Center for Molecular Modeling - M. Vergaelen

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

elias — Fri, 11 Feb 2022 13:56:20 +0000

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

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

Private attachment

1-s2.0-S016836592200623X-main.pdf

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

michel — Mon, 23 Mar 2015 09:25:40 +0000

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

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

Private attachment

15_JPolymerScienceA_xxxx_Bouten.pdf

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

dietmar — Wed, 19 Nov 2014 15:41:28 +0000

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

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

Private attachment

14_Polym-Chem_2015_6_514_Bouten.pdf

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

dietmar — Wed, 15 Jun 2016 14:59:58 +0000

D. Hertsen, M. Vergaelen, R. Hoogenboom, V. Van Speybroeck

ISBN/ISSN:

Talk

Conference / event / venue

IAP annual meeting

Hasselt, Belgium

Friday, 11 September, 2015

Theoretical Rationalization of the Cationic Ring-opening Polymerization of a Methyl Ester Functionalized 2-Oxazoline Monomer

dietmar — Wed, 19 Nov 2014 15:28:06 +0000

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

ISBN/ISSN:

Poster

Conference / event / venue

Annual IAP Meeting (P7/05)

Louvain-La-Neuve, Belgium

Friday, 19 September, 2014

Abstract (private)

poster_abstract.pdf