Supplementary Material To

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*

1University of Helsinki, Faculty of Pharmacy, Industrial Pharmacy, Helsinki, Finland

2AstraZeneca 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

HPMC-DC, 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.

Experime HPMC d50 HPMC level Metho nt (µm) (%) d 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)

Experimen Metho API d50 (µm) HPMC d50 (µm) t d 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

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.

HPMC HPMC particle Manufacturing Experiment T80/T50 (min) level size method D3 32% Small RC 290/130 D4 Large RC 290/120 D7 Small DC 260/110 D8 Large DC 150/60 D1 22% Small RC 50/30 D2 Large RC 80/50 D5 Small DC 50/30 D6 Large DC 50/30 D9 27% CP RC 90/30 D10 CP RC 100/50 D11 CP RC 110/50

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.

T80 pH T50 pH T80 pH T50 pH Experimen API particle HPMC particle 4.2 4.2 7.5 7.5 t size size (min) (min) (min) (min) I1 small small 500 280 220 120 I2 small large 580 280 280 140 I5 large small 540 320 230 130 I6 large large 700 340 280 140 I-Blend 2 small large 180 80 50 20 I-Blend 4 large large 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

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