318
Screw speed was influencing the granule size and shape in all four designs. Additionally, there was an
319
interaction between the effects of screw speed and powder feed rate. This interaction is attributed to the
320
extent of screw fill which is correlated to torque. An accelerated screw speed diminished the barrel filling
321
degree and resulted in lower torque values. This interaction was observed for the miscible formulations and is
322
linked to the specific granulation mechanism for miscible formulations as described above (Table 4)(Figure
323
1). Granule growth occurred by kneading nuclei together and therefore, a high barrel filling degree was
324
required. In any case, a correlation between the torque level and amount of fines was observed where higher
325
torque values generated granules containing less fines (Figure 4). The superior channel filling at low screw
326
speed caused adherence of the not-agglomerated powder to the surface of the already formed granules and
327
to each other [38]. As a result, the amount of fines was reduced.
328
329
Furthermore, screw speed affected the granule size distribution of the miscible drug-binder blends, but
330
the effect depended on the powder feed rate. When the powder feed rate was low (−1), a slower screw speed 16
25
Scr.sp. high (CAF/SLP)
Scr.sp. high (CAF/PEG) 20
30
Fines (%)
Torque (%)
40
20 10
Scr.sp. low (CAF/SLP) 15 Scr.sp. low (CAF/PEG)
high (CAF/SLP) high (CAF/PEG) low (CAF/SLP) low (CAF/PEG)
Scr.sp. Scr.sp. Scr.sp. Scr.sp.
high (MPT/SLP) high (MPT/PEG) low (MPT/SLP) low (MPT/PEG)
10 5 0
0 -1
0
-1
+1
0
+1
Powder feed rate (kg/h)
Powder feed rate (kg/h) 40
25
Scr.sp. high (MPT/SLP)
Scr.sp. high (MPT/PEG) 20
30
Fines (%)
Torque (%)
Scr.sp. Scr.sp. Scr.sp. Scr.sp.
20 10
Scr.sp. low (MPT/SLP) 15 Scr.sp. low (MPT/PEG) 10 5
0
0 -1
0
+1
-1
0
Powder feed rate (kg/h)
+1
Powder feed rate (kg/h)
Figure 4: Interaction plot for (left) torque (%) and (right) fines (%) between powder feed rate (kg/h) and screw speed (rpm) of (up) CAF/SLP and CAF/PEG and (low) MPT/SLP and MPT/PEG blends. Soluplusr is shown by the dotted and PEG by the solid lines. (•) and (◦) represent high screw speed, whereas () and () symbol the low screw speed. CAF/SLP
CAF/PEG 50
30
Thr (-1) scr (-1) 40 (+1) scr (-1) Thr Thr (-1) scr (+1) 30 Thr (+1) scr (+1)
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
Thr Thr Thr Thr
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
%
%
20
Thr Thr Thr Thr
20 10
10 0 100
1000
0 100
10000
1000
10000
Granule size (µm)
Granule size (µm)
MPT/SLP
MPT/PEG 40
25 20
%
%
15
Thr Thr 30 Thr Thr 20
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
10
10
5 0 100
1000
10000
0 100
1000
10000
Granule size (µm)
Granule size (µm)
Figure 5: Granule size distribution of runs with varying combinations of throughput and screw speed.
331
produced larger granules with a broader granule size distribution. This is demonstrated in figure 5. At
332
low screw speed, the channel filling degree of the screws (compared to high screw speed) and the residence 17
333
time of the material inside the barrel were enlarged. The additional time of the material inside the granu-
334
lator stimulated granule growth. When the powder feed rate was high (+1), accelerating the screw speed
335
produced more oversized granules, but the amount of fines remained equal. Hence, a broader distribution
336
was obtained. This is linked to the shortened material residence time of the material inside the barrel at
337
high screw speed and high powder feed rate. As a consequence, the screw channels were starved of powder
338
which limited powder compaction [38]. In order to reach an appropriate size distribution, both screw fill
339
degree and residence time inside the barrel must be controlled as they are both playing a key role. The
340
longer the residence time, the higher the collision frequency of the granules with the barrel wall will be.
341
Therefore, a prolonged residence time is required for granules to reduce the oversized fraction. On the other
342
hand, a high screw filling degree is preferred in order to bind the ungranulated powder on the surface of the
343
granular material reducing the fines. This explains the appearance of a fine granular material accompanied
344
by oversized granules when operating at fast screw speed and high powder feed rate.
345
CAF/SLP 50
T (-1) Bi (-1) Scr (-1) T (-1) Bi (-1) Scr (+1) T (+1) Bi (+1) Scr (-1) T (+1) Bi (+1) Scr (+1)
40
%
30 20 10 0 100
1000
10000
Granule size (µm)
Figure 6: Granule size distribution of the SLP/CAF blend when deviating screw speed from −1 to +1 at different levels of binder concentration and granulation temperature.
346
The behavior of the granules obtained from granulation of CAF-containing blends was deviating in
347
specific cases. Performing granulation of the CAF/PEG blend using a higher screw speed was always pro-
348
ducing a higher fraction of smaller sized granules, independent of the powder feed rate (Figure 5). For
349
the CAF/SLP blend, the behavior was deviating when a low binder content and low barrel temperature
350
or high binder concentration and high barrel temperature were used (Figure 6). The influence of powder
351
feed rate was negligible in these cases. Accelerating the screws during granulation of caffeine using a low
352
Soluplusr concentration at a low barrel temperature, produced both small and oversized granules. The
353
reason for this might be the shortened time to soften the limited amount of binder, thus hindering granule 18
354
growth. The few granules were formed via immersion of the solid particles on the surface of the softening
355
binder. Furthermore, a high granulation temperature and/or high binder concentration was required for this
356
blend in order to induce agglomeration [32]. On the other hand, speeding up the screws during granulation
357
of caffeine using a high Soluplusr content at elevated barrel temperature generated an excessive amount
358
of oversized granules. The higher screw tip speed induced mechanical shear which enhanced softening of
359
Soluplusr . Besides improved binder distribution also transition of the stable caffeine polymorphic form
360
to Form I occurred, facilitating granule growth [31](Figure 11). Furthermore, it can be assumed that the
361
granule size distribution depends on the type of binder, type of API and whether they interact or not. This
362
is in contrast with the observations from Dalziel and coworkers who suggested that granule particle size
363
is independent of the binder or drug-polymer ratio and that granule size is a function of the processing
364
techniques [44].
365
366
The influence of screw speed on the granule shape was related to the drug-binder miscibility and on
367
the type of binder (Table 4). When the miscibility between binder and API was sparse (caffeine-containing
368
blends), the produced granules became more needle-shaped when operating at slower screw speed. Due to
369
the prolonged residence time of the material inside the barrel, the binder had more time to distribute over
370
the solid particles. Hence, the shear in the mixing zone elongated the granules rather than fragmenting them.
371
This effect was limited for the CAF/PEG blend due to the less viscous and more brittle properties of the
372
PEG binder. When binder and API had a certain miscibility, a slower screw speed generated more spherical
373
granules. Due to the elongated material residence time inside the barrel, more binder-API interaction took
374
place, hindering the binder to distribute restricting elongation [20]. For the MPT/SLP blend, this could
375
only be observed when operating at high powder feed rate as shown in the interaction plot in figure 7. At
376
high screw speed and low powder feed rate, there was insufficient compaction due to the inadequate filling
377
degree of the barrel resulting in more fines and, thus more spherical granules. At superior barrel filling
378
(at higher powder feed rate) more compaction occurred and the influence of screw speed on granule size
379
was more pronounced. When sufficient compaction occurred for the MPT/SLP blend, a lower screw speed
380
generated more spherical granules as was seen for the for the MPT/PEG blend.
381
382
3.4.2. Tablet properties
383
The influence of screw speed on tablet tensile strength was only significant for the miscible blends where
384
accelerating the screws resulted in tablets with a lowered tensile strength (Table 5). However, the granule 19
25
0.75
0.70
15 10
Low screw speed (Fines) High screw speed (Fines) Low screw speed (A50) High screw speed (A50)
0.65
5 0
A50 (-)
Fines (%)
20
0.4
0.5
0.6
0.7
0.8
Powder feed rate (kg/h)
Figure 7: Interaction plot for (dotted lines) fines (%) and (solid lines) A50 (-) between powder feed rate (kg/h) and screw speed (rpm) of the MPT/SLP blend. The squares represent low screw speed, whereas the circles symbol the high screw speed.
385
properties determining the tensile strength (granule size vs granule friability) were different for brittle and
386
amorphous binders. Using an amorphous binder, the granule size is important regarding tablet quality.
387
Larger granules produced tablets with an enhanced tensile strength. For brittle binders, not size but gran-
388
ule friability should be taken into account to obtain tablets having a sufficient tensile strength. Brittle
389
granules can easily break up during compression, enlarging the available bonding surface stimulating tablet
390
tensile strength. Screw speed is only affecting the tablet tensile strength of the MPT-containing blends. In
391
contrast, caffeine-containing blends yielded stronger tablets when using a higher binder content. This will
392
be explained later.
393
394
Tablets obtained after compression of MPT/SLP granules showed a tensile strength which positively
395
correlated with granule size (X50). The R2 counted 0.7 for the MPT/SLP blend in contrast to only 0.07
396
for the MPT/PEG blend. The relationship between granule size and tensile strength was already observed
397
by Sun and coworkers. However, they explained a reduced tabletability as due to granule size enlargement
398
of plastic material [45]. In this research the opposite relation was observed, since larger granules (X50)
399
resulted in tablets with improved tensile strength. In the design of the MPT/SLP blend, larger granules
400
were obtained at parameters causing a high barrel filling. This stimulated binder and drug to interact
401
causing plasticization of the binder. Hence, one may assume that the larger particles were more deformable
402
compared to smaller granules and, hence, causing tablets with enlarged tensile strength. During compaction
403
of deformable granules, more intermolecular bonding sites are formed over an equal contact area compared
404
to less deformable granules [46]. On the other hand, accelerating the screw speed reduced the barrel filling
405
degree, and thus lowered the binder-drug interactions. As a result, the granules were less deformable during
406
compression generating tablets with a weaker tensile strength. (Table 5). 20
407
408
When granules were made using PEG, the tablet tensile strength was not correlated with the granule
409
size. PEG is a semi-crystalline polymer and is very brittle, in contrast to Soluplusr which is amorphous and
410
therefore more deformable. Since the PEG-containing granules broke-up during compression, the granule
411
friability was important for the tablet tensile strength and not the original granule size. During tablet com-
412
pression, the weak granules were fragmented in a large amount of smaller particles, enlarging the available
413
binding area which improved the tablet tensile strength. The R2 between the granule friability and tablet
414
tensile strength counted 0.62 for the MPT/PEG blend. Due to the negligible influence of screw speed on
415
the granule properties of the CAF/PEG blend, screw speed is not influencing its tablet properties (Table
416
5).
417
418
For the MPT/PEG blend, the influence of screw speed can be found in the interaction screw speed-binder
419
concentration. When granulation is executed using a low binder content, a faster screw speed favors granule
420
strength and, hence, tablets with a reduced tensile strength are generated. This is demonstrated in figure 8.
421
When granulation is performed using a high binder concentration, stronger granules are obtained (relative to
422
the granules having a lower binder content) which produced tablets with a lower tensile strength. At higher
423
PEG concentrations, the granule friability was less influenced by screw speed and more by powder feed rate.
424
The relationship between granule friability and tablet tensile strength was also studied by Wu and coworkers
425
and confirmed these findings [47]. These observations allow to reduce the effects of granule size variations
426
on the tablet properties by incorporating an appropriate amount of brittle binder to the formulation.
427
2.4 2.2
30 2.0 1.8
20 100
200
Tensile strength (MPa)
Friability granules (%)
2.6 40
Low binder conc (friability) High binder conc (friability) Low binder conc (TS) High binder conc (TS)
1.6
300
Screw speed (rpm)
Figure 8: Interaction plot for (dotted line) granule friability (%) and (solid line) tablet tensile strength (MPa) between screw speed (rpm) and binder concentration (%) of the MPT/PEG blend. The circle represents low binder concentration, whereas the triangle symbols the high binder concentration.
428
Additionally, screw speed affected the dissolution rate for the granules manufactured using Soluplusr . 21
429
Speeding up the screws, lowered the % drug released after 5 minutes (11.86% for MPT/SLP and 9.40%
430
for CAF/SLP) (Table 5). This can be linked to higher fraction of fines for these blends when operating at
431
high screw speed and low powder feed rate. The fines and oversized granules were excluded before tablet
432
production. If the fines contain mainly API, this can reduce the diffusion gradient and, hence, the % drug
433
released. This was the case, since the maximum drug release never exceeded 90% and 58%, for respectively
434
MPT/SLP and CAF/SLP, at these parameters (Figure 9). The increase in % fines could be attributed to
435
the limited barrel filling degree when operating at high screw speed and low powder feed rate, as afore-
436
mentioned. Furthermore, since Soluplusr needs to soften in order to allow binding, the shorter material
437
residence time inside the barrel (due to the higher screw speed) will have a superior impact on the Soluplusr
438
blends compared to the PEG blends.
439
CAF/SLP
20
80
15
70
10
60
5
% CAF released
90
100
Thr Thr 80 Thr Thr 60 Thr Thr 40
30
low (release 5min) high (release 5min) low (max release) high (max release) low (fines) high (fines)
20
10
% fines
25
% fines
% MPT released
MPT/SLP 100
Thr Thr Thr Thr Thr Thr
low (release 5min) high (release 5min) low (max release) high (max release) low (fines) high (fines)
20 50
200
300
400
0
200
300
400
0
Screw speed (rpm)
Screw speed (rpm)
Figure 9: Interaction plot for drug release after 5min, max drug release (90min) and fraction fines between screw speed (rpm) and powder feed rate (kg/h) of the (left) MPT/SLP and (right) CAF/SLP blend. The dotted lines represent high throughput, whereas the solid lines symbol low throughput.
440
3.5. Influence of temperature
441
3.5.1. Influence on granule properties
442
Temperature had almost no influence on the granule properties of PEG-containing blends. This can be
443
explained by the fact that PEG is a semi-crystalline polymer having a melting point. When the melting
444
point of a crystalline material is reached, the solid state transfers abrupt from the solid to the molten state.
445
The PEG binder was in the molten state in each run since the actual temperature was close to the melting
446
point throughout both designs. Hence, elevating barrel temperature barely affected the binder viscosity and
447
therefore the influence on the granule properties was negligible.
448
449
Soluplusr on the other hand is an amorphous binder, which softens gradually in function of tempera-
450
ture. A large influence of temperature was seen for the CAF/SLP blend. When granulation of this blend 22
451
was performed at elevated barrel temperature, stronger and larger granules with a smaller span distribution
452
were achieved. In contrast, almost no influence of temperature on the granule properties of the MPT/SLP
453
blend could be observed. This can be attributed to the fact that intermolecular interactions did occur be-
454
tween Soluplusr and MPT impeding binder and API to move as two separate phases. As a result, binder
455
distribution became difficult, and more friable granules were generated [20]. When drug-binder interactions
456
were absent (CAF/SLP), binder distribution was dominated by the viscosity of the binder and was not re-
457
stricted by the interactions. Elevating the granulation temperature, lowered the binder viscosity facilitating
458
distribution. In contrast, when intermolecular interactions did occur (MPT/SLP), binder and API could
459
not move independently and were moving rather as one mass, making viscosity of the binder less important
460
for the granule properties [20]. Furthermore, due to the hydrogen bond formation between MPT and SLP,
461
the maximum useable barrel temperature was 70 ◦ C (plasticizing effect), which is lower than the maximum
462
temperature of 130 ◦ C used for the CAF and SLP blend.
463
464
An improved binder distribution induces better overall binding for all particles favoring granule strength
465
and granule growth. A temperature increase from 50 to 130 ◦ C during granulation of the CAF/SLP blend
466
reduced granule friability by 28%. The reason for the better granule strength due to higher granulation
467
temperature can be twofold. On the one hand, the binder distribution is facilitated at higher temperatures
468
(due to lower viscosity) improving coalescence. On the other hand, caffeine anhydrous can turn into the
469
metastable polymorph (Form I) at high granulation temperature. Caffeine Form I is more deformable in
470
comparison with Form II and improved the granulation efficiency and compaction properties [48][31]. There-
471
fore, the polymorph transition into Form I can favor granule strength. This could be observed during DSC
472
analysis which is shown in figure 11. In contrast, temperature stimulated hydrogen bond formation between
473
MPT and SLP, restricting binder distribution and more fragile granules were obtained (Table 4).
474
475
3.5.2. Influence on tablet properties
476
Temperature was barely influencing the measured granule properties of the MPT/SLP blend, but did
477
affect the tablet properties of this blends. Increasing the granulation temperature facilitated the API-binder
478
interactions which improved the deformability of the granules. Earlier research revealed that interaction
479
between MPT and SLP plasticized the binder (lower Tg ) [43]. Furthermore, at low granulation tempera-
480
ture, granule growth occurred through binding several smaller nuclei together. At elevated temperature, the
481
binder molecules bound together forming larger nuclei which have a higher deformability [20]. During tablet 23
482
compression, the better deformability of the granules initiated a higher bonding capacity per unit area of
483
contact and, hence, the tablet tensile strength improved (Table 5).
484
485
Additionally, the enhanced miscibility occurring at higher barrel temperature stimulated the dissolution
486
rate of MPT into the dissolution medium (Table 5). Possible reasons are the enhanced wettability of the
487
drug when interaction occurred with the binder or the improved solubility of drug when it is in the amor-
488
phous state due to interaction [33]. Since temperature had a limited effect on the granule properties of the
489
MPT/PEG blend, the influence of temperature on dissolution rate was also less pronounced for this blend.
490
It has already been reported that hydrogen bonds were formed between MPT and Soluplusr . These were
491
rather limited at low barrel temperature, but highly expressed at elevated barrel temperature [20]. This
492
explains the pronounced effect of temperature (from Temperature (T ) setting −1 to +1) on the release rate
493
of MPT from the Soluplusr binder (9.6%) in comparison with the release from the PEG binder (5.4%).
494
However, the absolute values of the dissolution rate revealed that the release of MPT from the PEG binder
495
was faster in comparison with the Soluplusr binder which was due to the higher hydrophilicity of PEG (see
496
table 3).
497
498
3.6. Influence of Binder concentration
499
3.6.1. Influence on granule properties
500
In general, more binder generated larger and stronger granules (Table 4). A higher binder concentration
501
strengthens bonds between the drug particles as there is more binder available for bonding. Binder con-
502
centration did not affect the granule size of the MPT/SLP blend. The narrow range of the factor binder
503
concentration in the design of MPT/SLP can be a possible explanation. When granulation was performed
504
using PEG as a binder, increasing the binder concentration formed less fines. In contrast, for the Soluplusr
505
binder, the same effect could be obtained by reducing screw speed. The binding capacity of PEG appears
506
to be lower, and therefore, more binder was needed to bind the unagglomerated particles.
507
508
Melt granulation of the caffeine-containing blends using more binder produced more porous granules,
509
regardless which binder was used (Table 4). The reason for this might not be the binder itself but the lower
510
caffeine concentration (due to higher binder concentration). As aforementioned, the crystalline structure
511
of caffeine anhydrous can modify from the commercial Form II into the metastable and more deformable
512
and more compactable Form I due to the shear and heat during continuous twin-screw melt granulation. 24
513
The higher compactability of Form I can cause a higher density (lower porosity) of the granules when more
514
caffeine is used. As a result of improved compactability, also the fraction oversized granules became larger.
515
516
Executing melt granulation using a high binder concentration produced stronger granules (Table 4).
517
This was also observed by Gokhale et al. during high-shear granulation. Since more binder was used, more
518
bridges were formed between particles, resulting in stronger granules. Although the effect was common,
519
the size of the effect differed for each design. An interaction between temperature and binder concentra-
520
tion could be observed for the blends where interaction occurred between binder and API (MPT/SLP and
521
MPT/PEG)(Table 4). In both designs, an elevated temperature at low binder content yielded stronger
522
granules, due to a lower viscosity and subsequent improved binder distribution and bonding. When using
523
more binder, higher temperatures will yield weaker granules. Binder distribution is impeded due to hydrogen
524
bond formation between binder and API causing more fragile granules (Figure 10). However, these effects
525
were rather low.
526
Friability granules (%)
40
Binder Binder Binder Binder
30 20
% % % %
low (MPT/SLP) high (MPT/SLP) low (MPT/PEG) high (MPT/PEG)
10 0
-1
0
1
Granulation T (°C)
Figure 10: Interaction plot for granule friability (%) between binder concentration (%) and granulation temperature ( ◦ C) of blends MPT/SLP (solid lines) and MPT/PEG (dotted lines).
527
3.6.2. Influence on tablet properties
528
Regardless of the binder used during granulation of MPT, including more binder resulted in tablets with
529
a lower dissolution rate. A higher binder content allowed more binding between particles, on the one hand,
530
but caused a reduction in total amount of drug. Hence, a slower release of the drug molecules was achieved
531
(Table 5). This effect was higher for the fast dissolving MPT and is not significant for the poorly soluble
532
caffeine. Furthermore, the higher binder concentration increased the binding capacity and, hence, tablets
533
with a lower friability were obtained.
534
25
2.0 A
142.56°C 14.70J/g 162.76°C B 139.21°C 14.03J/g
Heat Flow (W/g)
147.86°C
C
143.03°C 11.96J/g 162.58°C D
138.58°C 8.924J/g
144.04°C E
0.2 100 Exo Up
150
200
Temperature (°C)
Universal V4.5A TA Instruments
Figure 11: Heat flow curve of (A) pure caffeine and (B) granules of blends CAF/PEG and (C) CAF/SLP prepared at low binder concentration and (D) granules of blends CAF/PEG and (E) CAF/SLP at high binder concentrations showing the transition of the remaining caffeine Form II into caffeine Form I.
535
Including more binder during continuous melt granulation lowered the tensile strength of the MPT/PEG
536
tablets. This is caused by the enhanced granule strength due to the superior binding derived from the higher
537
binder concentration. Stronger granules underwent less brittle fracture during tablet compression and, hence,
538
a weaker tablet strength was obtained. However, the opposite effect on tensile strength could be observed
539
for the caffeine-containing granules due to the higher deformability after polymorphic transition to the more
540
deformable caffeine Form I. From DSC analysis, it could be observed that more caffeine polymorph Form
541
I was formed when more binder was used during melt granulation (Figure 11). For the CAF/SLP blend,
542
no caffeine Form II could be observed after granulation at higher Soluplusr concentrations, whereas still
543
60% caffeine Form II was detected after granulation with high PEG concentrations. Hence, the effect of
544
binder concentration on tablet tensile strength was more expressed for the CAF/SLP blend. Furthermore,
545
since Soluplusr is ductile, increasing the concentration also generates deformable granules which maximizes
546
interparticle bonding per unit of contact area [49].
547
548
4. General conclusion
549
This research revealed that the type of binder, type of API and interactions between both affect the
550
granulation mechanism of the blend during the continuous melt granulation process and, hence, determine 26
551
the relationship between the influencing parameters and the CQAs (See summarizing table 7). Drug-binder
552
miscibility induces plasticizing of the binder which limited the maximum possible granulation temperature.
553
For these blends, granule growth was rather attained by kneading granules together and, thus the extent of
554
barrel filling was highly influencing the granule and tablet properties. Granule growth of immiscible drug-
555
binder blends was acquired after distribution of the binder allowing nuclei to stick together. Since the binder
556
did behave as a separate phase, the granulation temperature could exceed the Tg /Tm of the binder. For these
557
blends, binder concentration was the most influencing factor. Furthermore, these blends contained caffeine
558
anhydrous as a drug, which is able to convert from the commercial Form II into the more deformable Form
559
I, which facilitated granule growth. This conversion was favored at elevated granulation temperature and/or
560
higher binder concentration and was more expressed when Soluplusr was used as a binder. When using
561
an amorphous binder, the tablet tensile strength depended on granule size and deformability. In contrast,
562
granule strength was more important regarding tablet quality when using a brittle binder. However, this
563
was not the case for caffeine-containing blends, since these phenomena were dominated by the enhanced
564
compression properties of caffeine Form I. Therefore, it is important to gain knowledge about the behavior
565
of the blend during processing before the influence of the process parameters onto the granule and tablet
566
properties can be understood.
567
Based on the DOE models, optimal TS HMG parameter settings can be derived in order to obtain
568
granules having required characteristics to produce tablets with desired quality. In general, granules with
569
good flow properties (CI<15) and minimized amount of fines and oversized granules are preferred and tablets
570
should have a tensile strength >2MPa, tablet friability <1% and fast dissolution rate. For blend MPT/PEG,
571
the granule friability should be maximized which can be obtained by restricting the binder concentration.
572
In table 6, examples of such optimal parameter settings are given for the four studied formulations. The
573
calculated optima coincide with the findings of this research project. Table 6: Optimal factor settings for the four experimental designs based on the observations in current research project
MPT/PEG MPT/SLP CAF/PEG CAF/SLP
throughput (kg/h) max. (0.9) max. (0.8) max. (1.1) max. (1.0)
screw speed (rpm) min. (100) min. (200) max. (300) min. (200)
27
temperature ( ◦ C) > Tm < Tg > Tm Tg
% binder min. (5%) 10% (mean) max. (20%) 10% (mean)
574
Acknowledgment
575
Financial support for this research from the Agency for Innovation by Science and Technology (IWT
576
- Ph.D. fellowship Tinne Monteyne) is gratefully acknowledged. BASF is acknowledged for sending large
577
amounts of caffeine and Soluplusr .
578
579
580 581
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31
Table 7: Influence of varying throughput and screw speed on the material residence time in the barrel (RT) and the screw fill (SF) and the influence thereof on the granule size. In general Higher binder concentration → lower granule and tablet friability
Miscibility
Influence of throughput depends on ease of binder distribution (binder distribution is required for coalescence)
Immiscibility
Higher process torque → less fines
High influence of throughput and barrel filling degree (nuclei are kneaded together)
Low screw speed → more needle-shaped granules
High throughput → Higher torque, larger granules, less fines, stronger granules, smaller span, improved flow properties, improved drug binder interaction Low screw speed → more spherical granules
Relative larger granule size (larger binding capacity)
Granulation T can exceed Tg /Tm of the binder
Relative smaller granule size
Low screw speed → less fines
Miscibility limits max. possible granulation T High Temperature → higher dissolution rate
High binder concentration → less fines
Soluplus
No effect of temperature
Effect of temperature depends on miscibility (CAF/SLP: higher T → larger, stronger granules with smaller span distribution (MPT/SLP → limited influence due to improved hydrogen bond formation)
PEG
Higher granule friability stimulates tablet tensile strength
MPT
Polymorphic transition at high binder concentration and/or high granulation T produced more dense granules, larger (more oversized) granules, more deformable granules → higher TS
Caffeine
High Temp → lower dissolution rate
More binder → lower dissolution rate
High screw speed → lower dissolution rate
High screw speed → lower tensile strength
Granule deformability stimulates tablet tensile strength (For caffeine: more binder or more caffeine Form I) (For MPT: more drug binder interaction at high barrel filling degree)
32
Immersion Drug Binder (ini+al step)
0 0
Immiscible drug-binder blend 0 0 0 0 4 Miscible drug-binder blend
S0939-6411(16)30327-7 http://dx.doi.org/10.1016/j.ejpb.2016.07.021 EJPB 12259
To appear in:
European Journal of Pharmaceutics and Biopharmaceutics
Please cite this article as: T. Monteyne, J. Vancoillie, J-P. Remon, C. Vervaet, T. De Beer, Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties, European Journal of Pharmaceutics and Biopharmaceutics (2016), doi: http://dx.doi.org/10.1016/j.ejpb.2016.07.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties Tinne Monteynea,1 , Jochem Vancoilliea , Jean-Paul Remonb , Chris Vervaetb , Thomas De Beera a Laboratory
of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium b Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
Abstract The pharmaceutical industry has a growing interest in alternative manufacturing models allowing automation and continuous production in order to improve process efficiency and reduce costs. Implementing a switch from batch to continuous processing requires fundamental process understanding and the implementation of quality-by-design (QbD) principles. The aim of this study was to examine the relationship between formulation-parameters (type binder, binder concentration, drug-binder miscibility), process-parameters (screw speed, powder feed rate and granulation temperature), granule properties (size, size distribution, shape, friability, true density, flowability) and tablet properties (tensile strength, friability, dissolution rate) of four different drug-binder formulations using Design of experiments (DOE). Two binders (polyethylene glycol (PEG) and Soluplusr ) with a different solid state, semi-crystalline vs amorphous respectively, were combined with two model-drugs, metoprolol tartrate (MPT) and caffeine anhydrous (CAF), both having a contrasting miscibility with the binders. This research revealed that the granule properties of miscible drug-binder systems depended on the powder feed rate and barrel filling degree of the granulator whereas the granule properties of immiscible systems were mainly influenced by binder concentration. Using an amorphous binder, the tablet tensile strength depended on the granule size. In contrast, granule friability was more important for tablet quality using a brittle binder. However, this was not the case for caffeinecontaining blends, since these phenomena were dominated by the enhanced compression properties of caffeine Form I, which was formed during granulation. Hence, it is important to gain knowledge about formulation behavior during processing since this influences the effect of process parameters onto the granule and tablet properties. Keywords: Continuous hot melt granulation (HMG), granule and tablet properties, DOE, solid state binder, drug binder interaction
Preprint submitted to x
July 19, 2016
1
1. Introduction
2
Granulation is an important process step to improve processability, flowability, compactability and con-
3
tent uniformity of the raw materials to be formulated into a final solid dosage form (e.g., tablets). This
4
particle size enlargement process is often done via wet granulation using a solvent (mostly water) to initiate
5
binding between powder particles, followed by a drying step. However, some pharmaceutical actives are not
6
suitable for wet processing and drying because of stability and degradation problems. In this case, HMG
7
or thermoplastic granulation is a valuable alternative to overcome that problem [1][2]. HMG uses a molten
8
binder instead of a granulation liquid to agglomerate the pharmaceutical powder particles and, hence, no
9
drying step is needed, reducing process time and energy consumption.
10
11
The pharmaceutical industry has traditionally relied on batch processing to manufacture their drug
12
products. However, to improve process efficiency and reduce manufacturing costs, there is a growing inter-
13
est in alternative manufacturing models which allow automation and continuous production. Continuous
14
manufacturing processes are based on the one-in-one-out principle, avoid scale-up issues, ensure faster prod-
15
uct release, reduce production time/costs, reduce variability, increase flexibility and efficiency, and might
16
improve product quality [3][4]. Twin-screw wet granulation has already been examined extensively as con-
17
tinuous granulation technology, allowing fully continuous from-powder-to-tablet-manufacturing [5][6][7][8].
18
However, the research of twin-screw hot melt granulation is still in its infancy.
19
20
Implementing a switch from batch to continuous processing could be perceived as a challenge since this
21
requires fundamental process understanding. The Food and Drug Administration (FDA) published the pro-
22
cess analytical technology (PAT) and QbD concept in the 2004 guidance which were more broadly described
23
in the ICH guidelines Q8, Q9, and Q10 [9][10][11]. The initiative emphasizes the need to understand all
24
critical sources of variability (i.e. critical quality attributes (CQAs), critical material attributes (CMAs) and
25
critical process parameters (CPPs)) affecting a pharmaceutical process to ensure that drug products with
26
predefined quality attributes are consistently obtained. The implementation of QbD principles ultimately
27
aims at designing and developing formulations and processes to build quality into the end product (instead ∗ Corresponding
author Email addresses: [email protected] (Tinne Monteyne ), [email protected] (Jochem Vancoillie), [email protected] (Jean-Paul Remon), [email protected] (Chris Vervaet), [email protected] (Thomas De Beer) 1 Phone number: +32(0)9 264 80 68 2 Fax number: +32(0)9 264 82 36
2
28
of testing quality of the end product). Furthermore, this will enable stable operation, help to support feed-
29
back/feed forward controls, and resulting in fewer compliance problems since a manufacturer anticipates
30
these issues and addresses them more systematically if they occur [12].
31
32
The critical sources of variability are still not fully understood for the continuous melt granulation pro-
33
cess. It is known that the melt granule properties depend on the combination of several process and material
34
parameters and can affect subsequent processing steps, such as milling and tableting. For example, changes
35
in screw speed and configuration (number and location of transport and kneading elements), powder feed
36
rate, temperature, and formulation (type binder, concentration binder, drug-binder interaction) can induce
37
changes in granulation mechanism yielding different granule characteristics which will alter the tablet proper-
38
ties. Ultimately, this can affect the drug dissolution profiles and therefore the bioavailability of the final drug
39
product in a patient [13][14]. This emphasizes the need to define influencing parameters such as CMAs and
40
CPPs on CQAs and can be derived using an experimental design, which after optimization assists in creating
41
a design space for the product [15][16]. However, this has proven to be challenging due to the complex rela-
42
tionships between the granule properties (size, size distribution, shape, solid state, granule friability/strength
43
etc.), and the properties of the final product (tablet tensile strength, tablet friability, dissolution rate) [17][7].
44
45
Literature demonstrated that both the interaction between the initial materials and the type of meltable
46
binder (hydrophilic, hydrophobic, (semi)-crystalline, amorphous) used during the melt granulation process
47
are determining factors for the granulation mechanism [18][19]. Hence, these might have an impact on the
48
process and the final product quality [20]. The aim of this study was to examine the relationship between
49
the formulation parameters (type binder, binder concentration, drug-binder interaction), process-parameters
50
(screw speed, powder feed rate and temperature), granule properties (size, size distribution, shape, friabil-
51
ity, true density, flowability) and tablet properties (tensile strength, friability, dissolution) of four different
52
drug-binder formulations by using DOE. Two binders (PEG4000 and Soluplusr ) with a different solid state
53
(semi-crystalline vs. amorphous) were combined with two model-drugs, MPT and CAF, both having another
54
miscibility with both binders. Four screening DOEs were performed to enhance process understanding and
55
to define the critical material attributes and potential critical process parameters that impact intermediate
56
and final product quality attributes.
57
3
58
2. Materials and methods
59
2.1. Materials
60
PEG and Soluplusr (SLP) were used as hydrophilic meltable binders to develop immediate release for-
61
mulations. PEG4000 (BUFA, Uitgeest, Holland) is a semi-crystalline polymer with a melting temperature
62
(Tm ) of 53 ◦ C. Soluplusr (BASF, Ludwigshafen, Germany) is an amorphous polymer with a glass transi-
63
tion temperature (Tg ) of 70 ◦ C. The binders were used to agglomerate two model drugs, being MPT and
64
caffeine anhydrous. MPT (UTAG, Almere, The Netherlands)(Tm =120 ◦ C) was used as miscible model drug
65
in both binders. MPT has a solubility of 0.53 g per gram PEG4000 whereas it has a solubility of 0.72 g per
66
gram Soluplusr . MPT is a micronized powder having a particle size below 10 µm (X10=1 µm, X50=2.2 µm,
67
X90=7 µm). Caffeine anhydrous (BASF, Ludwigshafen, Germany)(Tm =236 ◦ C), on the other hand, was
68
used as a non-miscible model drug in both binders. CAF is insoluble in PEG4000 whereas it has a solubility
69
of 0.03 g per gram Soluplusr . The solubility parameters of both drugs were obtained from BASF and were
70
based on the Hansen solubility parameter and the Flory-Huggins solubility parameter estimation [21]. Caf-
71
feine has a particle size distribution below 150 µm (X10=1.4 µm, X50=11.1 µm, X90=106.6 µm) and appears
72
in two polymorphs, namely Form I and Form II, the latter being the commercially available polymorph [22].
73
Four different formulations were made: MPT/PEG, MPT/SLP, CAF/PEG, and CAF/SLP. Aerosilr 200
74
(Evonik Degussa Corp., Essen, Germany) was added to the initial powder blend (0.2% (w/w)) to increase
75
the flow properties and hence supporting the feeding into the twin-screw granulator. Before tablet compres-
76
sion, the granules in the size range 150-1400 µm were isolated and both magnesium stearate (0.5% (w/w))
77
and Explotabr (5% (w/w)) were added.
78
79
2.2. Continuous hot melt granulation
80
Melt granulation was performed using a co-rotating intermeshing twin-screw granulator (Prism Eurolab
81
16) (Thermofischer Scientific, Karlsruhe, Germany) with a barrel length of 25 L/D, where L is the axial
82
screw length of the machine and D is the inner bore diameter. The screw design was identical for all
83
experiments containing one kneading zone located in the fifth segment and consisting of 6 kneading discs
84
positioned at a 60 ◦ stagger angle in reversed direction. At the end of the screws, a screw mixing element
85
was placed in order to break up large lumps [23]. The premixed samples were fed into the granulator using
86
a DD Flexwallr 18 gravimetric feeder (Brabender Technologie, Germany), which was set in the gravimetric
87
feeding mode. The barrel was divided into 6 barrel zones. Barrel temperature from segment 2 to 5 was 4
88
varied according to the design. Segment 6, which is located at the end of the barrel, had a lower temperature
89
of 40 ◦ C during all runs in order to cool down the granules and hence avoiding them to stick together when
90
leaving the granulator. Granule samples were collected after melt granulation of each run. The sample
91
collection was started after 15 minutes, which is the time needed to reach a steady state process and a stable
92
torque and barrel wall temperature which were unstable at the beginning of each process due to layering of
93
the screws and the screw chamber walls with material. Sample collection was executed until 150 g sample
94
was collected. Afterwards, samples were stored at room temperature. The granulator was equipped with
95
a data logging system allowing monitoring of the screw torque and actual barrel wall temperature during
96
granulation. The torque (expressed as a percentage, which reflects on the fraction of the maximum torque
97
(12 Nm) that can be generated by the screw motor to rotate the screws) was recorded directly from the
98
twin-screw granulator panel every 30 s. The torque at steady state was averaged to give a single value.
99
2.2.1. Differential scanning calorimetry
100
Differential scanning calorimetry (DSC) was used to measure the melt enthalpy of the pure components,
101
physical mixtures and the corresponding granule samples obtained after melt granulation of the caffeine-
102
containing blends. The data were used to determine the remaining amount of caffeine polymorphic Form II
103
after melt granulation according the equation described by Hubert [24]:
% of caffeine Form II = 104
∆trans Hm(II→I) .100 ∆trans Hm(II→I) of pure Form II
(1)
where ∆trans Hm(II→I) is the enthalpy of transition of the sample.
105
106
A DSC Q2000 calorimeter (TA Instruments, Zellik, Belgium) was used. Samples were hermetically sealed
107
in aluminium pans and a heating rate of 10 ◦ C/min was applied. Analysis was performed in triplicate.
108
2.3. Design of experiments
109
Preliminary experiments were carried out for each formulation to determine the experimental ranges for
110
the DOE factors throughput, screw speed, temperature and binder concentration. The extreme parameter
111
settings where only powder was produced or where an excessive amount of lumps were created after twin-
112
screw hot melt granulation (TS HMG), were eliminated. Four two-level full factorial screening designs (24 )
113
were created (one for each formulation) and executed in order to evaluate the influence of the tested parame-
114
ters on granule and tablet properties. Four factors (powder feed rate, screw speed, binder concentration and 5
115
temperature) were used in each design. Three center points were executed to evaluate the reproducibility.
116
The different factor settings for each design are listed in table 1. The responses were regressed against the
117
factors via multiple linear regression (MLR) (using MODDE 10.0 software by Umetrics, Umea, Sweden). Table 1: Factor settings of the four experimental designs
Settings MPT/PEG MPT/SLP CAF/PEG CAF/SLP
throughput (kg/h) −1 0 +1 0.35 0.625 0.9 0.4 0.6 0.8 0.5 0.8 1.1 0.4 0.7 1
screw −1 100 200 150 200
speed (rpm) 0 +1 225 350 312.5 425 225 300 312.5 425
temperature −1 0 30 44 30 50 55 67.5 50 90
( ◦ C) +1 58 70 80 130
−1 5 5 7.5 5
% binder 0 +1 12.5 20 10 15 15 22.5 12.5 20
118
The influence of the factors is measured on both granule properties (granule friability, true density,
119
compressability index, size (fines, yield, oversized, X50), shape (A50), and span distribution) process torque,
120
and tablet properties (tensile strength, tablet friability, and dissolution rate in 5 minutes).
121
2.3.1. Effect and interactions of factors
122
For each design, the effects were calculated representing the response deviation when a factor is varied
123
from its low level (-1) to its high level (+1) keeping the other factors at their center points. The effects
124
were calculated with their respective 95% confidence interval. Insignificant effects are those where their
125
confidence intervals includes zero. Interaction plots has been calculated to study the predicted change in
126
the response when one factor varies, while a second factor is set at both its low (-1) and high (+1) level,
127
while all other factors being set at their center point.
128
2.4. Granule size distribution and granule shape
129
Size and shape of the final granules were determined (n=3) using an off-line image analysis tool (QicPic,
130
Sympatec, Germany). This high speed imaging tool is based on shadow projection and exists of a VIBRI
131
vibrational conveyor, which is a controlled feeding system, allowing the granules to fall through a shaft where
132
the granules are accelerated and finally pass a laser beam and camera, which records images of shadows of
133
the granules. In this configuration, the system is capable of capturing particles in the range of 10 µm to
134
10.2 mm. Size analysis was based on the equivalent projection of a circle (EQPC). The entire size distri-
135
bution was studied where the size values were classified into 39 classes between 0 and 3400 µm and 1 class
136
>3400 µm. The X10, X50 and X90 values represent the particle size at respectively, 10, 50, and 90% of
137
the cumulative distribution. The X50 values were used as a response in the designs to show the influence
138
of the factors on the granule size. The granule shape was represented by evaluating the aspect ratio which 6
139
measures the elongation of the granule. It is the ratio of the length of the minor and the major diameter of
140
the granule. The granule shape is expressed as A50, representing the aspect ratio at 50% of the cumulative
141
distribution. The width of the size distribution was incorporated as a response in the designs using the span
142
values ((X90-X10)/X50).
143
144
2.5. Granule density
145
The true density (TD) (g/m3 ) of the granules was determined (n=3) using an AccuPyc 1330 helium
146
pycnometer (Micromeritics Instruments Inc, Norcross, United States). A precisely measured amount of
147
sample was placed in the test cell, filling at least 65% of the cell. The pycnometer determined the volume
148
occupied by the sample via pressure changes.
149
2.6. Granule flow properties
150
The compressibility index (CI) describes the powder flow characteristics and can be determined by
151
measuring the bulk and tapped volume of the sample (n=3). The bulk volume (V0 ) of 30 g granules was
152
recorded in a 100 ml measuring cylinder, as well as the volume after 10 (V10 ), 500 (V500 ) and 1250 (V1250 )
153
taps in a tapping machine (J. Englesman, Ludwigshafen, Germany). If the difference between V500 and
154
V1250 was larger than 2 ml, the powder was subjected to another 1250 taps (V2500 ). The compressibility
155
index (%) was calculated from the bulk and tapped density using the following equation:
CI = ((ρi − ρf )/ρi )100 156
157
(2)
where ρi is the bulk density and ρf is the tapped density. 2.7. Friability of granules
158
The granule friability was determined (n=3) using a friabilator (PTF E Pharma Test, Hainburg, Ger-
159
many) at a speed of 25 rpm for 10 min, by subjecting 10 g of granules (Iwt ) together with 200 glass beads
160
(mean diameter of 4 mm) to falling shocks. Prior to determination, the granule fraction <250 µm was re-
161
moved to assure the same starting conditions for all evaluated granules. Afterwards, the glass beads were
162
removed and the weight (g) retained on a 250 µm sieve (Fwt ) was determined. The friability (%) was then
163
calculated as:
F riability = ((Iwt − Fwt )/Iwt )100 7
(3)
164
2.8. Tablet production
165
The granule fraction between 150 and 1400 µm was blended with 0.5% (w/w) magnesium stearate and
166
5% Explotabr in a tumbling mixer (W.A. Bachshofen, Basel, Switzerland). The tablets (115±5 mg) were
167
produced automatically using an eccentric tablet press (Korsch EKO, Berlin, Germany) equipped with a
168
concave punch of 7 mm diameter. The displacement of the upper punch into the die was controlled, resulting
169
in a compression force of 14.7 kN per tablet.
170
2.9. Tablet evaluation
171
The tablet friability was determined (n=3) by subjecting 20 dust free tablets (weight=Iwt ) to falling
172
shocks in a drum rotating at 25 rpm for 4 minutes. The tablets were dedusted and weighed (Fwt ). The per-
173
centage weight loss calculated with equation 3 is expressed as tablet friability and ideally does not exceed
174
1.0%.
175
176
177
The hardness, thickness and diameter of tablets (n=10) were determined (Sotax HT 10, Basel, Switzerland). The tablet tensile strength (TS) (Pa) was calculated using the equation [25]:
T S = 2F/π.dt 178
179
(4)
where F, d and t denote the diametrical crushing force or hardness, the tablet diameter and the tablet thickness, respectively.
180
181
Dissolution tests were performed (n=3) in 900 ml demineralised water using the paddle method (VK
182
7010, Vankel, Cary, NC, USA). The temperature of the dissolution medium was maintained at 37±0.5 ◦ C,
183
while the rotation speed was set at 100 rpm. 5 ml samples were withdrawn at 5, 10, 15, 20, 30, 45, 60, and
184
90 min after starting the dissolution. The drug content was determined at 222 nm for MPT and 273 nm for
185
CAF using an UV-1650PC double beam spectrophotometer (Shimadzu Benelux, Antwerp, Belgium).
186
187
3. Results
188
3.1. Factor ranges
189
The results revealed that the required granulation temperature range was shifted to lower temperatures
190
when the binder and active pharmaceutical ingredient (API) were miscible. This can be related to the 8
191
plasticizing effect of the drug on the binder lowering the temperature at which deformability is initiated.
192
Furthermore, an improved blend deformability during processing enlarged the bonding or contact area of
193
the nuclei when colliding, resulting in plastic deformation which resisted the breakup forces [26][27]. Hence,
194
deformability stimulated granule growth and as a result, the maximum process temperature was lower to
195
avoid overgranulation. On the other hand, when binder and API were immiscible, the maximum granulation
196
temperature exceeded the Tm or Tg of the binder as there was no plasticizing effect of the drug on the binder
197
which resulted in low-deformable granules. In this situation, granule coalescence could only occur if there
198
was a binder layer established at the surface of the particles or granules to bind them [27]. Hence, higher
199
temperatures were required to initiate binder distribution and large lumps were only formed at elevated
200
process temperature.
201
202
3.2. Responses
203
3.2.1. Granule properties
204
The comparison of the granule properties obtained after executing the four designs revealed differences
205
caused by the type of binder, type of API and extent of drug-binder miscibility. The SLP granules were
206
larger compared to the particle size of the PEG granules (table 2). PEG is a semi-crystalline polymer
207
having more elastic properties which can result in more brittle agglomerates compared to SLP, which is an
208
amorphous binder. These brittle agglomerates were not able to withstand the impact of the screw mixing
209
elements at the end of the barrel. The temperature in the last barrel segment was lowered allowing granules
210
already to solidify. Hence, the brittle granules break up more easily resulting into smaller granules. The
211
amorphous binder SLP, on the other hand, produced larger granules, even though when a lower % of binder
212
was used. This implies a larger binding capacity of SLP compared to PEG [28].
213
214
Besides this, the maximum size of the caffeine granules was larger than the size of the granules made
215
with MPT. Several explanations can be found. On the one hand, this might be due to the deviating initial
216
particle size of both APIs. The primary particle size of caffeine reached to 106 µm whereas MPT had an
217
initial size less than 10 microns. Smaller starting material results in smaller particles of the end product
218
as also reported by El Hagrasy and coworkers [29][30]. On the other hand, this might be due to the poly-
219
morph transition from the commercial available caffeine Form II to the metastable Form I, which can occur
220
during twin-screw melt granulation [31]. The metastable Form I has a higher deformability and improved
221
compaction properties favoring the compaction behavior during processing and, hence, stimulating granule 9
Table 2: Absolute values of min, mean and max particle size ( µm), true density (g/m3 ) and granule friability (%) in the four designs
Property Size (X50)
True density
Friability
Value Min. Mean Max. Min. Mean Max. Min. Mean Max.
MPT/PEG 282 675 956 1.213 1.217 1.222 15.6 29.7 43.3
MPT/SLP 363 1137 1700 1.170 1.193 1.214 5.1 13.3 31.6
CAF/PEG/ 478 832 1464 1.399 1.422 1.451 13.1 25.8 43.3
CAF/SLP 299 1092 2128 1.382 1.417 1.458 4.0 34.5 90.7
222
growth. The polymorphic transition to caffeine Form I could also be observed in this research and was more
223
expressed at higher binder concentrations (See below in Figure 11). Furthermore, the conversion was more
224
expressed when Soluplusr was used as a binder. Besides the initial drug particle size and the polymorphic
225
transition, also the granulation mechanism can attribute to the difference in granule size of the caffeine-
226
containing blends in comparison with the MPT-containing blends. During granulation of an immiscible
227
drug-binder blend, the binder behaves as a separate phase which distributes over the drug particles when
228
softened/molten [32]. This distinct binder distribution results in successful coalescence and hence to large
229
granules. Note that process parameters inducing a good binder distribution are necessary to reach successful
230
coalescence. In contrast, interaction (hydrogen bond formation) between drug and binder was discovered
231
during granulation of a miscible drug-binder formulation (MPT/SLP) which impeded proper binder distri-
232
bution making coalescence less evident [20]. In figure 1, a visualization of the granulation mechanism is
233
given based on the observations in previous work.
234
Immersion Drug Binder (ini+al step)
Immiscible drug-binder blend
0 0
0 0 0 0 4 Miscible drug-binder blend
Figure 1: Visualization of granule growth mechanism for a miscible and immiscible binder formulation during twinscrew hot melt granulation.
10
235
The true density measurements (Table 2) revealed that the caffeine-containing granules were more dense
236
(1.4) compared to MPT-containing agglomerates (1.2). Table 4 demonstrates that the granule density was
237
negatively influenced by binder concentration in the two caffeine-containing blends. Therefore, there can be
238
assumed that the higher true density is attributed to the different material properties of caffeine compared
239
to MPT. Furthermore, the conversion of caffeine anhydrous into the more deformable and compactable
240
Form I during granulation could have increased the true density of the granules (Figure 11). On the other
241
hand, it has already been demonstrated that drug-binder miscibility produced more porous granules [33].
242
PEG-containing granules were more fragile which can be related to the brittle properties of the binder. If
243
PEG was used as a binder, the friability was in all cases above 13.1% (CAF/PEG) or 15.6% (MPT/PEG)
244
compared to 4% for CAF/SLP and 5.1% for MPT/SLP. It has to be highlighted that a high temperature
245
or shear was required in order to induce granule growth of the CAF/SLP blend [32]. If not, a high fraction
246
of fines and high friability values were obtained which can be seen in table 2.
247
248
3.2.2. Tablet properties
249
The tablet properties revealed that tablets made with Soluplusr have the highest maximum tablet tensile
250
strength, with values of 3.73 MPa for CAF/SLP and 3.33 MPa for MPT/SLP. In comparison, CAF/PEG
251
and MPT/PEG have a maximum tablet tensile strength of 2.44 and 2.66 MPa, respectively. The more
252
ductile behavior of Soluplusr allowed plastic deformation of the granules during tableting, yielding stronger
253
tablets [34]. Besides tensile strength, also dissolution rate is different for both binders. When the API
254
is granulated at the same granulation conditions with both PEG and Soluplusr , the dissolution rate will
255
be 10% faster after granulation with PEG (for both MPT and CAF). Furthermore, when PEG is used to
256
agglomerate caffeine, the entire drug content is dissolved in 30 minutes, whereas only 70% caffeine is released
257
from Soluplusr mixtures. Earlier research on melt granulation already showed PEG to be a suitable binder
258
to enhance the dissolution rate of poorly water-soluble drugs [35][36]. The higher hydrophilicity of PEG
259
might be a possible explanation.
260
261
262
A list of significant effects of the factors and their interactions is given in tables 4 (granule properties) and 5 (tablet properties).
11
Table 3: Absolute values of min, mean and max tensile strength (MPa) and amount API (%) released in 5 minutes for the four designs
Property Tensile strength
API (%) released in 5 min
263
3.3. Influence of powder feed rate
264
3.3.1. Granule properties
Value Minimum Mean Maximum Minimum Mean Maximum
MPT/PEG 1.18 1.93 2.66 61.4 72.4 84.2
MPT/SLP 1.41 2.59 3.33 33.3 63.2 78.9
CAF/PEG 1.19 2.15 2.44 17.3 27.7 52.7
CAF/SLP 1.11 2.02 3.73 8.3 18.3 28.5
265
The influence of powder feed rate on the granule properties depended on the API. In general, throughput
266
had a large influence on the MPT-containing granules, whereas it had a minor effect on the caffeine-containing
267
granules (Table 4). Powder feed rate had even no influence on the granule properties of the CAF/SLP blend.
268
This is in accordance with the miscibility parameters of the APIs with the polymers, except for CAF/PEG.
269
It has to be highlighted that every run in the design of CAF/PEG was performed using a barrel temperature
270
exceeding the melting temperature of PEG and hence it can be stated that PEG was molten throughout
271
the whole design. Therefore, it is obvious that the enhanced compressive forces obtained at high powder
272
feed rate affected the granulation process of CAF/PEG, regardless the miscibility of both materials. The
273
importance of powder feed rate for the granulation properties of miscible systems could be found in the
274
specific granulation mechanism. In miscible drug-binder formulations, granule growth occurs when nuclei
275
deform after they collided. The nuclei are rather ‘kneaded’ instead of sticking together as was seen for
276
immiscible binder blends (Figure 1).
277
278
Performing granulation with a higher throughput resulted in larger and stronger granules with improved
279
flow properties. These effects were negligible for the CAF/SLP blend and less pronounced for CAF/PEG
280
blend (Table 4). These observations might be attributed to the higher screw fill in the barrel appearing
281
at increasing powder feed rate and constant screw speed. The degree of channel fill refers to the volume
282
occupied by the powder blend with respect to the total available volume in the conveying zones of the screw.
283
A higher powder feed rate induces superior screw filling, generating a high throughput force which conveys
284
the powder more quickly through the barrel [37][38]. As a result, the residence time of the material inside
285
the barrel is shortened, but the material packing and compressive forces in the material between the screws
286
is enhanced. The latter induce more interactions between the powder particles or the yet developed gran12
13
T*%bi
Scr*T
Scr*%bi
Thr*T
Thr*%bi
Thr*Scr
Temperature
Binder %
Screw speed
Throughput
Factor
Friability
-5.09 (±3.84) -8.08 (±3.47) -7.6 (±4.39) 24.15 (±18.5) -15.87 (±3.84) -5.07 (±3.47) -15.90(±4.39) -39.46 (±18.5) 4.3 (±3.47) -28.15 (18.5) -9.28 (±3.47) 5.13 (±4.39) 3.47 (±3.47) 5.07 (±3.84) -5.4 (±3.47) -6.69 (±4.39) 6.68 (±3.47) 6.79 (±3.84) 7.90 (±3.47) -
Design
MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP
-0.0175 (±0.01) -0.042 (±0.0043) -0.056 (±0.006) -
Density -3.61 (±2.85) -6.7 (±5.38) 8.70 (±6.40) -3.68 (±2.85) -5.91 (±5.38) -5.35 (±2.92) 2.95 (±2.92) -7.30 (±6.40)
Comp. index -5.59 (±2.2) -9.75 (±4.34) 9.76 (±4.34) 17.25 (±12.5) -10.17 (±2.2) -8.99 (±6.33) -16.51 (±12.50) -2.89 (±2.2) -9.97 (±4.34) 4.11 (±2.2) -
Fines 5.63 (±4.05) -15.12 (±6.85) -7.56 (±5.11) 13.75 (±5.11) 17.51 (±4.05) 4.45 (±4.05) -15.64 (±6.85) -
24.86 (±10.23) 11.6 (±10.7) -13.95 (±10.23) -16.70 (±10.7) 12.09 (±10.7) 32.07 (±17.40) 10.94 (±10.35) 25.61 (±10.23) -
Granule properties Yield Oversized 276.97 (±146.43) 578.92 (±228.77) 270.1 (±226.96) -256.96 (±228.77) -257.71 (±226.96) 348.299 (±226.96) 627.57 (±575) 630.117 (±575) 577.58 (±228.77) -
X50
-0.0422 (±0.022) -0.017 (±0.0127) 0.026 (±0.022) 0.0275 (±0.018) 0.045 (±0.043) -0.0175 (±0.0127) -0.054 (±0.022) 0.015 (±0.0127) -
A50
Table 4: List of significant effects of the factors and their interactions on granule properties of the four designs: granule friability (%), true density (g/m3 ), compressability index (CI)(%), fines (%), yield (%), oversized (%), X50 (µm), A50 (-) and SPAN (-). SPAN -0.44 (±0.39) -0.28 (±0.19) 0.20 (±0.19) -0.51 (±0.39) -2.54 (±0.92) -0.34 (±0.19) -1.14 (±0.92) -
Table 5: List of significant effects of the factors and their interactions on process and tablet properties of the four designs: torque (%), tensile strength (MPa), tablet friability (%) and % drug released after 5 minutes.
Factor Throughput
Screw speed
Binder %
Temperature
Thr*Scr
Thr*%bi
Thr*T
Scr*%bi
Scr*T
T*%bi
Design
Process property Torque
Tensile strength
MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP MPT-PEG MPT-SLP CAF-PEG CAF-SLP
9.06 (±2.05) 4.375 (±2.41) -14.19 (±2.05) -10.125 (±2.41) -22.29 (±7.73) 10.29 (±7.73) -3.062 (±2.05) -4.06 (±2.05) 2.88 (±2.41) -2.06 (±2.05) -
0.58 (±0.36) -0.483 (±0.24) -0.56 (±0.36) -0.51 (±0.24) 0.4 (±0.20) 0.93 (±0.74) -0.36 (±0.24) 0.5 (±0.36) -0.27 (±0.24) 0.39 (±0.36) -0.36 (±0.24) 0.536 (±0.24) 0.83 (±0.74) 0.78 (±0.74)
14
Tablet properties Friability -3.24 (±2.61) -1.0 (±0.84) -2.16 (±1.4) -4.79 (±2.61) -1.41 (±1.4) -0.89 (±0.84) 3.36 (±2.61) -
Release -11.86 (±8.29) -9.40 (±3.96) -11.7 (±3.73) -20.37 (±8.29) 5.44 (±3.73) 9.6 (±8.29) 10.75 (±8.29) -
287
ules and the ungranulated powder, causing the powder to efficiently attach on the surface of the granules
288
or around each other which stimulates granule growth. The higher the powder feed rate, the better the
289
interlocking of the primary particles onto the structure of the granules, the stronger the granules become.
290
As a consequence, lower friability rates were obtained when a high powder feed rate was used (Table 4).
291
Furthermore, it is evidenced that the high material packing facilitated interaction between drug and binder
292
explaining the higher influence of throughput on the granule properties for blends having the possibility of
293
interacting (MPT/PEG and MPT/SLP) [39]. Additionally, the superior screw filling reduced the amount of
294
fines since binding of ungranulated powder particles took place at enhanced compression forces [38]. These
295
outcomes were similar to these obtained in continuous wet granulation [40][41].
296
297
The flow properties of the granules obtained from the miscible blends depended on the amount of fines
298
and the span distribution and therefore they are influenced by powder feed rate (Figure 2). The granules
299
have an improved flowability when the amount of fines is sparse, or/and when the span distribution is narrow
300
which is achieved at elevated powder feed rate. However, the throughput can not be too high in order to
301
limit the amount of oversized granules[42].
302
4
20
3
10
1.5
0
1
-10
0
Y=1.3088x-8.066 R2= 0.55349
10
15
20
25
20
2
Compressability index (%)
10 Y=0.600x-10.02 R2= 0.70549
10
15
20
25
SPAN Fines Fines (%)
2.0
1.0
30
SPAN Y=0.0365x+1.3033 Fines R2= 0.65576 Fines (%)
SPAN (-)
2.5
30 Y=5.79x+0.2055 R2= 0.3934
SPAN (-)
3.0
0
Compressability index (%)
Figure 2: Correlation plots for MPT/SLP (left) and MPT/PEG (right) between compressability index (%) and span distribution (◦) and between compressability index (%) and fines (%)(N).
303
3.3.2. Tablet properties
304
The powder feed rate had almost no influence on the tablet properties of the caffeine-containing gran-
305
ules, which is in accordance with its effect on the granule properties (Table 5). MPT/SLP tablets had a
306
sufficient strength with a friability lower than 1% in all cases. For MPT/PEG containing tablets, on the
307
other hand, capping was observed at parameter settings where adhesion was impeded and is demonstrated
308
in figure 3. When the binder concentration or granulation temperature were low, an increase in powder feed 15
4
Temp high Temp low
3
Tablet friability (%)
Tablet friability (%)
4
2 1 0 0.3
0.6
Binder % high Binder % low
3 2 1 0 0.3
0.9
Powder feed rate (kg/h)
0.6
0.9
Powder feed rate (kg/h)
Figure 3: Interaction plot for tablet friability between (left) powder feed rate and granulation temperature and (right) powder feed rate and binder concentration of the MPT/PEG blend.
309
rate affected tablet friability. Increasing the powder feed rate shortened the material residence time inside
310
the barrel which impeded the binder to melt and, hence, to distribute/bind drug particles. Compressing
311
these granules into tablets led to capping of the tablets [43]. If the binder concentration and/or process
312
temperature was higher, the binding capacity was better making the material residence time inside the
313
granulator or the material throughput less important since under these conditions, tablet friability values
314
remained constant below 0.5% and a good tablet strength was obtained.
315
316
3.4. Influence of screw speed
317
3.4.1. Granule properties
318
Screw speed was influencing the granule size and shape in all four designs. Additionally, there was an
319
interaction between the effects of screw speed and powder feed rate. This interaction is attributed to the
320
extent of screw fill which is correlated to torque. An accelerated screw speed diminished the barrel filling
321
degree and resulted in lower torque values. This interaction was observed for the miscible formulations and is
322
linked to the specific granulation mechanism for miscible formulations as described above (Table 4)(Figure
323
1). Granule growth occurred by kneading nuclei together and therefore, a high barrel filling degree was
324
required. In any case, a correlation between the torque level and amount of fines was observed where higher
325
torque values generated granules containing less fines (Figure 4). The superior channel filling at low screw
326
speed caused adherence of the not-agglomerated powder to the surface of the already formed granules and
327
to each other [38]. As a result, the amount of fines was reduced.
328
329
Furthermore, screw speed affected the granule size distribution of the miscible drug-binder blends, but
330
the effect depended on the powder feed rate. When the powder feed rate was low (−1), a slower screw speed 16
25
Scr.sp. high (CAF/SLP)
Scr.sp. high (CAF/PEG) 20
30
Fines (%)
Torque (%)
40
20 10
Scr.sp. low (CAF/SLP) 15 Scr.sp. low (CAF/PEG)
high (CAF/SLP) high (CAF/PEG) low (CAF/SLP) low (CAF/PEG)
Scr.sp. Scr.sp. Scr.sp. Scr.sp.
high (MPT/SLP) high (MPT/PEG) low (MPT/SLP) low (MPT/PEG)
10 5 0
0 -1
0
-1
+1
0
+1
Powder feed rate (kg/h)
Powder feed rate (kg/h) 40
25
Scr.sp. high (MPT/SLP)
Scr.sp. high (MPT/PEG) 20
30
Fines (%)
Torque (%)
Scr.sp. Scr.sp. Scr.sp. Scr.sp.
20 10
Scr.sp. low (MPT/SLP) 15 Scr.sp. low (MPT/PEG) 10 5
0
0 -1
0
+1
-1
0
Powder feed rate (kg/h)
+1
Powder feed rate (kg/h)
Figure 4: Interaction plot for (left) torque (%) and (right) fines (%) between powder feed rate (kg/h) and screw speed (rpm) of (up) CAF/SLP and CAF/PEG and (low) MPT/SLP and MPT/PEG blends. Soluplusr is shown by the dotted and PEG by the solid lines. (•) and (◦) represent high screw speed, whereas () and () symbol the low screw speed. CAF/SLP
CAF/PEG 50
30
Thr (-1) scr (-1) 40 (+1) scr (-1) Thr Thr (-1) scr (+1) 30 Thr (+1) scr (+1)
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
Thr Thr Thr Thr
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
%
%
20
Thr Thr Thr Thr
20 10
10 0 100
1000
0 100
10000
1000
10000
Granule size (µm)
Granule size (µm)
MPT/SLP
MPT/PEG 40
25 20
%
%
15
Thr Thr 30 Thr Thr 20
(-1) scr (-1) (+1) scr (-1) (-1) scr (+1) (+1) scr (+1)
10
10
5 0 100
1000
10000
0 100
1000
10000
Granule size (µm)
Granule size (µm)
Figure 5: Granule size distribution of runs with varying combinations of throughput and screw speed.
331
produced larger granules with a broader granule size distribution. This is demonstrated in figure 5. At
332
low screw speed, the channel filling degree of the screws (compared to high screw speed) and the residence 17
333
time of the material inside the barrel were enlarged. The additional time of the material inside the granu-
334
lator stimulated granule growth. When the powder feed rate was high (+1), accelerating the screw speed
335
produced more oversized granules, but the amount of fines remained equal. Hence, a broader distribution
336
was obtained. This is linked to the shortened material residence time of the material inside the barrel at
337
high screw speed and high powder feed rate. As a consequence, the screw channels were starved of powder
338
which limited powder compaction [38]. In order to reach an appropriate size distribution, both screw fill
339
degree and residence time inside the barrel must be controlled as they are both playing a key role. The
340
longer the residence time, the higher the collision frequency of the granules with the barrel wall will be.
341
Therefore, a prolonged residence time is required for granules to reduce the oversized fraction. On the other
342
hand, a high screw filling degree is preferred in order to bind the ungranulated powder on the surface of the
343
granular material reducing the fines. This explains the appearance of a fine granular material accompanied
344
by oversized granules when operating at fast screw speed and high powder feed rate.
345
CAF/SLP 50
T (-1) Bi (-1) Scr (-1) T (-1) Bi (-1) Scr (+1) T (+1) Bi (+1) Scr (-1) T (+1) Bi (+1) Scr (+1)
40
%
30 20 10 0 100
1000
10000
Granule size (µm)
Figure 6: Granule size distribution of the SLP/CAF blend when deviating screw speed from −1 to +1 at different levels of binder concentration and granulation temperature.
346
The behavior of the granules obtained from granulation of CAF-containing blends was deviating in
347
specific cases. Performing granulation of the CAF/PEG blend using a higher screw speed was always pro-
348
ducing a higher fraction of smaller sized granules, independent of the powder feed rate (Figure 5). For
349
the CAF/SLP blend, the behavior was deviating when a low binder content and low barrel temperature
350
or high binder concentration and high barrel temperature were used (Figure 6). The influence of powder
351
feed rate was negligible in these cases. Accelerating the screws during granulation of caffeine using a low
352
Soluplusr concentration at a low barrel temperature, produced both small and oversized granules. The
353
reason for this might be the shortened time to soften the limited amount of binder, thus hindering granule 18
354
growth. The few granules were formed via immersion of the solid particles on the surface of the softening
355
binder. Furthermore, a high granulation temperature and/or high binder concentration was required for this
356
blend in order to induce agglomeration [32]. On the other hand, speeding up the screws during granulation
357
of caffeine using a high Soluplusr content at elevated barrel temperature generated an excessive amount
358
of oversized granules. The higher screw tip speed induced mechanical shear which enhanced softening of
359
Soluplusr . Besides improved binder distribution also transition of the stable caffeine polymorphic form
360
to Form I occurred, facilitating granule growth [31](Figure 11). Furthermore, it can be assumed that the
361
granule size distribution depends on the type of binder, type of API and whether they interact or not. This
362
is in contrast with the observations from Dalziel and coworkers who suggested that granule particle size
363
is independent of the binder or drug-polymer ratio and that granule size is a function of the processing
364
techniques [44].
365
366
The influence of screw speed on the granule shape was related to the drug-binder miscibility and on
367
the type of binder (Table 4). When the miscibility between binder and API was sparse (caffeine-containing
368
blends), the produced granules became more needle-shaped when operating at slower screw speed. Due to
369
the prolonged residence time of the material inside the barrel, the binder had more time to distribute over
370
the solid particles. Hence, the shear in the mixing zone elongated the granules rather than fragmenting them.
371
This effect was limited for the CAF/PEG blend due to the less viscous and more brittle properties of the
372
PEG binder. When binder and API had a certain miscibility, a slower screw speed generated more spherical
373
granules. Due to the elongated material residence time inside the barrel, more binder-API interaction took
374
place, hindering the binder to distribute restricting elongation [20]. For the MPT/SLP blend, this could
375
only be observed when operating at high powder feed rate as shown in the interaction plot in figure 7. At
376
high screw speed and low powder feed rate, there was insufficient compaction due to the inadequate filling
377
degree of the barrel resulting in more fines and, thus more spherical granules. At superior barrel filling
378
(at higher powder feed rate) more compaction occurred and the influence of screw speed on granule size
379
was more pronounced. When sufficient compaction occurred for the MPT/SLP blend, a lower screw speed
380
generated more spherical granules as was seen for the for the MPT/PEG blend.
381
382
3.4.2. Tablet properties
383
The influence of screw speed on tablet tensile strength was only significant for the miscible blends where
384
accelerating the screws resulted in tablets with a lowered tensile strength (Table 5). However, the granule 19
25
0.75
0.70
15 10
Low screw speed (Fines) High screw speed (Fines) Low screw speed (A50) High screw speed (A50)
0.65
5 0
A50 (-)
Fines (%)
20
0.4
0.5
0.6
0.7
0.8
Powder feed rate (kg/h)
Figure 7: Interaction plot for (dotted lines) fines (%) and (solid lines) A50 (-) between powder feed rate (kg/h) and screw speed (rpm) of the MPT/SLP blend. The squares represent low screw speed, whereas the circles symbol the high screw speed.
385
properties determining the tensile strength (granule size vs granule friability) were different for brittle and
386
amorphous binders. Using an amorphous binder, the granule size is important regarding tablet quality.
387
Larger granules produced tablets with an enhanced tensile strength. For brittle binders, not size but gran-
388
ule friability should be taken into account to obtain tablets having a sufficient tensile strength. Brittle
389
granules can easily break up during compression, enlarging the available bonding surface stimulating tablet
390
tensile strength. Screw speed is only affecting the tablet tensile strength of the MPT-containing blends. In
391
contrast, caffeine-containing blends yielded stronger tablets when using a higher binder content. This will
392
be explained later.
393
394
Tablets obtained after compression of MPT/SLP granules showed a tensile strength which positively
395
correlated with granule size (X50). The R2 counted 0.7 for the MPT/SLP blend in contrast to only 0.07
396
for the MPT/PEG blend. The relationship between granule size and tensile strength was already observed
397
by Sun and coworkers. However, they explained a reduced tabletability as due to granule size enlargement
398
of plastic material [45]. In this research the opposite relation was observed, since larger granules (X50)
399
resulted in tablets with improved tensile strength. In the design of the MPT/SLP blend, larger granules
400
were obtained at parameters causing a high barrel filling. This stimulated binder and drug to interact
401
causing plasticization of the binder. Hence, one may assume that the larger particles were more deformable
402
compared to smaller granules and, hence, causing tablets with enlarged tensile strength. During compaction
403
of deformable granules, more intermolecular bonding sites are formed over an equal contact area compared
404
to less deformable granules [46]. On the other hand, accelerating the screw speed reduced the barrel filling
405
degree, and thus lowered the binder-drug interactions. As a result, the granules were less deformable during
406
compression generating tablets with a weaker tensile strength. (Table 5). 20
407
408
When granules were made using PEG, the tablet tensile strength was not correlated with the granule
409
size. PEG is a semi-crystalline polymer and is very brittle, in contrast to Soluplusr which is amorphous and
410
therefore more deformable. Since the PEG-containing granules broke-up during compression, the granule
411
friability was important for the tablet tensile strength and not the original granule size. During tablet com-
412
pression, the weak granules were fragmented in a large amount of smaller particles, enlarging the available
413
binding area which improved the tablet tensile strength. The R2 between the granule friability and tablet
414
tensile strength counted 0.62 for the MPT/PEG blend. Due to the negligible influence of screw speed on
415
the granule properties of the CAF/PEG blend, screw speed is not influencing its tablet properties (Table
416
5).
417
418
For the MPT/PEG blend, the influence of screw speed can be found in the interaction screw speed-binder
419
concentration. When granulation is executed using a low binder content, a faster screw speed favors granule
420
strength and, hence, tablets with a reduced tensile strength are generated. This is demonstrated in figure 8.
421
When granulation is performed using a high binder concentration, stronger granules are obtained (relative to
422
the granules having a lower binder content) which produced tablets with a lower tensile strength. At higher
423
PEG concentrations, the granule friability was less influenced by screw speed and more by powder feed rate.
424
The relationship between granule friability and tablet tensile strength was also studied by Wu and coworkers
425
and confirmed these findings [47]. These observations allow to reduce the effects of granule size variations
426
on the tablet properties by incorporating an appropriate amount of brittle binder to the formulation.
427
2.4 2.2
30 2.0 1.8
20 100
200
Tensile strength (MPa)
Friability granules (%)
2.6 40
Low binder conc (friability) High binder conc (friability) Low binder conc (TS) High binder conc (TS)
1.6
300
Screw speed (rpm)
Figure 8: Interaction plot for (dotted line) granule friability (%) and (solid line) tablet tensile strength (MPa) between screw speed (rpm) and binder concentration (%) of the MPT/PEG blend. The circle represents low binder concentration, whereas the triangle symbols the high binder concentration.
428
Additionally, screw speed affected the dissolution rate for the granules manufactured using Soluplusr . 21
429
Speeding up the screws, lowered the % drug released after 5 minutes (11.86% for MPT/SLP and 9.40%
430
for CAF/SLP) (Table 5). This can be linked to higher fraction of fines for these blends when operating at
431
high screw speed and low powder feed rate. The fines and oversized granules were excluded before tablet
432
production. If the fines contain mainly API, this can reduce the diffusion gradient and, hence, the % drug
433
released. This was the case, since the maximum drug release never exceeded 90% and 58%, for respectively
434
MPT/SLP and CAF/SLP, at these parameters (Figure 9). The increase in % fines could be attributed to
435
the limited barrel filling degree when operating at high screw speed and low powder feed rate, as afore-
436
mentioned. Furthermore, since Soluplusr needs to soften in order to allow binding, the shorter material
437
residence time inside the barrel (due to the higher screw speed) will have a superior impact on the Soluplusr
438
blends compared to the PEG blends.
439
CAF/SLP
20
80
15
70
10
60
5
% CAF released
90
100
Thr Thr 80 Thr Thr 60 Thr Thr 40
30
low (release 5min) high (release 5min) low (max release) high (max release) low (fines) high (fines)
20
10
% fines
25
% fines
% MPT released
MPT/SLP 100
Thr Thr Thr Thr Thr Thr
low (release 5min) high (release 5min) low (max release) high (max release) low (fines) high (fines)
20 50
200
300
400
0
200
300
400
0
Screw speed (rpm)
Screw speed (rpm)
Figure 9: Interaction plot for drug release after 5min, max drug release (90min) and fraction fines between screw speed (rpm) and powder feed rate (kg/h) of the (left) MPT/SLP and (right) CAF/SLP blend. The dotted lines represent high throughput, whereas the solid lines symbol low throughput.
440
3.5. Influence of temperature
441
3.5.1. Influence on granule properties
442
Temperature had almost no influence on the granule properties of PEG-containing blends. This can be
443
explained by the fact that PEG is a semi-crystalline polymer having a melting point. When the melting
444
point of a crystalline material is reached, the solid state transfers abrupt from the solid to the molten state.
445
The PEG binder was in the molten state in each run since the actual temperature was close to the melting
446
point throughout both designs. Hence, elevating barrel temperature barely affected the binder viscosity and
447
therefore the influence on the granule properties was negligible.
448
449
Soluplusr on the other hand is an amorphous binder, which softens gradually in function of tempera-
450
ture. A large influence of temperature was seen for the CAF/SLP blend. When granulation of this blend 22
451
was performed at elevated barrel temperature, stronger and larger granules with a smaller span distribution
452
were achieved. In contrast, almost no influence of temperature on the granule properties of the MPT/SLP
453
blend could be observed. This can be attributed to the fact that intermolecular interactions did occur be-
454
tween Soluplusr and MPT impeding binder and API to move as two separate phases. As a result, binder
455
distribution became difficult, and more friable granules were generated [20]. When drug-binder interactions
456
were absent (CAF/SLP), binder distribution was dominated by the viscosity of the binder and was not re-
457
stricted by the interactions. Elevating the granulation temperature, lowered the binder viscosity facilitating
458
distribution. In contrast, when intermolecular interactions did occur (MPT/SLP), binder and API could
459
not move independently and were moving rather as one mass, making viscosity of the binder less important
460
for the granule properties [20]. Furthermore, due to the hydrogen bond formation between MPT and SLP,
461
the maximum useable barrel temperature was 70 ◦ C (plasticizing effect), which is lower than the maximum
462
temperature of 130 ◦ C used for the CAF and SLP blend.
463
464
An improved binder distribution induces better overall binding for all particles favoring granule strength
465
and granule growth. A temperature increase from 50 to 130 ◦ C during granulation of the CAF/SLP blend
466
reduced granule friability by 28%. The reason for the better granule strength due to higher granulation
467
temperature can be twofold. On the one hand, the binder distribution is facilitated at higher temperatures
468
(due to lower viscosity) improving coalescence. On the other hand, caffeine anhydrous can turn into the
469
metastable polymorph (Form I) at high granulation temperature. Caffeine Form I is more deformable in
470
comparison with Form II and improved the granulation efficiency and compaction properties [48][31]. There-
471
fore, the polymorph transition into Form I can favor granule strength. This could be observed during DSC
472
analysis which is shown in figure 11. In contrast, temperature stimulated hydrogen bond formation between
473
MPT and SLP, restricting binder distribution and more fragile granules were obtained (Table 4).
474
475
3.5.2. Influence on tablet properties
476
Temperature was barely influencing the measured granule properties of the MPT/SLP blend, but did
477
affect the tablet properties of this blends. Increasing the granulation temperature facilitated the API-binder
478
interactions which improved the deformability of the granules. Earlier research revealed that interaction
479
between MPT and SLP plasticized the binder (lower Tg ) [43]. Furthermore, at low granulation tempera-
480
ture, granule growth occurred through binding several smaller nuclei together. At elevated temperature, the
481
binder molecules bound together forming larger nuclei which have a higher deformability [20]. During tablet 23
482
compression, the better deformability of the granules initiated a higher bonding capacity per unit area of
483
contact and, hence, the tablet tensile strength improved (Table 5).
484
485
Additionally, the enhanced miscibility occurring at higher barrel temperature stimulated the dissolution
486
rate of MPT into the dissolution medium (Table 5). Possible reasons are the enhanced wettability of the
487
drug when interaction occurred with the binder or the improved solubility of drug when it is in the amor-
488
phous state due to interaction [33]. Since temperature had a limited effect on the granule properties of the
489
MPT/PEG blend, the influence of temperature on dissolution rate was also less pronounced for this blend.
490
It has already been reported that hydrogen bonds were formed between MPT and Soluplusr . These were
491
rather limited at low barrel temperature, but highly expressed at elevated barrel temperature [20]. This
492
explains the pronounced effect of temperature (from Temperature (T ) setting −1 to +1) on the release rate
493
of MPT from the Soluplusr binder (9.6%) in comparison with the release from the PEG binder (5.4%).
494
However, the absolute values of the dissolution rate revealed that the release of MPT from the PEG binder
495
was faster in comparison with the Soluplusr binder which was due to the higher hydrophilicity of PEG (see
496
table 3).
497
498
3.6. Influence of Binder concentration
499
3.6.1. Influence on granule properties
500
In general, more binder generated larger and stronger granules (Table 4). A higher binder concentration
501
strengthens bonds between the drug particles as there is more binder available for bonding. Binder con-
502
centration did not affect the granule size of the MPT/SLP blend. The narrow range of the factor binder
503
concentration in the design of MPT/SLP can be a possible explanation. When granulation was performed
504
using PEG as a binder, increasing the binder concentration formed less fines. In contrast, for the Soluplusr
505
binder, the same effect could be obtained by reducing screw speed. The binding capacity of PEG appears
506
to be lower, and therefore, more binder was needed to bind the unagglomerated particles.
507
508
Melt granulation of the caffeine-containing blends using more binder produced more porous granules,
509
regardless which binder was used (Table 4). The reason for this might not be the binder itself but the lower
510
caffeine concentration (due to higher binder concentration). As aforementioned, the crystalline structure
511
of caffeine anhydrous can modify from the commercial Form II into the metastable and more deformable
512
and more compactable Form I due to the shear and heat during continuous twin-screw melt granulation. 24
513
The higher compactability of Form I can cause a higher density (lower porosity) of the granules when more
514
caffeine is used. As a result of improved compactability, also the fraction oversized granules became larger.
515
516
Executing melt granulation using a high binder concentration produced stronger granules (Table 4).
517
This was also observed by Gokhale et al. during high-shear granulation. Since more binder was used, more
518
bridges were formed between particles, resulting in stronger granules. Although the effect was common,
519
the size of the effect differed for each design. An interaction between temperature and binder concentra-
520
tion could be observed for the blends where interaction occurred between binder and API (MPT/SLP and
521
MPT/PEG)(Table 4). In both designs, an elevated temperature at low binder content yielded stronger
522
granules, due to a lower viscosity and subsequent improved binder distribution and bonding. When using
523
more binder, higher temperatures will yield weaker granules. Binder distribution is impeded due to hydrogen
524
bond formation between binder and API causing more fragile granules (Figure 10). However, these effects
525
were rather low.
526
Friability granules (%)
40
Binder Binder Binder Binder
30 20
% % % %
low (MPT/SLP) high (MPT/SLP) low (MPT/PEG) high (MPT/PEG)
10 0
-1
0
1
Granulation T (°C)
Figure 10: Interaction plot for granule friability (%) between binder concentration (%) and granulation temperature ( ◦ C) of blends MPT/SLP (solid lines) and MPT/PEG (dotted lines).
527
3.6.2. Influence on tablet properties
528
Regardless of the binder used during granulation of MPT, including more binder resulted in tablets with
529
a lower dissolution rate. A higher binder content allowed more binding between particles, on the one hand,
530
but caused a reduction in total amount of drug. Hence, a slower release of the drug molecules was achieved
531
(Table 5). This effect was higher for the fast dissolving MPT and is not significant for the poorly soluble
532
caffeine. Furthermore, the higher binder concentration increased the binding capacity and, hence, tablets
533
with a lower friability were obtained.
534
25
2.0 A
142.56°C 14.70J/g 162.76°C B 139.21°C 14.03J/g
Heat Flow (W/g)
147.86°C
C
143.03°C 11.96J/g 162.58°C D
138.58°C 8.924J/g
144.04°C E
0.2 100 Exo Up
150
200
Temperature (°C)
Universal V4.5A TA Instruments
Figure 11: Heat flow curve of (A) pure caffeine and (B) granules of blends CAF/PEG and (C) CAF/SLP prepared at low binder concentration and (D) granules of blends CAF/PEG and (E) CAF/SLP at high binder concentrations showing the transition of the remaining caffeine Form II into caffeine Form I.
535
Including more binder during continuous melt granulation lowered the tensile strength of the MPT/PEG
536
tablets. This is caused by the enhanced granule strength due to the superior binding derived from the higher
537
binder concentration. Stronger granules underwent less brittle fracture during tablet compression and, hence,
538
a weaker tablet strength was obtained. However, the opposite effect on tensile strength could be observed
539
for the caffeine-containing granules due to the higher deformability after polymorphic transition to the more
540
deformable caffeine Form I. From DSC analysis, it could be observed that more caffeine polymorph Form
541
I was formed when more binder was used during melt granulation (Figure 11). For the CAF/SLP blend,
542
no caffeine Form II could be observed after granulation at higher Soluplusr concentrations, whereas still
543
60% caffeine Form II was detected after granulation with high PEG concentrations. Hence, the effect of
544
binder concentration on tablet tensile strength was more expressed for the CAF/SLP blend. Furthermore,
545
since Soluplusr is ductile, increasing the concentration also generates deformable granules which maximizes
546
interparticle bonding per unit of contact area [49].
547
548
4. General conclusion
549
This research revealed that the type of binder, type of API and interactions between both affect the
550
granulation mechanism of the blend during the continuous melt granulation process and, hence, determine 26
551
the relationship between the influencing parameters and the CQAs (See summarizing table 7). Drug-binder
552
miscibility induces plasticizing of the binder which limited the maximum possible granulation temperature.
553
For these blends, granule growth was rather attained by kneading granules together and, thus the extent of
554
barrel filling was highly influencing the granule and tablet properties. Granule growth of immiscible drug-
555
binder blends was acquired after distribution of the binder allowing nuclei to stick together. Since the binder
556
did behave as a separate phase, the granulation temperature could exceed the Tg /Tm of the binder. For these
557
blends, binder concentration was the most influencing factor. Furthermore, these blends contained caffeine
558
anhydrous as a drug, which is able to convert from the commercial Form II into the more deformable Form
559
I, which facilitated granule growth. This conversion was favored at elevated granulation temperature and/or
560
higher binder concentration and was more expressed when Soluplusr was used as a binder. When using
561
an amorphous binder, the tablet tensile strength depended on granule size and deformability. In contrast,
562
granule strength was more important regarding tablet quality when using a brittle binder. However, this
563
was not the case for caffeine-containing blends, since these phenomena were dominated by the enhanced
564
compression properties of caffeine Form I. Therefore, it is important to gain knowledge about the behavior
565
of the blend during processing before the influence of the process parameters onto the granule and tablet
566
properties can be understood.
567
Based on the DOE models, optimal TS HMG parameter settings can be derived in order to obtain
568
granules having required characteristics to produce tablets with desired quality. In general, granules with
569
good flow properties (CI<15) and minimized amount of fines and oversized granules are preferred and tablets
570
should have a tensile strength >2MPa, tablet friability <1% and fast dissolution rate. For blend MPT/PEG,
571
the granule friability should be maximized which can be obtained by restricting the binder concentration.
572
In table 6, examples of such optimal parameter settings are given for the four studied formulations. The
573
calculated optima coincide with the findings of this research project. Table 6: Optimal factor settings for the four experimental designs based on the observations in current research project
MPT/PEG MPT/SLP CAF/PEG CAF/SLP
throughput (kg/h) max. (0.9) max. (0.8) max. (1.1) max. (1.0)
screw speed (rpm) min. (100) min. (200) max. (300) min. (200)
27
temperature ( ◦ C) > Tm < Tg > Tm Tg
% binder min. (5%) 10% (mean) max. (20%) 10% (mean)
574
Acknowledgment
575
Financial support for this research from the Agency for Innovation by Science and Technology (IWT
576
- Ph.D. fellowship Tinne Monteyne) is gratefully acknowledged. BASF is acknowledged for sending large
577
amounts of caffeine and Soluplusr .
578
579
580 581
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31
Table 7: Influence of varying throughput and screw speed on the material residence time in the barrel (RT) and the screw fill (SF) and the influence thereof on the granule size. In general Higher binder concentration → lower granule and tablet friability
Miscibility
Influence of throughput depends on ease of binder distribution (binder distribution is required for coalescence)
Immiscibility
Higher process torque → less fines
High influence of throughput and barrel filling degree (nuclei are kneaded together)
Low screw speed → more needle-shaped granules
High throughput → Higher torque, larger granules, less fines, stronger granules, smaller span, improved flow properties, improved drug binder interaction Low screw speed → more spherical granules
Relative larger granule size (larger binding capacity)
Granulation T can exceed Tg /Tm of the binder
Relative smaller granule size
Low screw speed → less fines
Miscibility limits max. possible granulation T High Temperature → higher dissolution rate
High binder concentration → less fines
Soluplus
No effect of temperature
Effect of temperature depends on miscibility (CAF/SLP: higher T → larger, stronger granules with smaller span distribution (MPT/SLP → limited influence due to improved hydrogen bond formation)
PEG
Higher granule friability stimulates tablet tensile strength
MPT
Polymorphic transition at high binder concentration and/or high granulation T produced more dense granules, larger (more oversized) granules, more deformable granules → higher TS
Caffeine
High Temp → lower dissolution rate
More binder → lower dissolution rate
High screw speed → lower dissolution rate
High screw speed → lower tensile strength
Granule deformability stimulates tablet tensile strength (For caffeine: more binder or more caffeine Form I) (For MPT: more drug binder interaction at high barrel filling degree)
32
Immersion Drug Binder (ini+al step)
0 0
Immiscible drug-binder blend 0 0 0 0 4 Miscible drug-binder blend