(W1230-07-41) Novel Inter-Polymer Complexes in the Development of Spray-Dried Dispersions: A Computational and Experimental Study

Purpose: Stable inter-polymer complexes are formed through interactions such as hydrogen bonding (H-bonding), electrostatic attractions, and hydrophobic interactions between different macromolecular polymeric species. These complexes exhibit unique properties that differ significantly from those of the individual component polymers, offering a range of advanced functionalities. Recent research underscores the growing applications of these complexes in drug delivery, showcasing their significant potential to advance the field. The objective of this study was to investigate inter-polymer complexes for potential use in solid dispersions to deliver poorly soluble drugs, utilizing both computational and experimental techniques. Inter-polymer complexes of Polyvinyl-pyrrolidone (PVP) and Eudragit-L100 or Eudragit-L100-55 were selected. The properties were evaluated experimentally using FTIR, solid-state NMR, mDSC, and SEM, and computationally through molecular dynamics (MD) simulations. The results demonstrate that stable inter-polymer complexes of PVP and Eudragit-L100-55 can be manufactured via spray drying, providing the foundation for further investigation into the use of these complexes in the formation of solid dispersions for the delivery of poorly soluble drugs.

Methods: Computational: PVP and Eudragit (L100 and L100-55) polymer models (~500,000 atoms) were constructed with weight ratios of 1:1 and 1:2 and randomly placed in a 200x200x200 simulation box. A series of MD simulations were performed using the NAMD software package (v.3.0b3) with CHARMM36 and CGENFF all-atom force field parameters to investigate polymer-polymer interaction energies and understand the inter-polymer complex formation mechanism. The models were energy-minimized, followed by a 10 ns NVT simulation with gradual heating to 310 K. Production runs were conducted at 310 K and 1 atm for 10 ns. Experimental: Inter-polymer complexes were produced via film casting and spray drying. Ethanol or methanol-based solutions were prepared with 5 wt% of PVP and Eudragit (L100 or L100-55) respectively, and then mixed in equal mass proportions, either by mixing in a vessel, or by metered delivery into a three fluid nozzle. Eudragit-L100-55 was used for the spray dried complexes. Spray drying was performed on a Buchi B-290 Spray Dryer with an inert loop. Both films and dried powder were subjected to convective secondary drying at 40 °C (VWR Signature Forced Air Safety Oven). Films and powder were analyzed via FTIR (Thermo Scientific Nicolet iS10), mDSC (TA Instruments Discovery DSC), TGA (TA Instruments Discovery TGA 5500), SEM imaging (Thermo Scientific Phenom XL 100), and Solid-State NMR (Bruker NEO NMR spectrometer, Topspin 4.0.8) was performed at Kansas Analytical Services.

Results: Computational: Interactions between PVP and both Eudragit-L100 and Eudragit-L100-55 were observed in MD simulations (Figure 1a). The interaction energies between Eudragit-L100 polymer chains are significantly stronger than those between Eudragit-L100-55 chains in both 1:1 and 1:2 systems, as shown in Figure 1b. Based on the time-averaged total PVP-Eudragit binding interaction energies in Figure 1c, the PVP:Eudragit-L100-55 1:2 system demonstrates the highest binding affinity. To further assess the complexation between the polymers, both qualitative and quantitative estimations of H-bond formation were conducted. Figure 1d shows the H-bond formation predominantly between Eudragit hydroxyl groups and carbonyl oxygen in pyrrolidone. Based on time-averaged H-bond counts, the inter-polymer complexations were ranked as follows: PVP:Eudragit-L100-55 1:2 > PVP:Eudragit-L100 1:2 > PVP:Eudragit-L100-55 1:1 > PVP:Eudragit-L100 1:1. This ranking corroborates the previously observed total interaction energy trends, further emphasizing the higher binding and complexation capabilities of the PVP:Eudragit-L100-55 1:2 system. Experimental: Based on the computational results PVP:Eudragit-L100-55 1:2 system was used for experimental analysis. Using a three-fluid nozzle, complexes of PVP with Eudragit-L100-55 were produced via spray drying. Collected powder was analyzed via SEM and showed a mix of collapsed spheres and string like particles (Figure 2). FTIR and Solid-state NMR results indicate that complexation occurs largely through H-bonding between Eudragit's hydroxyl groups and pyrrolidone's carbonyl oxygen. This is evidenced by peak shifts in the carbonyl regions in both FTIR (Figure 3a) and NMR (Figure 3b), and is further supported by computational results. NMR ¹H T₁ and ¹H T_1rho relaxation parameters of the spray dried complex (Figure 3c-d) implied only partial complexation and may be due to the short duration of external mixing of solutions. This is corroborated by the non-homogenous nature of the resulting particles, as shown by SEM. Thermal analysis suggested a stabilization of Eudragit-L100-55 by PVP, with weight loss and thermal events typically observed starting at 150 °C[2] for Eudragit-L100-55 being pushed to higher temperatures or not present at all.

Conclusion: This study provides a detailed mechanistic understanding of the inter-polymer complexes formed between PVP and Eudragit-L polymers. Computational results offer valuable insights into the molecular interactions and binding efficiencies of PVP with different Eudragit polymers. Both computational and experimental spectral analysis indicate that complexation occurred through H-bonds between the hydroxyl groups of Eudragit polymers and the carbonyl oxygen of PVP. Additionally, it was shown that this complex could be produced via spray drying with a three-fluid nozzle, allowing for manufacturing of pseudo-crosslinked amorphous dispersions.

References: 1. Lau, C. (2002). A study of blending and complexation of poly(acrylic acid)/poly(vinyl pyrrolidone). Polymer, 43(3), 823–829.
2. Parikh, Tapan & Gupta, Simerdeep Singh & Meena, Anuprabha & Serajuddin, Abu. (2014). Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - III: Polymethacrylates and polymethacrylic acid based polymers. Journal of Excipients and Food Chemicals. 5. 56-64.

Acknowledgements: Equal contributions by Nathan Spurgin(experimental) and Dineli T.S. Ranathunga(computational).

Figure 1: Computational modeling results. a) Initial and final (10 ns) MD trajectory snapshots of PVP:Eudragit-L100-55 system. Coloring as follows: Eudragit-L100-55 (blue), PVP (green). b) The total interaction energies between polymeric chains in both 1:1 and 1:2 systems. c) Time averaged total interaction energies (electrostatic and dispersion) and H-bond counts. d) H-bond formation between PVP and Eudragit-L100-55 inter-polymer chains. Zoomed-in image shows hydrogen bonding between the hydroxyl groups of Eudragit and the carbonyl oxygen in pyrrolidone . Coloring as follows: Eudragit-L100-55 (transparent blue), PVP ( transparent green), Oxygen (red), Hydrogen (white), Carbon (cyan), Nitrogen (dark blue), Inter-polymer H-bonds (red dotted lines), and Intra-polymer H-bonds (light blue dotted lines).

Figure 2: SEM image of spray dried inter-polymer complex, exhibiting a mix of collapsed spheres and string like particles.

Figure 3: a) FTIR spectra of PVP (blue trace), Eudragit L100-55 (purple trace), and 1:1 by weight Eudragit L100-55:PVP spray dried interpolymer complex (red trace), focus on the carbonyl region. b) 13C Solid State NMR Spectra of PVP (blue trace), Eudragit L100-55 (black trace), and 2:1 by weight Eudragit L100-55:PVP film-cast inter-polymer complex (green trace), focused on the carbonyl region c) 1H T1 and 1H T1rho Relaxation Parameters for 1:1 by weight Eudragit-L100-55:PVP spray dried interpolymer complex. d) 1H T1 and 1H T1rho Relaxation Parameters for 2:1 by weight Eudragit L100-55:PVP film-cast interpolymer complex. The assignment at 58.0ppm is attributed to ethanol.