Performance of Torasemide-Based Indicator System with 10 %w/w

Based on the wide range of CQAs that can be observed with the model formulation with a 10 %w/w concentration of PEG 1500, additional process variables such as the effect of screw configuration, screw speed and moisture content were studied.

4.4.3.1 Effect of Screw Configuration

Three screw configurations were studied with varied numbers of mixing zones (one or two) and different combinations of forward and backward 60° kneading disks (Figure 4.2). The screw configuration had only a minor impact on the total degradation within the mean residence time range of 80-160 s, while temperature and mean residence time showed more prominent effects (Figure 4.14a). No difference in degradation was seen between the two screws composed of only forward kneading blocks; the MRTs were nearly identical (Figure 4.14c). The backwards kneading blocks in the more complex screw increased the MRT for a given feed rate (Figure 4.14c). However, when the MRT was the same as for the 1-mixing zone screw, approximately 90-160 s, degradation levels were similar (Figure 4.14a).

Conversely, the amount of residual crystallinity was impacted by screw configuration, especially at lower temperatures and shorter residence times (Figure 4.14b). The extrudates manufactured with the harsher screw contained less residual crystallinity than those manufactured with the simple screw.

Figure 4.14 Effect of screw configuration on a) torasemide degradation, b) residual crystallinity and c) mean residence time vs. feed rate for constant screw speed of 150 rpm.

4.4.3.2 Impact of Screw Speed

The impact of screw speed was studied in order to assess the shear sensitivity of the CQAs. The standard screw speed of 150 rpm was compared with 125 and 175 rpm.

The lower limit was selected based upon prior knowledge that back mixing can occur at a low screw speed of 100 rpm. The upper limit was selected based upon observations of barrel over-heating when a screw speed of 200 rpm is used. With increasing screw speed, the degradation level increased slightly while residual crystallinity decreased, but the predominant factor was the main barrel and die

temperature (Figure 4.15). In addition, higher degradation and lower crystallinity were seen with the more aggressive screw (Figure 4.2).

Figure 4.15 Effect of screw speed on CQAs as a function of screw design and process temperature. Throughput was constant at ~2.4 g/min via feeder screw speed of 15 rpm. MRT for 1-mixing zone screw was ~115 s while MRT for 2-mixing zone screw was ~150 s.

The melt temperature at the die exit did not differ between the two screw configurations when the main barrel and die temperature was set to 115 and 125 °C, but for 105 °C, the melt temperature was noticeably higher for the screw with only one mixing zone (data not shown).

4.4.3.3 Influence of Moisture on Torasemide Degradation

Due to the propensity for hydrolysis degradation with torasemide, the impact of moisture was also studied. In a head-to-head study varying the main barrel and die temperature and MRT, blends with 2 and 2.5 %w/w moisture were evaluated based on the observed moisture content of packaged SOL. Within this range, the effect of

the initial moisture content of the blend was found to be insignificant on hydrolysis degradant levels (data not included).

Multiple venting configurations were compared to investigate the potential utility of torasemide to study the effect of the transient amount of moisture in a HME formulation on process performance and resulting extrudate quality. The blend used for this study contained an initial amount of 2.5 %w/w moisture. Three venting configurations were studied utilizing two available vent ports on the extruder (Figure 4.2). The three venting configurations studied were 1) early closed-end closed, 2) early open-end closed, and 3) early open-end open. In this experiment, the main barrel and die temperatures were kept constant at 115 °C, the screw speed was held constant at 150 rpm, the 1-mixing zone screw was used, and the feed rate was varied in order to observe the progression of degradation over time spent in the extruder.

The torasemide degradation as a function of venting and residence time is shown in Figure 4.16. The highest amount of hydrolysis degradation was seen when both vent ports were closed (Figure 4.16, middle graph). However, the same amount of hydrolysis degradant was seen independent of the number of open vent ports. This observation was surprising due to quite different experimental observations of the two venting configurations. Very little moisture was detected escaping from the first port, partly due to material filling and plugging the opening. In contrast, a substantial amount of moisture and potentially other vapors, visualized by placing a glass beaker over the port for a short period of time, was seen escaping from the second port.

With regards to thermal degradation, little difference was seen between venting configurations 1 and 2 (Figure 4.16, top graph). However, the amount of thermal degradation produced, especially at longer residence times, was distinctly different for venting configuration 3. The torque was observed to increase slightly when the second vent port was open. It was also observed that the extrudates produced with venting configuration 3 contained fewer bubbles than those produced with a closed 2^nd vent port. Overall, venting configuration 2 produced extrudates with the least amount of total degradation (Figure 4.16, bottom graph).

Figure 4.16 Effect of venting configuration on torasemide degradation at various feed rates. Main barrel and die temperature held constant at 115 °C and constant screw speed of 150 rpm with 1-mixing zone screw.