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.

Figure 1

Chemical Structure of the active pharmaceutical ingredient, ibuprofen, (a) and of the excipients used for preparing the microencapsulation system: Aerosil R972 (b), maltodextrin-glucidex 2 (c), cyclooctane, CO (d), and cyclomethicone, CM (e).

Figure 2

Schematic representation of the two-step process used in the production of ibuprofen encapsulated in the silica antibubbles. (a) A solid-in-oil-in-water (S/O/W) emulsion containing oil droplets that include ibuprofen in crystalline form in the case of cyclomethicone. When cyclooctane is used, ibuprofen completely dissolves in the oil, and hence ibuprofen particles will form during the removal of the oil in the process of freeze-drying. (b) Antibubbles freeze-dried powder obtained after removing the oil and the water. R972 particles were also present in the oil phase and thus in the gas phase, forming a kind of network in which the crystals are entrapped.

Figure 3

SEM image of freeze-dried maltodextrin containing an “antibubble” filled with a network of silica containing small drug particles. With the arrows, we identify the maltodextrin network where the silica shells are located and where the ibuprofen is encapsulated.

Figure 4

(a) Thermogravimetric analysis and (b) first derivatives (DTG) of ibuprofen encapsulated in the antibubbles (Ibuprofen_on_ABS_CM and Ibuprofen_on_ABS_CO), compared with empty antibubbles (ABS_R972), Pure_Maltodextrin, and Pure_Ibuprofen.

Figure 5

(a) Ion current for m/z = 18 showing the emission of water related to the evaporation of moisture under 100 °C and around the decomposition temperature of the pure drug, as highlighted in gray. (b) Mass spectrum for m/z = 44 showing that CO₂ emission attributed to maltodextrin and ABS_R972 is also observed in the encapsulated systems at distinct ROIs. (c) Mass spectrum for m/z = 41, related to the loss of HCOOH in Pure_Ibuprofen, is observed at the second ROI. For better comparison, the mass spectrum for water and CO₂ were normalized first on the sample mass and then to unity, while the signal at m/z = 41 was only normalized to mass.

Figure 6

FTIR spectra for the 5 samples. (a) ABS_R972 shows mostly the maltodextrin degradation at 300 °C. (b) Pure_Maltodextrin shows carbohydrate degradation at 300 °C. (c) Pure_Ibuprofen shows a higher absorption intensity at 220 °C related to the faster rate of degradation observed in the DTG curve. (d) Ibuprofen_on_ABS_CM shows a small emission at 170 °C and (e) Ibuprofen_on_ABS_CO at 120 °C. Note that water and carbon dioxide signals were over subtracted from the beginning of the measurement in (b). This common artifact is related to the presence of these gases in the TGA furnace.

Figure 7

Differential scanning calorimetry measurements for Pure_Ibuprofen (black line), Ibuprofen_on_ABS_CM (red line), and Ibuprofen_on_ABS_CO (blue line). The results show a strong endothermic peak at 77 °C for Pure_Ibuprofen, at 74 °C for Ibuprofen_on_ABS_CM and at 73 °C for Ibuprofen_on_ABS_CO. The full range of the thermograms are presented in Figure S5. Note that for clarity each sample has a unique y-axis.

Figure 8

XRPD patterns for Pure_Ibuprofen, Ibuprofen_on_ABS_CM, and Ibuprofen_on_ABS_CO. (a) Between 5° and 8°, the decrease of the Bragg reflection intensity indicates a successful encapsulation. (b) The observation of new reflections with different peak shapes in the range of 19°–22° confirms that new crystalline forms were obtained (as arrows shown at 20.2°, 20.4°, and 21.2°); see also Figure S7.

Figure 9

Raman maps showing the freeze-dried maltodextrin in red (a) covering an ibuprofen crystallite encapsulated in the antibubbles prepared using cyclomethicone D4. The crystallite is shown in green in (b).

Figure 10

Visual light microscopy image representation of the free drug molecule (a) as well as the drug encapsulated in the R972 antibubbles: Ibuprofen_on_ABS_CM (b) and Ibuprofen_on_ABS_CO (c). Raman spectra for all samples are shown in d–f. All spectra were normalized to the highest internal vibration of each sample.