MECHANISM OF THE OPERATING CONDITIONS ON DISPERSIVE MIXING AND HUMIDITY OF POLYMER IN A TWIN SCREW EXTRUSION PROCESS

Transcription

1 MECHANISM OF THE OPERATING CONDITIONS ON DISPERSIVE MIXING AND HUMIDITY OF POLYMER IN A TWIN SCREW EXTRUSION PROCESS Masuma Khatoon Ema, Ben Dryer, Nitish Balakrishnan, and David I. Bigio, Department of Mechanical Engineering,University of Maryland, College Park Chad Brown, Francis Flanagan, and Fengyuan Yang, Merck & Co., Inc. Abstract Effective operational methodology of extrusion could impact pharmaceutical properties of polymer ranging from fundamental studies of mechanical and chemical mechanisms. Applied shear stress can regulate the polymer mixing as well as properties such as percentage of relative humidity. Polymer behavior differs in different operating conditions such as screw speed of extruder, specific throughput and barrel temperature. Combinations of such process parameters could directly affect the degree of polymer reaction in terms of percentage of breakup and water degradation. Yet, it is very complicated to determine the effective methodology for polymer extrusion process because the viscous drag pressure depends on some other parameters such as maximum temperature, screw design and the fill ratio. Here we present a vel approach to include barrel temperature and number of revolutions of extruder to correlate the pharmaceutical properties with the degree of combined mechanical mechanism. Design of Experiment (DOE) was being modified to determine property responses based on statistical significance. A 3-D Central Composite Design (CCD) grid was formulated to predict operational equation for percentage breakup and percentage of relative humidity. Introduction Research ability on polymer mixing phemena into a co-rotating twin screw extruder requires an ability to understand the electro-chemical mechanism to determine the different types of pharmaceutical properties [1-2]. In manufacturing process for pharmaceutical application, it is very important to determine the process parameters with desired screw geometries [3]. For this reason, solid agglomerates into polymer need to be broken and evenly distributed to achieve the desired properties by controlling operational process of the twin screw extrusion machine [4]. The mixing phemena were explained by the fluid velocity profile and heat transfer into the extrusion machine using control volume technique [5]. Also, the mixing phemena will be attributed by the effect of shear stress and shear rate. Process parameters such as speed, throughput as well as physical properties such as molecular weight, particle size were found responsible for shear degradation [6]. In addition, process parameters in terms of shear intensity and shear uniformity have been also evaluated for a better understand of twin screw mixing element [7]. In recent years, hot melt extrusion (HME) has received widespread attention from the pharmaceutical industry for the production of oral solid dispersions. HME has different benefits including avoidance of solvents and applicability to drugs and adjutants for which a suitable solvent is lacking. It enables sufficient mixing in a short residence time and can be used to produce formulations with controlled, sustained or targeted release [8-9]. Selected polymers can serve to mask the bitter taste of certain APIs [10]. In addition, HME is a continuous and controllable process that can be scaled up to a commercially meaningful level [11]. However, HME is limited in its application to thermally unstable drugs that degrade at the high temperatures and shear forces employed in the extrusion process. Characterization of dispersion within an extruder machine was developed through an inline process measurement by the Residence Stress Distribution (RSD) method [12-13]. Using the RSD method, stress within a polymer melt is measured with polymeric stress beads that release an encapsulated dye when they experience a critical stress. The percentage of beads that experience their critical stress in a twin screw extruder (TSE) process is quantified as the percent break-up (%BU). This paper presents the mechanism of a combined effect of operating conditions of twin screw extruder including, the effect of barrel temperature and specific mechanical energy. Finally, this paper demonstrates the effect of total revolutions within extruder as well as the flow path on the amount of water content. Screw Elements The physical experiment was completed on a 16 mm thermo extruder with an L/D ratio of 40. The screw geometry consisted of mainly conveying elements, with a melting and mixing section. The melting section had kneading blocks (KBs) with a 30 stagger angle. The mixing section had a series of four KBs. The first was a 30 KB, consisting of 5 paddles, totaling 20 mm in length. The second KB had a 60 stagger angle, and having 20 mm length. The final two KBs were neutral elements (90 stagger angle) totaling a combined 40 mm in length. SPE ANTEC Anaheim 2017 / 1107

2 Material Used The material used in this experiment were 72/23/5 wt% blend of Kollidon VA-64, an API, and a surfactant. The polymer carrier used in this study was copovidone of brand Kollidon VA-64, manufactured by BASF. Kollidon VA 64 is water-soluble, encouraging its use as a solvent in solid dispersion formulation. Kollidon is also hygroscopic having tendency to absorb and retain water. The glass transition temperature of Kollidon VA 64 is approximately 101 o C. The viscosity of this polymer varies depending on temperature and shear rate. It has increasing viscosity as temperature decreases. Operating Condition Operating conditions were selected across a range of typical conditions depending upon the processing of this material. The operating conditions were varied across five levels of screw speed (N) and specific throughput (Q/N) on a Central Composite Design (CCD) grid to investigate the effects of the operating conditions on percentage of breakup as well as the pharmaceutical properties. The 2D CCD - grid was repeated at three barrel temperatures (T b): 170, 190, and 220 C (Figure 1). Figure 1. CCD grid of operating conditions for experimentation. For the second step of experiment, results for percentage of breakup (%BU) and relative humidity (%RH) from 2D CCD grid will be transformed into a 3D CCD grid with the variables of N, Q/N, and T b. The purpose of this phase of experiments was to generate predictive equations for %BU and %RH as combined function of N, Q/N and T b. The shape of the 3D CCD grid is shown in Figure 2.The coordinate system of 3D CCD grid is shown in Table 1. Table 1: Coordinate system in a 3D grid Point Coordinate Point Coordinate Point Coordinate 1-2,0,0 6 0,0, ,1,-1 2-1,1,-1 7 0,2,0 12 1,-1,-1 3-1,-1,-1 8 0,0,0 13 1,1, ,1, ,-2,0 14 1,-1, ,-1, ,0,2 15 2,0,0 The results of %BU and %RH for 6 and 10 (at 150 and 230 o C), were assumed as a (polymial) function of barrel temperature by interpolating the results for the condition of N=150 rpm and Q/N = 0.3 at three temperatures (170, 190, 220 o C). Experiment The residence time distribution (RTD) and residence stress distribution (RSD) calculation were performed in this study. It was done by injecting shots of ink and stress sensoring beads into an open vent port upstream of the mixing section of the extruder machine. For each operating condition shown in Figure 1, the screw speed and feed rate were set and the feed was allowed to reach steady state. A baseline voltage in LabVIEW was established before each injection condition for approximately fifteen seconds. The respective ink or beads shot was, then, released into the extruder. Optical probe was placed before dye zone to measure the intensity of the stained polymer melt when it passed through the mixing section. The optical probe produced a continuous curve based on the amount of light scattered by the stained polymer. Once, all of the ink or stress beads exited the extruder and the polymer returns to a white color, the run was complete. Figure 2. 3D CCD Grid with three variables. Figure 3. Example RTD and RSD curves [14] SPE ANTEC Anaheim 2017 / 1108

3 RTD curve was produced by injecting ink shot while RSD curve was produced by injecting stress beads. The blue line is a RTD curve and the green and magenta lines are RSD curves. The percentage of broken beads was measured by dividing the area under the RSD curve by the area under the RTD curve. Sample RTD and RSD curves are shown in Figure 3 [14]. At the time of the experiment, specialized vials were used to lock the water content of polymer at 25 o C for at least 24 hours with a re-measurement at 72 hours to ensure that the extrudate had equilibrated with the headspace. Water content as percentage of relative humidity (%RH) was calculated using a Lighthouse Instruments FMS- 1400H to determine the water activity. Also, Ludovic simulation software was used, which predicts process behavior (pressure, residence time, and melt temperature) along entire screw geometry. Mixing phemena in term of percentage of break up are also related with specific mechanical energy to understand the combined effect of torque, mass flow rate and screw speed. Therefore, specific mechanical energy (SME) is also calculated by the following equation at different barrel temperatures: SME T N m (1) where,t, N and m o means torque, screw speed (2π*Screw speed) and mass flow rate, respectively. Results and Discussion The coefficient of N and Q/N in 2D equations for % break up (%BU) at three different temperatures 170,190 and 220 o C are given below in the following table: Table 2: Predictive equations for %BU as a function of N and Q/N at each barrel temperature (T b) [15]. T b ( o C) Intercept N Q/N Statistical analysis of all results produced a predictive equation to determine %BU as a function of the operating conditions including barrel temperature shown in Equation 2. %BU It was ticed that the effect of specific throughput decreases as the barrel temperature increases (Table 2). The equation considering the effect of temperature also indicated the significant effect of specific throughput in a twin screw extruder. Increase in specific throughput caused higher fill in the screw channels resulting in more melt (2) contacting the heated barrel walls. Higher specific throughput will increase the fill lengths in the screw mixing sections, or the regions with the highest shear heating [14]. To understand the mixing process of polymer melt in a twin screw extruder, it is necessary to consider the effect of specific mechanical energy. %BU y = x y = x R² = R² = y = x R² = SME (Kg -1 ) Figure 4. Relation between SME and %BU. The relation between percentage of breakup and SME is shown in Figure 4. A change in the degree of fill in a twin screw machine significantly changed the energy transport between the polymer and the extruders [15]. At a constant extruder screw speed, an increase in the mass flow rate i.e.; increase of specific throughput is associated with an increase in the shear rate and a decrease in the SME. Increasing screw speed causes an increase in the volumetric flow rate that result in an increased shear rate. At a constant mass flow rate, an increase in extruder speed is associated with an increase in SME as well as increase of higher frictional heat and the simultaneous increase in melt temperature. It was found that percentage of breakup was almost linear in certain range of specific mechanical energy though it decreases at higher specific mechanical energy (Figure 4). The effect of increasing the screw speed is an increase in shear rate and a decrease in residence time in the extruder but an increase in the intensity of the mechanical energy. %BU does t increase after certain level of increase the SME because of viscous dissipation [15]. The controlling factor in the mixing process is shear rate. In a twin screw extrusion at a constant mass flow rate, a constant shear rate can be obtained. Increase in screw speed does t result more dispersive mixing because the volumetric flow rate is controlled by the mass flow rate. Therefore, it is important to control specific throughput by controlling the overall SME to achieve the desired value of SPE ANTEC Anaheim 2017 / 1109

4 %BU. Thus at a constant barrel temperature, it is possible to maintain linearity in percentage of break up by controlling specific mechanical energy and shear rate in twin screw extruder. A previous study demonstrated the effect of N, Q/N and Q on the amount of water into polymer (Table 3) [16]. It was ticed that effect of specific throughput decreases at higher temperature. Effect of screw speed was t significant in previous study. Table 3. Predictive equations for water content as function of N and Q/N at each barrel temperature (α =.05) T b ( o C) Intercept N Q/N Q To determine the effect of barrel temperature, %RH results for the points in Table 1 were combined and evaluated. A 3D equation was formulated by statistical analysis shown in Equation 3. %RH= (3) Both linear and nlinear relationship between barrel temperature and %RH were ticed in this equation. The intercept value of this equation is very close to that of the equation at 190 o C. Therefore it can be attributed that the effect of temperature should be considered on %RH at higher temperature above 190 o C. However, interaction between %BU and water content was ticed in the study The number of total revolutions was also considered to determine the total path length followed by fluid particle, which is related to water content. A one dimensional Ludovic program was used to determine physical properties of Kollidon VA-64. Residence time and total number of screw revolution were derived from this program. The effect of residence time and revolutions versus %RH is shown in Figure 5 and 6. The results in Figure 5 show that the residence time is a poor predictor of water content in the melt (R 2 = 0.28). Across all three T b, the residence time does t significantly affect the water content in the melt. Increasing residence time from 50 to 300 seconds does t guarantee a lower %RH value. The linear trend lines have low R 2 values (< 0.30) and there are other common trends. Conversely, the total number of revolutions has a significant effect on the water content. The linear trend lines in Figure 6 indicate a relatively linear relationship (R ) and there is a clear decreasing trend in %RH as the total number of revolutions increases. Increasing the number of revolutions increases the total surface regeneration of the melt pool after the mixing section, thereby resulting in a lower %RH. To clarify this interpretation, the same Q/N, regardless of the screw speed, results in the same %RH. This underlines the observation that the controlling factor is surface regeneration, t the time in the extruder. %RH y = x y = x R² = R² = y = x R² = Residence Time (sec) Figure 5: Effect of Residence time on water content. While linear trend lines were added to Figure 6, the data displays a potential asymptotic decay as the number of revolutions increases as well as a convergence of all three T b. This suggests the existence of a minimum water content that can be achieved regardless of T b. While all three T b converge to a similar %RH after a large number of revolutions, they display unique behavior at lower revolution totals. Under approximately 300 revolutions, the hotter barrel temperatures result in clearly lower water content. Devolatilization was improved if the polymer melt experienced more revolutions during processing and thus water content was reduced. Thus, total surface regeneration increased during processing if the revolutions and the length of flow path increased. %RH y = x R² = y = x R² = y = x R² = Figure 6. Effect of Revolution on %RH Revolutions (rev) SPE ANTEC Anaheim 2017 / 1110

5 If more revolutions (and hence a longer path) are required during processing, the melt will experience more total cross-channel flow, which constantly serves to regenerate the devolatilization surface. Also the surface area of polymer molecule was strained by more revolution as well as shear rate; thus water molecules obtained more free space in polymer chain to escape. Conclusion It can be concluded that percentage of breakup in Kollidon VA-64 has a nlinear relation between the operating parameters of twin screw machines. Both operating condition and energy transport within the extruder machine is responsible for percentage of breakup and %RH. Also, %RH is dependent on revolution of the extruder due to devolatilization and change of molecular structure of polymer due to at higher temperature. References 1. A. Shah and M. Gupta, "Comparison of th flow in co-rotating and counter-rotating twin screw," ANTEC Technical Paper (2004). 2. R. V. Chiruvella, Y. Jaluria, M. V. Karwe and V. Sernas, Polymer Engineering and Science, 36, (1996). 3. S. R. V. Tomme, G. Storm and W. E. Hennink, International Journal of Pharmaceutics, 355 (2008). 4. D. Q. Craig, International Journal of Pharmaceutics, 231, , (2002). 5. W. Zhu and Y. Jaluria, Polymer Engineering and Science, 41, ( 2001). 6. A. Casale, Polymer Stress Reactions, Elsevier Inc, (1978). 7. H.-X. Huang, Journal of Materials Science,40, (2005). 8. MM1. Crowly, F. Zhang, M. A. Repka, S Thumma, S. B. Upadhya, S. K. Battu, C. Martin., Drug Development and Industrial Pharmacy, 33, (2007). 9. N. Follonier, E. Doelker and E. T. Cole, Drug Development and Industrial Pharmacy, 20, (1994). 10. N. Shah, H. Sandhu, D. S. Choi, H. Chokshi and A. W. Malick, Amorphous Solid Dispersions, Springer-Verlag New York (2014). 11. C. Brown, J. DiNunzio, M. Eglesia, S. Forster, M. Lamm, M. Lowinger, P. Marsac, C. McKelvey, R. Meyer, L. Schenck, G. Terife, G. Troup, B. Smith- Goettler and C. Starbuck, Amorphous Solid Dispersions, Springer New York, (2014). 12. D. Bigio, W. Pappas, H. Brown, B. Debebe and W. Dunham, ANTEC Technical Paper (2011). 13. G. M. Fukuda, R. Adnew, H. Brown, J. Kim and D. I. Bigio, ANTEC Technical paper (2013). 14. B. Dryer, J. Webb, D. I. Bigio, C. Brown, F. Flanagan and F. Yang, ANTEC Technical Paper, (2016). 15. Y. K.Chang, F.Martinez-Bustos, T. Park and J. Kokini, Brazilian Journal of Chemical Engineering, 16 (1999). 16. B. Dryer, J. Webb, D. I. Bigio, C. Brown, F. Flanagan and F. Yang, ANTEC Technical Paper, (2016). SPE ANTEC Anaheim 2017 / 1111