Molecular/micro-macroscopic characteristics of effervescent eutectic ibuprofen-poloxamer matrices fabricated with melt granulation

Abstract

Employing a combination of conventional and advanced techniques, the multiscale characterization of effervescent matrix tablets containing the ibuprofen (IBU)-poloxamer 407 (P407) eutectic mixture yielded valuable insights into their molecular, microscopic, and macroscopic characteristics. Traditional methods, such as thermal analysis, powder X-ray diffractometry (PXRD), and Fourier-transformed infrared (FT-IR) spectroscopy, confirmed the dispersion of IBU as a solid solution in the eutectic system with hydrogen bonding interaction with P407. Stereomicroscope and imaging analysis demonstrated enhanced wetting properties in IBU tablets with P407. Effervescent agents in eutectic tablets, observed under stereomicroscopy, facilitated CO2 liberation, augmenting tablet surface roughness through matrix erosion. The interplay of effervescent agents and P407 in enhancing IBU dissolution was suggested by the relationship between observed physical properties and dissolution parameters. According to the impact of effervescent agents on tablet surface modification, it is interesting to incorporate into hydroxypropyl methylcellulose (HPMC) matrix tablets containing IBU-P407 eutectic mixture. The eutectic effervescent matrix tablets were successfully developed with controlled drug release characteristic. The impact of effervescent agents on tablet characteristics was explored using texture analysis and imaging approaches. Effervescent agents (5-10% (w/w)) promoted a rapid effervescence reaction, leading to high gel layer formation with low gel strength, as evidenced by texture analysis. Digital microscope and scanning electron microscope (SEM) revealed enhanced surface roughness, porosity, and a microporous structure in the gel layer. Three-dimensional images from synchrotron radiation X-ray tomographic microscopy (SRXTM) displayed interconnected pores in microporous networks, influencing the gel layer's strength, drug release patterns, and release mechanism. Furthermore, simultaneous real-time monitoring of tablet behavior and drug release using UV-visible imaging provided microscopic insights. Effervescent matrix tablets exhibited increased water penetration when exposed to HCl buffer, as indicated by the development of finger-like structures and gel layer structures with high porosities. Changing the medium to phosphate buffer at pH 6.8 led to modified gel layer structures, resulting in a significantly decreased drug release rate and a more prolonged release. Numerical approximation based on developed mathematical model was employed to estimate diffusion parameters during drug liberation studies. The mechanistic nature of effervescent agents and HPMC in controlling the release of drug in effervescent matrix tablets was clearly elucidated by determining the correlation between the estimated diffusion parameters and drug release profiles. To extend preformulation knowledge to the manufacturing phase, scaling up via high-shear melt granulation was conducted, varying process parameters. The IBU-P407 eutectic mixture served as a meltable binder, aiding particle agglomeration into granules. Granules and tablets prepared at 70 ºC displayed satisfactory appearance and physical characteristics. Changes in processing temperature notably influenced granule properties, subsequently modifying the physical attributes and dissolution behavior of the eutectic tablets. Comprehending the multiscale characteristics in pharmaceutical development provides valuable insights that can influence and guide the direction of future developments in pharmaceutical product design.

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