Effects of polymer microstructure introduced by radical ring-opening polymerization on nanoencapsulation and controlled release

In this study, the effect of the polymer structural difference introduced by radical ring-opening polymerization (rROP) of a cyclic ketene acetal (CKA) monomer, analogous to ε-caprolactone (CL), on the nanoencapsulation and controlled release of hydrophobic actives curcumin and fenofibrate was explored. The two chosen polymers are amphiphilic diblock copolymers namely methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL) and methoxy poly(ethylene glycol)-b-poly(2-methylene-1,3-dioxepane) (mPEG-b-PMDO). Both polymers serve as a good comparison as they have a similar average molecular weight (Mn) and the same hydrophilic PEG chains with the main difference in microstructure of hydrophobic PCL and PMDO chains. Nuclear magnetic resonance spectroscopy (NMR) (1H and 13C), gel permeation chromatography (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray diffraction (X-RD) confirmed the structures of the polymers. mPEG-b-PMDO possesses less crystallinity or is more amorphous as compared to the linear mPEG-b-PCL due to branching or polymer disorder in the hydrophobic segment as a result of radical mechanism operating in rROP. The subsequent nanoencapsulation of hydrophobic active curcumin with mPEG-b-PMDO yielded higher loading content (LC) and encapsulation efficiency (EE) in the hydrophobic core of the nanoparticle (NP) due to more hydrophobic interactions between hydrophobic core and hydrophobic active. In contrast, lower LC and EE were observed for the nanoencapsulation of fenofibrate with mPEG-b-PMDO. The further release experiments were carried out in the aqueous and hydro-alcoholic systems over a period of 24 h at 37 °C. These experiments further supported our hypothesis regarding the influence of polymer structure, revealing slower, controlled, and more consistent release profiles for both curcumin and fenofibrate with mPEG-b-PMDO compared to mPEG-b-PCL. Our approach could open new opportunities for utilizing this polymer in personal care and biomedical applications.</p

Molecular Interactions between APIs and Enteric Polymeric Excipients in Solid Dispersion: Insights from Molecular Simulations and Experiments

Solid dispersion of poorly soluble APIs is known to be a promising strategy to improve dissolution and oral bioavailability. To facilitate the development and commercialization of a successful solid dispersion formulation, understanding of intermolecular interactions between APIs and polymeric carriers is essential. In this work, first, we assessed the molecular interactions between various delayed-release APIs and polymeric excipients using molecular dynamics (MD) simulations, and then we formulated API solid dispersions using a hot melt extrusion (HME) technique. To assess the potential API–polymer pairs, three quantities were evaluated: (a) interaction energy between API and polymer [electrostatic (Ecoul), Lenard-Jones (ELJ), and total (Etotal)], (b) energy ratio (API–polymer/API–API), and (c) hydrogen bonding between API and polymer. The Etotal quantities corresponding to the best pairs: NPX-Eudragit L100, NaDLO–HPMC(P), DMF–HPMC(AS) and OPZ–HPMC(AS) were −143.38, −348.04, −110.42, and −269.43 kJ/mol, respectively. Using a HME experimental technique, few API–polymer pairs were successfully extruded. These extruded solid forms did not release APIs in a simulated gastric fluid (SGF) pH 1.2 environment but released them in a simulated intestinal fluid (SIF) pH 6.8 environment. The study demonstrates the compatibility between APIs and excipients, and finally suggests a potential polymeric excipient for each delayed-release API, which could facilitate the development of the solid dispersion of poorly soluble APIs for dissolution and bioavailability enhancement

Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches

Cocrystallization has matured into an established technique for fine-tuning the physicochemical properties of active pharmaceutical ingredients (APIs). This technique has been adopted by pharmaceutical drug companies, with increasing numbers of cocrystal-based drug products now entering the market. Surprisingly, however, studies into the formulation aspects of cocrystal-based drugs are relatively few and far between compared to the vast literature on their design, synthesis, and characterization. We herein report the results of our investigations into cocrystal–excipient interactions in water that determine the dissolution properties of cocrystals in formulation by a combination of molecular dynamics (MD) simulation and experimental approaches. Two cocrystals of an antirheumatic drug, leflunomide (LEF) with 3-hydroxybenzoic acid (HBA) and 2-picolinic acid (PIC), were assessed in formulation with the frequently used excipients lactose and dibasic calcium phosphate (DCP). For comparison, the dissolution of neat LEF formulations with these excipients was also evaluated. The parameters deduced from MD simulations, such as solvent-accessible surface area, intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators in the prediction of cocrystal formulation dissolution trends. It was found that the presence of lactose as an excipient improved the dissolution of the cocrystal formulation compared to the neat cocrystals, most notably for the LEF-PIC cocrystal. In contrast, DCP was seen to have a detrimental effect on the dissolution of cocrystal formulations, all exhibiting lower dissolution than their neat cocrystal counterparts and LEF. Careful analysis of these results revealed that the nature of the excipient plays a significant role in the dissolution properties. While the improved dissolution of the lactose formulations was attributed to its hydrophilic nature, the ionic and hydrophobic nature of DCP was likely responsible for its detrimental effect. The results of the MD simulations were found to be in excellent agreement with the experimentally observed dissolution hierarchy