Impact of Eudragit EPO and Hydroxypropyl Methylcellulose on Drug Release Rate

Abstract

The purpose of this work was to evaluate the impact of polymer(s) on the dissolution rate, supersaturation and precipitation of indomethacin amorphous solid dispersions (ASD), and to understand the link between precipitate characteristics and redissolution kinetics. The crystalline and amorphous solubilities of indomethacin were determined in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit ® EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersaturation of the drug by effectively inhibiting solution crystallization while EPO increased both the crystalline and amorphous solubility of the drug, but did not inhibit crystallization. The HPMC dispersion dissolved relatively slowly without undergoing crystallization while the supersaturation generated by rapid dissolution of the EPO ASD was short-lived due to crystallization. The crystals thus generated underwent rapid redissolution upon pH increase, dissolving faster than the reference crystalline material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion containing both EPO and HPMC dissolved rapidly, generating an apparent drug concentration that exceeded the amorphous solubility of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concentration-time profiles achieved from indomethacin ASD dissolution are a complex interplay of drug release rate, precipitation kinetics and outcome, and precipitate redissolution rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation.

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Indomethacin.
Dissolution profiles of indomethacin amorphous solid dispersions.

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