(I=0.1, 37 °C, 50 rpm). Tablets made by roller compaction (RC)

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SUPPLEMENTARY MATERIAL TO
Roller compaction of hydrophilic extended release tablets - Combined effects of processing variables
and drug/matrix former particle size
Johanna Heiman1, 2, Farhad Tajarobi2, Bindhumadhavan Gururajan2, Anne Juppo1,
Susanna Abrahmsén-Alami2*
1
University of Helsinki, Faculty of Pharmacy, Industrial Pharmacy, Helsinki, Finland
2
AstraZeneca R&D Mölndal, Formulation science, Mölndal, Sweden
ABSTRACT
Roller Compaction was compared to direct compression to prepare hydroxypropyl methylcellulose (HPMC)
based extended release matrix tablets containing a high drug load of paracetamol and ibuprofen. The
combined effect of roller compaction (RC) process variables and composition on the drug release was
investigated. Standard wet granulation grade HPMC was compared with a larger particle size direct
compressible HPMC grade. Tablet dissolution testing showed that when using critically low amounts and
direct compression the large sized HPMC particles were unable to percolate through the tablet and form a
consistent network. However, granulation by roller compaction prior to tablet compression helped to break
down the large HPMC agglomerates and distribute them more evenly within the tablets, hence increasing
the dissolution robustness at HPMC levels close to the percolation threshold of the polymer. It is likely that
when the HPMC level lies near the percolation threshold, significant changes can occur in the drug release
rate due to changes in other factors (raw material characteristics and processing).
Materials and Methods
Raw materials
The model active substances in the study were paracetamol (Sri Krishna pharmaceuticals, Hyderabad, India)
and ibuprofen (IOL chemicals and pharmaceuticals limited, Punjab, India). Two different particle size grades
of HPMC USP type 2208 (Dow Chemical company, Midland, USA) were used as matrix formers, standard
grade Methocel K100LV Premium (HPMC-S) and Methocel K100LV Premium DC Gen I (HPMC-DC)
having a larger particle size. Mannitol (Parteck M200, Merck GaA, Darmstadt, Germany) was added as a
soluble filler and sodium stearyl fumarate (PRUV, Moehs, Barcelona, Spain) as a lubricant.
Composition and manufacturing of tested formulations
The compositions used in the study were 30% API (paracetamol/ibuprofen), 22 to 32% HPMC-S or HPMCDC, 35 to 45% mannitol and 3% sodium stearyl fumarate (2% added to the powder blend before roller
compaction and 1% intergranularly). Mixing and roller compaction was performed as described in the main
article. A roll pressure of 3 MPa was used for all roller compacted composition of the present study. For
paracetamol new formulations were manufactured where the level of HPMC was varied from a point
assumed to be below percolation threshold (22%) and to a point above (32%) according to literature (1). The
particle size of paracetamol was the same as in the original study (d50 = 35m). For ibuprofen some of the
compositions of the original design, containing 32% (w/w) HPMC, were used (see Main article). All
compositions for which release was determined are listed in Table 1 a and b below.
Table 1S a (Paracetamol) and b (Ibuprofen). Compositions and process variables for which drug
dissolution was investigated. Rat= ratio between feeder screw speed and roll speed, Rol= roll pressure,
HPMC d50 = particle size of HPMC, API d50 = particle size of API (P=Paracetamol & I=Ibuprofen). DC=
Direct compression, RC= Roller compaction.
a)
Experiment HPMC d50 (µm) HPMC level (%) Method
D1
71
22
RC
D2
177
22
RC
D3
71
32
RC
D4
177
32
RC
D5
71
22
DC
D6
177
22
DC
D7
71
32
DC
D8
177
32
DC
D9
124
27
RC
D10
124
27
RC
D11
124
27
RC
b)
Experiment
API d50 (µm)
HPMC d50 (µm)
Method
I1
21
71
RC
I2
21
177
RC
I5
37
71
RC
I6
37
177
RC
I-Blend 2
21
177
DC
I- Blend 4
37
177
DC
In-vitro drug release
Dissolution testing of drug release from tablets was carried out in a USP dissolution apparatus (Hanson
research SR8-Plus, Chatsworth, USA) using UV-detection with fibre-optics (Varian Cary 50 Bio, C
Technologies, Inc, Bridgewater, USA). A fibre-optics probe was inserted directly into each vessel and the
absorption measured in situ. The USP II method was modified by incorporating a quadrangular stationary
basket above the paddles, where tablets were placed. The paddle rotation speed was set to 50 rpm and
temperature was kept at 37 °C. Paracetamol is known to have a stable solubility of approximately 20 mg/ml
at the in vivo relevant area of pH 1.2-8.0 (2). Therefore, 900 ml of phosphate buffer pH 6.8 (I=0.1) was
chosen as the release medium to simulate the release of a freely soluble drug substance from the hydrophilic
matrix. Ibuprofen on the other hand, has an intrinsic solubility of approximately 0.06 mg/ml and a pKa of
4.4, which makes it poorly soluble at the acidic regions of the gastrointestinal tract. To simulate the erosion
dependent release of a poorly soluble drug, 1000 ml of phosphate buffer pH 4.2 (I=0.1) was used as the
release medium. Additional dissolution testing with ibuprofen was done in 1000 ml phosphate buffer pH 7.5
(I=0.1), in which the drug is soluble.
Results and Discussion
Dissolution from Paracetamol compositions
The aim the drug dissolution testing was to see the effect of HPMC particle size and the manufacturing
method on the percolation threshold. The dissolution profiles are presented in Figure 1S.
Figure 1S. The average (n=2) paracetamol dissolution profiles of 350 mg tablets with 30% drug load.
USP26, 900 ml phosphate buffer pH 6.8 (I=0.1, 37 °C, 50 rpm). Tablets made by roller compaction (RC) and
direct compression (DC).
Tablets with 22 % HPMC level (D1, D2, D5, and D6) were below the percolation threshold and all,
independent of manufacturing method, released the drug in an abrupt manner, having T80 (time to 80% drug
release) at around 50-70 minutes. At this low content, HPMC could not form a robust network. All tablets
except for the direct compacted formulation with large sized HPMC (D8), containing 32% all HPMC
showed a robust sustained release behaviour (Figure 1 and Table 2S). This is likely due to that the large
HPMC particles were unable to percolate through the tablet and form a robust gel layer, resulting in higher
percolation threshold for the directly compacted compositions. It is well known from literature that the
particle size of HPMC is a critical factor for drug release (3). A particle size threshold of 113 µm has been
identified, over which the tablets disintegrate and release the drug in an abrupt manner (4). The mean HPMC
particle size (d50) in this study was 177 m and 71 m for large and small particle size grade, respectively.
No significant difference can be observed in the release times of the two different HPMC grades after roller
compaction. It is therefore plausible that the energy exerted during roller compaction helped to more
effectively de-agglomerate the HPMC-DC particles and distribute them more homogenously in the tablets.
This in turn implies larger surface area and higher probability that HPMC particles could occupy a given
volume in the matrix. At the intermediate HPMC concentration (27% w/w) where a mixture of HPMC-DC
and HPMC-S was used to produce tablets via roller compaction very fast release rates were obtained
indicating poor robustness (Table 2S). These observations show that when the HPMC level lies near the
percolation threshold, significant changes can occur in the drug release rate due to changes in other factors
(raw material characteristics and processing).
Table 2S. The times for 80 % (T80) and 50 % (T50) Paracetamol release. CP= Centre point, RC= Roller
compaction, DC= Direct compaction.
Experiment
HPMC
level
HPMC particle
size
Manufacturing
method
T80/T50 (min)
D3
32%
Small
RC
290/130
D4
Large
RC
290/120
D7
Small
DC
260/110
D8
Large
DC
150/60
Small
RC
50/30
D2
Large
RC
80/50
D5
Small
DC
50/30
D6
Large
DC
50/30
CP
RC
90/30
D10
CP
RC
100/50
D11
CP
RC
110/50
D1
D9
22%
27%
Batch variation in substitution degree and pattern can also cause significant differences in the drug release
(5). This is however more noteworthy for poorly soluble drugs that have erosion controlled release. The data
on the CoA for the used HPMC batches indicate that the differences in characteristics between the two
HPMC grades are all small apart from the particle size.
Dissolution from Ibuprofen Compositions
Tablets made by roller compaction with both combinations of different HPMC and ibuprofen particle sizes,
were compared to directly compressed tablets of containing the HPMC-DC with regards to dissolution
behaviour. Ibuprofen has a solubility of around 0.058 mg/ml and 27.5 mg/ml at the tested pH 4.2 and pH 7.5,
respectively (2). Therefore, the drug release is assumed to be more diffusion controlled at the higher pH and
mostly erosion controlled at the lower pH (Figures 2S a and b and Table 3S).
Figure 2S a. Average (n ≥ 2) ibuprofen dissolution profile of 150 mg tablets with 30% drug load. USP26,
1000 ml phosphate buffer pH 4.2 (I=0.1, 37 °C, 50 rpm).
Figure 2S b. Average (n ≥ 2) ibuprofen dissolution profile of 150 mg tablets with 30% drug load. USP26,
1000 ml phosphate buffer pH 7.5 (I=0.1, 37 °C, 50 rpm).
Table 3S. The times for 80 % (T80) and 50 % (T50) Ibuprofen release (pH 4.2 and 7.5), RC= Roller
compaction, DC= Direct compaction.
Experiment API particle size HPMC particle size
I1
I2
I5
I6
I-Blend 2
I-Blend 4
small
small
large
large
small
large
small
large
small
large
large
large
T80 pH T50 pH T80 pH T50 pH
4.2 (min) 4.2 (min) 7.5 (min) 7.5 (min)
500
280
220
120
580
280
280
140
540
320
230
130
700
340
280
140
180
80
50
20
300
140
50
20
The drug release rate was markedly slower at pH 4.2 compared to pH 7.5 for all compositions. No large
difference in the release can be seen between tablets made via roller compaction, whereas direct compacted
powder blends had significantly faster drug release rate at both pH’s. During dissolution testing, the directly
compacted tablets were observed to disintegrate fast after introduction into the release medium. This result is
in accordance to the observation made for directly compacted paracetamol tablets containing large sized
HPMC. These results indicate that at a content of 32 % (w/w) the HPMC-DC is unable to percolate through
the tablet and from a protective gel layer. The dry granulation process, on the other hand, appears to break
down the HPMC-DC agglomerates and increase the homogeneity of the matrix system leading to slower and
more robust release.
At pH 4.2 the directly compressed tablets consisting of the two extremes of particle sizes, small API and
large HPMC particles, had a faster release rate than the corresponding formulation with large sized API. This
might be because of the slower dissolution of larger API particles, and because the small size poorly soluble
drug particles are able to surround the HPMC particles and interfere with the hydration of HPMC and
preventing the rapid formation of a release controlling gel layer. In order to obtain a better understanding of
the underlying mechanism polymer release studies could be informative.
Consideration was also taken to the fact that the slight differences between granules made of the two HPMC
particle size grades can also be due to batch variation in substitution degree and substitution pattern. The
HPMC-S was according to batch certificate only somewhat less substituted with regards to metoxy (22.7
compared to 22.8%) and slightly more substituted with regards to hydroxpropyl (9.1 compared to 8.7%) than
the HPMC-DC grade. However, since no large differences between granulated tablets of the different grades
can be seen, the effect of batch variation is assumed to be minor within the range investigated.
Conclusions
The drug dissolution was affected by the choice of HPMC particle size and manufacturing method.
Dissolution tests suggest that when direct compressed the large size HPMC particles were unable to
percolate through the tablet and form a consistent network at HPMC concentrations of 22 to 32%. Roller
compaction was assumed to break down the large agglomerates and distribute them more evenly within the
tablet. No significant difference could be seen between drug releases from tablets made from granules roller
compacted with different process parameters. These observations show that when the HPMC level lies near
the percolation threshold, significant changes can occur in the drug release rate due to changes in other
factors (raw material functionality related characteristics and processing). Therefore care needs to be taken to
assure that developed formulation have a composition with an amount of ER matrix former (HPMC in this
case) sufficiently high to be above the critical point and that characterisation is performed in order to assure
formulation robustness.
References
1.
Tajarobi F, Abrahmsén-Alami S, Hansen M, Larsson A. The impact of dose and solubility of
additives on the release from HPMC matrix tablets – Identifying critical conditions. Pharm Res, 26:
1496-1503, 2009. http://dx.doi.org/10.1007/s11095-009-9861-y
2.
Shaw LR, Irwin WJ, Grattan TJ, Conway BR. The effect of selected water-soluble excipients on the
dissolution of paracetamol and ibuprofen. Drug Dev Ind Pharm, 31: 515-525, 2005
3. Alderman DA: A review of cellulose ethers in hydrophilic matrices for oral controlled-release
dosage forms. Int J Pharm Technol Prod, 5 (1984) 1-9.
4. Heng PWS, Chan LW, Easterbrook MG, Li X. Investigation of the influence of mean HPMC particle
size and number of polymer particles on the release of aspirin from swellable hydrophilic matrix
tablets. J Control Release, 76: 39-49, 2001. http://dx.doi.org/10.1016/S0168-3659(01)00410-2
5. Viridén A, Wittgren B, Andersson T, Larsson A. The effect of chemical heterogeneity of HPMC on
polymer release from matrix tablets. Eur J Pharm Sci, 36: 392-400, 2009.
http://dx.doi.org/10.1016/j.ejps.2008.11.003
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