Modulation of Entrapment Efficiency and In Vitro Release Properties of BSA-Loaded Chitosan Microparticles Cross-Linked with Citric Acid as a Potential Protein–Drug Delivery System

Microparticles, aimed for oral protein and peptide drug delivery, were prepared via emulsion cross-linking using citric acid as cross-linker and polyglycerol polyricinoleate as surfactant. A comparative study of the interaction between chitosan and citric acid and its effect on the resulting microparticle properties was performed using different chitosan-to-cross-linker mass ratios and pH-values during fabrication of the microparticles. Non-cross-linked and cross-linked microparticles were studied in terms of size (4–12 μm), zeta potential (−15.7 to 12.8 mV), erosion (39.7–75.6%), a model protein encapsulation efficiency (bovine serum albumin) (6.8–27.6%), and loading capacity (10.4–40%). Fourier transform infrared spectroscopy and X-ray diffraction confirmed the ionic interaction between the protonated amine groups of chitosan and the carboxylate ions of the cross-linking agent. Scanning electron microscopy revealed that the non-cross-linked microparticles had an uneven shape with wrinkled surfaces, while the cross-linked formulations were spherical in shape with smooth surfaces. On the basis of these data, the role of the surfactant and microparticle structure on the release mechanism was proposed. Control of the microparticle shape and release mechanisms is expected to be crucial in developing carriers for the controlled delivery of proteins and peptides.