Encapsulation of Ibuprofen by Pickering-Stabilized Antibubbles

Abstract

Ibuprofen, one of the most widely used nonsteroidal anti-inflammatory drugs, is a poor-tasting and poorly soluble drug. As an alternative approach to overcome these issues, ibuprofen was encapsulated in Pickering antibubbles using two different oils, cyclomethicone and cyclooctane, as processing aids. The amount of the loaded active agent was determined by thermogravimetry (TG), while the analysis of the evolved gases, performed by online coupling of the heating device to an infrared and a mass spectrometer (EGA-FTIR-MS), allowed for describing the drug decomposition mechanism. Although the dissolution profile and zeta potential values were found to be independent of the preparation method, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Raman microscopy confirmed the occurrence of a slight amorphization of the drug inside the antibubbles. The reported results suggest that this relatively simple encapsulation technique might be an alternative for ibuprofen taste masking and targeted delivery.

Introduction

Even though ibuprofen, (R,S)-2-(4-(2-methylpropyl)phenyl)propanoic acid, is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), (1,2,3) it is still the focus of widespread research into the development of smarter formulations for targeted or localized delivery, as well as for taste masking. (4,3) To this end, microencapsulation, a technology wherein particles are enclosed within a core material, surrounded by a protective shell, is widely used. (5−8) Indeed, several encapsulation methods, including emulsification, extrusion, spray drying, freeze-drying, and coacervation, have been reported, providing microparticles in the range of a few to a hundred microns. (6,9) However, obtaining homogeneous mixtures during such formulation processes can be challenging; (10,11) therefore, as an alternative strategy, we propose the use of antibubbles, defined as bubbles containing one or more cores that can either be solid or liquid. (12) Although it has been shown that antibubbles significantly improve in vitro drug delivery, (13) until recently, a real challenge with this method was their short lifespan of about 1 min when dispersed in water. This issue has been, however, solved through the application of the so-called Pickering stabilization, which increased the lifespan to at least 7 days under the same conditions. (14,15) This process involves generating a water-in-oil-in-water (W/O/W) double emulsion, stabilized by hydrophobized silica particles, where the two water phases contain a solute that solidifies upon drying and the oil phase is volatile. Water and oil are removed from the W/O/W emulsion through freeze-drying, and reconstituting the freeze-dried material in water leads to the formation of the desired antibubbles. (16−18)

In this work, we used a slightly modified method in the sense that ibuprofen crystals were not first dissolved in water, due to its lower solubility of around 11 μg/mL, (19) but were directly dispersed in the oil phase, using either cyclooctane or cyclomethicone D4, to create a so-called solid-in-oil-in-water emulsion (S/O/W). To study the bulk properties of the encapsulated ibuprofen in the two different oils in the dry state, we employed thermal analysis techniques, X-ray powder diffraction (XRPD), and Raman confocal microscopy. Additionally, the zeta potential and the dissolution profile of the formulations were compared to those of the pure drug.

Thermal analysis of encapsulated pharmaceuticals (5,20,21) is an excellent analytical methodology to evaluate the properties of composite materials, giving valuable insights into their stability, reactivity, and diverse thermodynamic characteristics. Particularly, data collected through evolved gas analysis (EGA) by integrating mass spectrometry (MS) and Fourier-transform infrared spectroscopy (FTIR) (22) with thermogravimetric (TG) facilitates the identification of gaseous species produced during thermal degradation, resulting in a comprehensive analysis of the drug release process and decomposition mechanism. (23−25) On the other hand, by combining differential scanning calorimetry (DSC) with XRPD, it is possible to assess the degree of crystallinity of the studied samples. Furthermore, 2D maps acquired using Raman microscopy, a technique utilizing scattered light to probe the molecular composition within an irradiated volume, allow for a clear label-free spatial representation of drug distribution within the matrix. (26) Here, this approach gave valuable insight into the intricate interactions between ibuprofen, the sugar matrix covering the antibubbles and the micron-sized antibubbles.

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Materials

Ibuprofen, donated by BASF (Germany), Aerosil R972, a hydrophobized fumed silica particle from Evonik (Germany), maltodextrin-glucidex 2, cyclooctane (CO), and cyclomethicone D4 (CM) from Sigma-Aldrich were used without further purification.

Charalampos Tsekeridis, Paloma Manuelle Marques da Silva, Guilherme B. Strapasson, Albert T. Poortinga, and Heloisa Nunes Bordallo, Encapsulation of Ibuprofen by Pickering-Stabilized Antibubbles, ACS OMEGA, Cite This: https://doi.org/10.1021/acsomega.4c10244

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