Extrusion experiments (Figure 4.8, Figure 4.14 and Figure 4.15) and the high degree of correlation between degradation and residual crystallinity (Figure 4.17 and Figure 4.18) also confirmed the dissolve-then-degrade mechanism. The torasemide system, as already demonstrated in this study on a standard design twin-screw extruder with various kneading block screw configurations, showed a wide and measurable range of degradation and residual crystallinity within typical residence times for twin-screw extrusion. This rate of dissolution and degradation occurring within a more representative range of residence time in the torasemide system is an advantage over the spironolactone system studied by Vigh, et.al. For that system, materials were extruded in recirculation mode on a Haake® Mini-lab extruder in which processing times of up to 25 min were required to see the evolution of degradation and residual crystallinity (31). In fact, the residence time data in this TOR study, for a given screw speed and configuration, showed that the MRT was a strong function of feed rate and reached both maximum and minimum limits (Figure 4.6), which agrees with the literature (104). The MRT reached a maximum limit of about 150 s at low feed rates and a minimum limit of about 60 s at high feed rates, which can be explained by the MRT’s dependency on extruder free volume and fill ratio (104).
Given this dependency and the practical desire for process efficiency enabled by high throughputs, an indicator system like torasemide which shows sensitivity within practical and realistic process boundaries is advantageous. The MRT, as well as the residence time distribution, could be increased and/or adjusted by introducing more mixing or backwards conveying elements to the screw configuration, but not without causing considerable changes to other process conditions.
Measurement and quantification of the residual crystallinity in this TOR system was only feasible by XRPD. Utilization of the melting endotherm via DSC was not possible because none was detected (data not included), indicating that torasemide fully dissolved before melting. This observation has been described previously and the present work corroborates this finding (3,31).
The high degree of correlation shown between torasemide degradation and residual crystallinity over a wide range of different process parameter combinations (Figure 4.18) also indicates that a more general process condition, rather than several independent process variables, is responsible for the evolution of the CQAs. In this
case, the integral of the time > 115 °C correlated well with the relationship between residual crystallinity and sum of degradants (Figure 4.23). This approach neglects the kinetics of the reaction, namely that the API will both dissolve and degrade at a faster rate at higher temperatures. In fact, due to the dissolve-then-degrade mechanism of TOR in this system, and absent of a method to quantify the dissolution rate of TOR into the matrix, development of a coupled dissolution and degradation kinetics relationship is at present not feasible. However, the integral approach is a preliminary attempt to identify a general process characteristic which correlates with multiple CQAs which could also guide scaling. If confirmed for other systems, it could be highly efficient to design extrusion development and scale-up studies around varying this type of general process characteristic, or perhaps another type of imparted energy and residence time distribution, for example. This concept has been discussed in the literature, and the present data confirms and supports this approach towards process understanding and development (9).
The plasticizing effects of torasemide and the presence of its degradants on the overall system melt viscosity are not fully understood. Due to the high concentration of degradants and potentially yet-to-be degraded torasemide present in the extrudate samples, it was important to investigate the impact of their presence on the melt viscosity of the system. Pure un-extruded Soluplus® was compared to extruded placebo and active-containing extrudates with 5 and 10 %w/w PEG 1500 (Figure 4.11). The placebos and active formulations were extruded to ensure mixing of the matrix components as well as to ensure the presence of dissolved and degraded torasemide. These formulations were considered to be extremes in sample composition and should indicate the maximum extent that plasticization by dissolved and degraded torasemide could have on the system, if indeed there were to be an observable difference in melt viscosity. The extremes in sample composition were tested, rather than for example low, middle and high amounts of degradation, due to the time-dependent nature of rheological experiments. It is impossible to eliminate the time component from such testing because samples must be thermally equilibrated, and the frequency sweeps also last at least a few minutes. This is an important consideration for measuring the rheology of reactive systems. Although feasible temperature windows for rheological measurements differed for placebo vs.
active, the melt viscosity data and Tg analysis indicate that the concentration of PEG 1500 strongly plasticized the SOL, while the presence of torasemide and its degradants had a minor impact (Figure 4.11, Figure 4.12 and Figure 4.13). Further, the glass transition temperature of SOL, approximately 70 °C (62) is similar to that of torasemide, approximately 80 °C (105). Therefore, it is expected that torasemide will modify the melt viscosity of the system to a lesser extent than PEG 1500 as the torasemide dissolves into the surrounding matrix, assuming no specific interaction, and hence the Gordon-Taylor law would apply. SOL as a matrix polymer was chosen in part for this exact reason, to avoid a reactively-plasticizing effect of the API on the matrix. Moreover, the similarity of the degradants’ molecular structures to that of torasemide might also result in a non-plasticizing effect. If this is the case, the extent of reaction of torasemide dissolving and then degrading may not substantially impact the overall melt viscosity of the system. These attributes lend the system well to the study of melt viscosity as a function of plasticizer content as well as the study of shear in the extruder.
The effect of plasticization was seen as the processing space was adjusted exclusively via the PEG 1500 concentration (Figure 4.7). The minimum main barrel and die temperature for each formulation was limited by high torque due to higher material melt viscosity at lower temperatures. However, when processed at the same temperature, formulations with varying PEG 1500 concentration showed almost the same amount of degradation, indicating that in this small extruder, material temperature was controlled more by barrel heat conduction than viscous dissipation (Figure 4.8). This conduction-dominated heating was also apparent when two different screw configurations were compared (Figure 4.14) as well as when screw speed was varied, although the screw speed range was limited by equipment constraints (Figure 4.15). On the other hand, residual crystallinity levels varied both with PEG 1500 concentration and screw configuration (Figure 4.8 and Figure 4.14).
Lower residual crystallinity levels at lower PEG 1500 concentration can be explained by a higher level of viscous dissipation. For screw configuration, more shear simply led to fresh surfaces of the torasemide crystals which could more readily dissolve into the surrounding matrix. However, some of these relationships, particularly the conduction dominated heating, may not be the case at larger scales when shear
rates are higher, especially at the outer diameter of the screws near the barrel wall, and as the surface area to volume ratio decreases. Lastly, the fact that a difference in residual crystallinity is observed but little difference in degradation corroborates the finding that torasemide does not immediately degrade once dissolved, as shown in Figure 4.17.
Overall, the loss in crystallinity and degradation at main barrel and die temperatures lower than the onset dissolution temperature of torasemide (115 °C) is indicative of at least some viscous dissipation, regardless of the plasticizer concentration. The presence of viscous dissipation is also supported by two observations: 1) melt temperatures at die exit were higher than the main barrel and die temperatures for all process conditions and 2) the measured barrel temperature in the last heated zone of the extruder rose above the set temperature at the lowest temperature settings.
However, comparison of the melt temperature at die exit to barrel and die set temperatures does not reveal the melt’s complete thermal history. On the other hand, the use of torasemide as an indicator can support process understanding and provide an indirect view of the effect of processing conditions, since the degradation is a function of the entire thermal history. In addition, the highly plasticized 15 %w/w PEG 1500 formulation offered no advantage in terms of minimizing the main barrel and die temperature to limit degradation due to the fact that processing at a temperature, for example 95 °C, below the onset dissolution temperature of torasemide (115 °C; note: not melting point) would lead to no dissolution. Therefore, before processing a new API via HME which exhibits a dissolving mechanism for ASD formation, it is useful to know its onset dissolution temperature, in addition to other material characteristics such as melt viscosity and degradation temperatures.
The combination of both thermal and hydrolytic degradation mechanisms in the torasemide system offers a unique opportunity to study the impact of moisture as well as transient plasticization via moisture on the extrusion process. The fact that the most thermal degradation was observed when the extruder was fully vented (Figure 4.16) indicates that moisture was serving as a plasticizer. Removing the moisture near to the exit of the extruder resulted in a strong increase in melt viscosity, which lead to increased viscous dissipation, increased melt temperature and therefore thermal degradation. The expected rise in torque also supported this conclusion.
These findings are in agreement with the observations regarding torque and extrudate appearance, namely the presence of bubbles, reported previously (95,106). Furthermore, the present data links these observations to important degradation CQAs by adjusting the process setup to limit hydrolysis degradation. In addition, the effect of moisture, in particular residual moisture in a finished product, is important to understand as it could result in reduced physical stability, due to the reduction in glass transition temperature and elevated molecular mobility favoring recrystallization (65,102).
In these studies, the blend moisture content within the range of 2-2.5 %w/w resulted in negligible differences in thermal and hydrolysis degradation levels. However, in preliminary studies (data not included), 10 %w/w drug load torasemide in SOL blends prepared with SOL artificially equilibrated to contain 0.5 and 6 %w/w moisture did show considerable differences. In this case, the ratio of thermal to hydrolysis degradants was reversed, similar to in the DSC study (Figure 4.5). The presence of a hydrolysis degradation mechanism is certainly a complicating aspect of this model formulation, especially in terms of normal processing. However, open-pan controlled heating DSC experiments showed that it is possible to eliminate the hydrolysis degradation pathway, if water is removed. Further, isolated feeding systems capable of drying feed material and controlling ambient moisture are available on the market.
Such systems are used in the extrusion of polyethylene terephthalate and poly(lactic acid), for example, which are highly hygroscopic and hydrolysis in the melt phase can lead to a reduction in molecular weight (107–109).