R. Hoogenboom

Stable Amorphous Solid Dispersion of Flubendazole with High Drug Loading via Solvent Electrospinning

J. Becelaere, E. Van den Broeck, E. Schoolaert, V. Vanhoorne, J. F.R. Van Guyse, M. Vergaelen, S. Borgmans, K. Creemers, V. Van Speybroeck, C. Vervaet, R. Hoogenboom, K. De Clerck

Journal of controlled release

351, November 2022, Pages 123-126

2022

A1

Abstract

In this work, an important step is taken towards the bioavailability improvement of poorly water-soluble drugs, such as flubendazole (Flu), posing a challenge in the current development of many novel oral-administrable therapeutics. Solvent electrospinning of a solution of the drug and poly(2-ethyl-2-oxazoline) is demonstrated to be a viable strategy to produce stable nanofibrous amorphous solid dispersions (ASDs) with ultrahigh drug-loadings (up to 55 wt% Flu) and long-term stability (at least one year). Importantly, at such high drug loadings, the concentration of the polymer in the electrospinning solution has to be lowered below the concentration where it can be spun in absence of the drug as the interactions between the polymer and the drug result in increased solution viscosity. A combination of experimental analysis and molecular dynamics simulations revealed that this formulation strategy provides strong, dominant and highly stable hydrogen bonds between the polymer and the drug, which is crucial to obtain the high drug-loadings and to preserve the long-term amorphous character of the ASDs upon storage. In vitro drug release studies confirm the remarkable potential of this electrospinning formulation strategy by significantly increased drug solubility values and dissolution rates (respectively tripled and quadrupled compared to the crystalline drug), even after storing the formulation for one year.

DOI

https://doi.org/10.1016/j.jconrel.2022.09.028

Cation−π Interactions Accelerate the Living Cationic Ring-Opening Polymerization of Unsaturated 2-Alkyl-2-oxazolines

E. Van den Broeck, B. Verbraeken, K. Dedecker, P. Cnudde, L. Vanduyfhuys, T. Verstraelen, K. Van Hecke, V. V. Jerca, S. Catak, R. Hoogenboom, V. Van Speybroeck

Macromolecules

53, 10, 3832-3846

2020

A1

Abstract

Cation–dipole interactions were previously shown to have a rate-enhancing effect on the cationic ring-opening polymerization (CROP) of 2-oxazolines bearing a side-chain ester functionality. In line with this, a similar rate enhancement—via intermolecular cation−π interactions—was anticipated to occur when π-bonds are introduced into the 2-oxazoline side-chains. Moreover, the incorporation of π-bonds allows for facile postfunctionalization of the resulting poly(2-oxazoline)s with double and triple bonds in the side-chains via various click reactions. Herein, a combined molecular modeling and experimental approach was used to study the CROP reaction rates of 2-oxazolines with side-chains having varying degrees of unsaturation and side-chain length. The presence of cation−π interactions and the influence of the degree of unsaturation were initially confirmed by means of regular molecular dynamics simulations on pentameric systems. Furthermore, a combination of enhanced molecular dynamics simulations, static calculations, and a thorough analysis of the noncovalent interactions was performed to unravel to what extent cation−π interactions alter the reaction kinetics. Additionally, the observed trends were confirmed also in the presence of acetonitrile as solvent, in which experimentally the polymerization is performed. Most intriguingly, we found only a limited effect on the intrinsic reaction kinetics of the CROP and a preorganization effect in the reactive complex region. The latter effect was established by the unsaturated side-chains and the cationic center through a complex interplay between cation−π, π–π, π–induced dipole, and cation–dipole interactions. These findings led us to propose a two-step mechanism comprised of an equilibration step and a CROP reaction step. The influence of the degree of unsaturation, through a preorganization effect, on the equilibration step was determined with the following trend for the polymerization rates: n-ButylOx < ButenOx < ButynOx ≥ PentynOx. The trend was experimentally confirmed by determining the polymerization rate constants.

Open Access version available at UGent repository

Gold Open Access

DOI

http://dx.doi.org/10.1021/acs.macromol.0c00865

Halochromic properties of sulfonphthaleine dyes in a textile environment: the influence of substituents

T. De Meyer, I. Steyaert, K. Hemelsoet, R. Hoogenboom, V. Van Speybroeck, K. De Clerck

Dyes and Pigments

124 (2016), 249-257

2016

A1

Abstract

The application of pH-sensitive dye molecules onto textile materials is a promising method for the development of sensor materials. Ten commonly used pH-indicators, namely sulfonphthaleine dyes, are applied onto polyamide 6 using two distinct methods: conventional dyeing of fabrics and dye-doping of nanofibres. The influence of the substituents of each dye on their interaction with polyamide, as well as the difference between both application methods is investigated. For the conventionally dyed fabrics, halogen substituents are needed to result in a pH-sensitive fabric. This can be traced back to halogen bonding and is supported by theoretical simulations. Dye-doped nanofibrous non-wovens show significant dye leaching, which can be understood based on the very acidic electrospinning solution. The use of a complexing agent improves the leaching properties, especially for dyes containing four bromine substituents. These findings indicate the importance of halogen substituents on sulfonphthaleines for further research in the development of pH-sensitive sensors.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1016/j.dyepig.2015.09.007

Synthesis of poly(2-oxazoline)s with side chain methyl ester functionalities: Detailed understanding of copolymerization behavior of methyl ester containing monomers with 2-alkyl-2-oxazolines

P. Bouten, D. Hertsen, M. Vergaelen, B. Monnery, S. Catak, J. van Hest, V. Van Speybroeck, R. Hoogenboom

Journal of Polymer Science Part A: Polymer Chemistry

7 (17), 2711-2719

2015

A1

Abstract

Poly(2-oxazoline)s with methyl ester functionalized side chains are interesting as they can undergo a direct amidation reaction or can be hydrolyzed to the carboxylic acid, making them versatile functional polymers for conjugation. In this work, detailed studies on the homo- and copolymerization kinetics of two methyl ester functionalized 2-oxazoline monomers with 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, and 2-n-propyl-2-oxazoline are reported. The homopolymerization of the methyl ester functionalized monomers is found to be faster compared to the alkyl monomers, while copolymerization unexpectedly reveals that the methyl ester containing monomers significantly accelerate the polymerization. A computational study confirms that methyl ester groups increase the electrophilicity of the living chain end, even if they are not directly attached to the terminal residue. Moreover, the electrophilicity of the living chain end is found to be more important than the nucleophilicity of the monomer in determining the rate of propagation. However, the monomer nucleophilicity can be correlated with the different rates of incorporation when two monomers compete for the same chain end, that is, in copolymerizations. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015

DOI

http://dx.doi.org/10.1002/pola.27733

Accelerated living cationic ring-opening polymerization of a methyl ester functionalized 2-oxazoline monomer

P.J.M. Bouten, D. Hertsen, M. Vergaelen, B. Monnery, M.A. Boerman, H. Goossens, S. Catak, J.C.M. van Hest, V. Van Speybroeck, R. Hoogenboom

Polymer Chemistry

6, 514-518

2015

A1

Abstract

Kinetic studies on the homo- and copolymerization of 2-methoxycarboxyethyl-2-oxazoline (MestOx) with 2-methyl-2-oxazoline (MeOx) and 2-ethyl-2-oxazoline (EtOx) were performed. For the homopolymerisation of MestOx an increased propagation rate constant was observed compared to MeOx and EtOx while the copolymerization of MestOx with MeOx or EtOx unexpectedly revealed slower incorporation of MestOx. Density functional theory (DFT) calculations show that nearby MestOx residues in the living chain can activate both the oxazolinium chain end and the attacking monomer, stabilizing the propagation transition state, leading to faster homopolymerisation of MestOx. These effects also accelerate incorporation of both monomers in the copolymerisations. However, since MeOx is shown to be more nucleophilic than MestOx, the incorporation order is reversed in the copolymerisations.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1039/C4PY01373E

Cationic ring-opening polymerization of 2-propyl-2-oxazolines: Understanding structural effects on polymerization behavior based on molecular modeling

H. Goossens, S. Catak, M. Glassner, V. De La Rosa, B. Monnery, F. De Proft, V. Van Speybroeck, R. Hoogenboom

ACS Macro Letters

2, 651-654

2013

A1

Abstract

The surprising difference in the cationic ring-opening polymerization rate of 2-cyclopropyl-2-oxazoline versus 2-n-propyl-2-oxazoline and 2-isopropyl-2-oxazoline was investigated both experimentally and theoretically. The polymerization kinetics of all three oxazolines were experimentally measured in acetonitrile at 140 °C, and the polymerization rate constant (kp) was found to decrease in the order c-PropOx > n-PropOx > i-PropOx. Theoretical free energy calculations confirmed the trend for kp, and a set of DFT-based reactivity descriptors, electrostatics, and frontier molecular orbitals were studied to detect the factors controlling this peculiar behavior. Our results show that the observed reactivity is dictated by electrostatic effects. More in particular, the charge on the nitrogen atom of the monomer, used to measure its nucleophilicity, was the most negative for c-PropOx. Furthermore, the electrophilicity of the cations does not change substantially, and thus, the nucleophilicity of the monomers is the driving factor for kp.