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. 2020 May 16;12(5):455.
doi: 10.3390/pharmaceutics12050455.

The Correlation between Physical Crosslinking and Water-Soluble Drug Release from Chitosan-Based Microparticles

Emilia Szymańska  1 , Katarzyna Woś-Latosi  2   3 , Julia Jacyna  4 , Magdalena Dąbrowska  1 , Joanna Potaś  1 , Michał Jan Markuszewski  4 , Katarzyna Winnicka  1
Affiliations

The Correlation between Physical Crosslinking and Water-Soluble Drug Release from Chitosan-Based Microparticles

Emilia Szymańska et al. Pharmaceutics. .

Abstract

Microparticles containing water-soluble zidovudine were prepared by spray-drying using chitosan glutamate and beta-glycerophosphate as an ion crosslinker (CF). The Box-Behnken design was applied to optimize the microparticles in terms of their drug loading and release behavior. Physicochemical studies were undertaken to support the results from dissolution tests and to evaluate the impact of the crosslinking ratio on the microparticles' characteristics. The zidovudine dissolution behavior had a complex nature which comprised two phases: an initial burst effect followed with a prolonged release stage. The initial drug release, which can be modulated by the crosslinking degree, was primarily governed by the dissolution of the drug crystals located on the microparticles' surfaces. In turn, the further dissolution stage was related to the drug diffusion from the swollen polymer matrix and was found to correlate with the drug loading. Differential Scanning Calorimetry (DSC) studies revealed the partial incorporation of a non-crystallized drug within the polymer matrix, which correlated with the amount of CF. Although CF influenced the swelling capacity of chitosan glutamate microparticles, surprisingly a higher amount of CF did not impact the time required for 80% of the drug to be released markedly. The formulation with the lowest polymer:CF ratio, 3:1, was selected as optimal, providing satisfactory drug loading and displaying a moderate burst effect within the first 30 min of the study, followed with a prolonged drug release of up to 210 min.

Keywords: chitosan glutamate; drug release; ion crosslinker; microparticles; zidovudine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Predicted optimal factors settings (in red) for each studied response, with the use of a maximized desirability function. (A–C)—the individual optimization of each factor, (D)—the simultaneous optimization of all the studied factors.
Figure 1
Figure 1
Predicted optimal factors settings (in red) for each studied response, with the use of a maximized desirability function. (A–C)—the individual optimization of each factor, (D)—the simultaneous optimization of all the studied factors.
Figure 2
Figure 2
In vitro Zidovudine (ZVD) release from microparticles M2, M4, and M12 differed in chitosan glutamate (gCS):CF ratios compared to the ZVD blend with placebo microparticles (gCS:CF 2:1, w/w), displaying the impact of the ion crosslinker (CF) ratio on the dissolution profile (mean ± SD; n = 3).
Figure 3
Figure 3
SEM images of zidovudine (ZVD)-loaded microparticles with chitosan glutamate and beta-glycerophosphate disodium in a ratio 3:1: M4 (A); 2:1: M2 (B) and M5 (C); 1:1: M3 (D) and M12 (E); original magnification ×2000.
Figure 3
Figure 3
SEM images of zidovudine (ZVD)-loaded microparticles with chitosan glutamate and beta-glycerophosphate disodium in a ratio 3:1: M4 (A); 2:1: M2 (B) and M5 (C); 1:1: M3 (D) and M12 (E); original magnification ×2000.
Figure 4
Figure 4
Number (A) and volume (B) size distribution of the selected gCS/CF microparticles with zidovudine.
Figure 4
Figure 4
Number (A) and volume (B) size distribution of the selected gCS/CF microparticles with zidovudine.
Figure 5
Figure 5
X-Ray Powder Diffraction (XRPD) patterns of (A) pure zidovudine (ZVD), placebo microparticles with chitosan glutamate crosslinked with β-glycerophosphate (gCS:CF 2:1, w/w), and the formulation M4 (gCS:CF ratio 3:1, w/w); (B) selected drug-loaded formulations differed in their crosslinking ratio (M2 2:1; M3 1:1; M4 3:1; M5 2:1; M12 1:1, w/w).
Figure 6
Figure 6
Raman surface distribution map of microparticle formulation M4: ZVD (red), gCS/CF matrix (green), ZVD- gCS/CF mixed regions (yellow), glass surface (blue).
Figure 7
Figure 7
Thermograms of pure zidovudine (ZVD), placebo microparticles with chitosan glutamate crosslinked with beta-glycerophospahe (gCS:CF 2:1), and selected drug-loaded formulations differed in the crosslinking ratio gCS:CF (M2 (2:1); M4 (3:1); M12 (1:1), w/w).
Figure 8
Figure 8
Swelling index study of the selected microparticle formulations with a ratio gCS:CF of 1:1 (M12), 2:1 (M2), 3:1 (M4) (mean ± SD; n = 3).
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