Miscibility, phase behavior, and mechanical properties of copovidone/HPMC ASLF and copovidone/Eudragit EPO polymer blends for hot-melt extrusion and 3D printing applications

Introduction

Amorphous solid dispersions (ASDs) are a widely used formulation strategy to enhance the solubility and consequently, the oral bioavailability of poorly soluble drugs. However, formulating ASDs is often challenging due to the inherent physical instability of the initial amorphous state and the difficulty of maintaining the long-term physical stability of drug formulations (Alzahrani et al., 2022). To tackle this issue, various polymeric carriers have been extensively used to achieve a high degree of supersaturation and stabilize the amorphous form of the poorly water-soluble drug in preparation for solid dispersion. Several hydrophilic non-ionic polymers such as copovidone (Kollidon® VA64, PVP VA64), hypromellose (HPMC E5), povidone (PVP K30), and hydrophobic ionic polymers such as HPMC ASLF, Eudragit L100-55, Eudragit EPO have been used as concentration-enhancing polymers for hot-melt extrusion (HME) based solid dispersion for drug delivery. These concentration-enhancing polymers can maintain supersaturation for prolonged durations by inhibiting drug precipitation in aqueous environments. However, the use of a single polymeric carrier for solid dispersion has limitations with respect to drug loading and physical stability, resulting in the large size of the pill and poor stability. Researchers have discovered that polymer combinations can synergistically increase glass transition temperature, decrease molecular mobility, and enhance drug-polymer miscibility and interaction. This enables high drug loading, tailored dissolution profile, improved physical stability, and oral absorption of solid dispersions (Liu et al., 2013, Prasad et al., 2016, Rahman, 2019, Xie, 2016).

The blending of two polymers approach is often used to improve or combine polymer properties without markedly altering the structure and function of the individual polymers. The primary motivation behind this approach is the high costs and time associated with developing new polymers, in addition to the ability to customize properties by blending, which may result in new, desirable, and, in some cases, unexpected synergistic properties (Nyamweya, 2021). Thermodynamically, mixing two polymers can either result in miscibility, immiscibility, or partial miscibility, depending on the free energy of mixing. The miscibility of polymer–polymer blend requires a negative free energy of mixing (ΔGmix = ΔHmix − TΔSmix < 0). Unlike small molecules, for high molecular weight polymers, the entropy of mixing (ΔSmix) is negligibly small, and the sign of ΔGmix is dominated by the enthalpy of mixing (ΔHmix). Hence, the enthalpy of mixing (ΔHmix) is a deciding factor for miscibility in polymer blends (Lu and Weiss, 1992, Thomas and Jyotishkumar, 2015). When two polymers are fully miscible, they form a homogeneous blend. Conversely, when polymers are partially miscible or completely immiscible, the resulting blend is typically heterogeneous. Typically, the enthalpy of mixing for polymer blends is negative when specific interactions such as hydrogen bonding, ionic interactions, and dipole–dipole interactions occur between individual polymers. These interactions play a vital role in determining the miscibility and phase behavior of the blend, which in turn determines the final properties of the blend (Yang et al., 2013). Given the critical role of miscibility in determining blend properties, a thorough analysis of prepared polymer blends is essential. For this reason, a detailed analysis of the polymer blends is necessary to identify the blend miscibility and the factors that control miscibility. Such understanding is crucial for predicting and tailoring the performance of polymer blends in various applications.

For fused deposition modeling (FDM-3DP) based 3D printing applications, polyvinyl alcohol (PVA), polylactic acid (PLA), and PVP (Kollidon® 12PF) are frequently used pharmaceutical-grade polymers due to their sufficient thermoplastic property and low melting temperature (Pereira et al., 2020, Yang et al., 2021). However, relying on these limited polymer options restricts the ability to customize drug release profiles and limits the application of any delivery system produced from them (Alhijjaj et al., 2016). Several other polymers that are suitable for HME are often very brittle, and a common approach to overcome brittleness and reach mechanical resilience is achieved using the addition of plasticizers (Zhang et al., 2019) or the use of polymer blends (Alhijjaj et al., 2016). A recent study on 3D printing by Nassereddin et al. using Soluplus®, Eudragit EPO, and Copovidone (PVP VA64) polymers indicated that these polymers were not feedable due to excessive brittleness even with low incorporation of plasticizer. On the other hand, it has been reported that an increased amount of plasticizers resulted in over-flexible filaments with poor feedability (Nasereddin et al., 2018, Tabriz et al., 2021). A study by Zhang et al. showed that hypromellose acetate succinate (HPMC AS) is a polymer with good stiffness, and no plastic deformation or surface cracking is observed during the printing process (Zhang et al., 2019). Therefore, we hypothesized that HPMC ASLF can act as a plasticizer in combination with Copovidone (PVP VA64), producing filaments with exceptional mechanical and flexible properties. Similarly, Eudragit EPO is a branched methacrylic polymer with a low Tg that can provide a plasticizing effect when mixed with Copovidone (PVP VA64), eventually reducing the viscosity of the molten polymer combination, and producing filaments suitable for 3D printing via hot melt extrusion.

Several techniques have been employed to assess the suitability of filament formulations for the FDM process; however, currently, there is no standard test method to screen filaments for their suitability for the FDM process. In this study, a widely used three-point flexural bending test was employed to assess the brittleness or flexibility of the strands using a texture analyzer. The mechanical properties of the different formulations were evaluated and compared using the resulting breaking force, breaking distance, and stress–strain curves (Gottschalk et al., 2021, Nasereddin et al., 2018).

Based on these premises, the key objective of this study was to investigate the potential of combining Copovidone (PVP VA64) with either HPMC ASLF or Eudragit EPO as binary carriers for solid dispersions using HME and to assess its suitability for FDM-based 3D printing applications. To the best of the authors’ knowledge, a detailed solid-state characterization of this polymer blend combination has not been reported previously. The model polymers, Copovidone (PVP VA64, Kollidon® VA 64), HPMC ASLF, and Eudragit EPO, were selected based on their different physicochemical properties. Initially, an estimation of solubility parameters, polarity values, enthalpy of mixing, and Flory-Huggins (F-H) interaction parameters was conducted to understand the polymer–polymer miscibility. This was followed by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) to assess the thermal stability of materials and polymer–polymer miscibility by glass transition temperature (Tg) estimation via experimental and theoretical approaches. Polymer blend films were then prepared and examined by visual and optical microscopy as well as scanning electron microscopy (SEM) for miscibility, morphology, and phase behavior. Fourier transform infrared spectroscopy (FTIR) was performed to understand the type of interaction between two polymers. Finally, hot melt extrusion of Copovidone/HPMC ASLF and Copovidone/Eudragit EPO (EPO) polymer blends at different compositions were extruded to produce filaments or strands. A three-point bend test was conducted to measure the mechanical properties of the extruded filaments, including breaking force, breaking distance, Young’s modulus, and elongation at break. The impact of the measured mechanical properties on the printability of the polymer blend extrudate was discussed. This correlation can be utilized to predict the printability for FDM based 3D printing filaments and assist in the development of future 3D printing dosage forms.

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Materials

Copovidone (PVP VA64), Poly (1-vinylpyrrolidone-co-vinyl acetate)) was received from BASF Corporation (New Jersey, US). Hypromellose Acetate Succinate, NF (HPMC ASLF, Viscosity 3cps, Soluble in pH 5.5 and above) was obtained from Shin-Estu Chemical Co. Ltd (Tokyo, Japan). Amino Methacrylate copolymer, NF [Eudragit EPO, Soluble up to pH 5.0, MW approximately 47,000, Chemical name: Poly (butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1] was provided by Evonik.

Gaurang Patel, Tamara Minko, Miscibility, phase behavior, and mechanical properties of copovidone/HPMC ASLF and copovidone/Eudragit EPO polymer blends for hot-melt extrusion and 3D printing applications, International Journal of Pharmaceutics, Volume 670, 2025, 125124, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125124.

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