(M0930-09-50) Predicting Filaments Behavior in Milling and Printing via 3 Point Bend Test

Purpose: Understanding the mechanical properties of extrudates produced via hot melt extrusion is a key point for the downstream-processing especially looking at the milling and tableting steps as reduced brittleness resulting and loss of compressibility can be seen [1]. The 3 point bend test [2-3] was define as a technique to analyse flexibility and strength of extrudates. This study shows an investigation of mechanical properties of ASD filaments prepared by HME and relationship to their milling behavior.

Methods: Itraconazole (ITZ) and fenofibrate (FF) were purchased from Ash Ingredients (Glen Rock, NJ, USA) and Biddle Sawyer Pharma LLC (New York, NY, USA), respectively. Three grades of Shin-Etsu AQOAT^®  (HPMCAS) AS-LMP, AS-MMP and AS-HMP manufactured by Shin-Etsu Chemicals Co. Ltd. (Tokio, Japan) were used for this study. Preparation of amorphous solid dispersion. Itraconazole and fenofibrate were individually blended with Shin-Etsu AQOAT^® (HPMCAS: AS-LMP, -MMP and AS-HMP) in a ratio 20:80. Extrudates were produced using a twin screw extruder (Pharma 11, ThermoFischer Scientific) at 160°C and 150 rpm screw speed. A 2 mm die was selected. The extrudates were cooled on a conveyor belt and cute by hand into filaments of around 5-7 cm. The melting point (T_m) of ITZ and FF and the glass transition temperature (T_g) of ASD of ITZ:HPMCAS and FF:HMCAS were accessed by DSC analysis (Perkin Elmer, CT) – table 1. 3 point bend test. Hand-cut filaments were tested using a TA. XT plus texture analyser (HDP/M3PB, Stable Micro Systems, Ltd.). The filaments were placed on 3-point bend ring at pretesting speed of 1mm/s and test speed of 0.1 mm/s using a 50 kg load cell. The force displacement curve was generated and converted into stress strain curve in order to calculate the tensile strength and Young’s modulus (n=5) [3]. The tensile strength was calculated as maximum stress before the failure happens at the bend test. Young’s modulus was calculated from the slope of the stress strain curve with best fit. Milling. The ASD filaments of both mixture selected for further processing were ITZ:HPMCAS-MMP (20:80) and FF:HPMCAS-MMP (20:80) and were milled in two steps on a hammer mill (HM1, Frewitt USA) first using a 4 mm screen at 15000 rpm, then using a 1 mm screen at different milling speed: 500, 10000, 15000 rpm. The particle size distribution of the milled filaments was analysed by sieve analysis.

Results: The tensile strength can be calculated as maximum stress before the failure happens during bend test. Thus, filaments showing higher tensile strength require higher stress/pressure to break. Young's modulus is a measure of the stiffness of a solid material defining the relationship between the applied stress and the resultant strain and can be calculated from the slope of the stress-strain curve [3]. Filaments of FF ASD showed higher tensile strength and lower Young’s’ modulus compared to ITZ ASD with all three grades of HPMCAS. Thus, indicating high elasticity/ductility for FF ASD compared to ITZ ASD – figure 2. As a result, the FF ASD requires high pressure to undergo deformation/breakage and it is expected to be more challenging to undergo downstream process like milling and tableting. The higher tensile strength and lower Young’s modulus in case of FF ASD compared to ITZ ASD could be attributed to the lower Tg of the FF ASD thus exhibiting higher molecular mobility compared to ITZ.

Conclusion: The plasticity/brittleness of the ASDs produced via hot melt extrusion were analysed by a 3 point bend test with the respective filaments. Itraconazole: HPMCAS ASDs having a high glass transition temperature showed a lower tensile strength and high young’s modulus of the filaments allowing to predict a smooth milling in standard conditions with a hammer mill. On the other hand, fenofibrate: HPMCAS ASDs had a comparatively lower glass transition temperature and showed a higher tensile strength and lower young’s modulus and challenges in milling can be expected. Indeed, during the milling at room temperature, melted material was found in the milling chamber. A cryo-milling would be required in that case.

References: 1. Solanki, N.G.; Gumaste, S.G.; Shah, A.V.; Serajuddin ATM; Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion. II: Rheological Analysis and Extrudability Testing, J. Pharm. Sci. 108, 3063-3073 (2019).
2. Hill, H.E.; Physical-Mechanical Properties of Extrudates and Tablets Manufactured thereof. University of Basel Thesis (2015).
3. Palekar, S.; Nukala, PK.; Mishra, SM.; Kipping, T. and Patel, K. Application of 3D Printing Technology and Quality by Design Approach for Development of Age-Appropriate Pediatric Formulation of Baclofen. Int. J. Pharm., 10:556, 106-116 (2019).