Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt

Molecular Pharmaceutics
Jumpei OkiKiyohiko Sugano

Abstract

Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, p Ka = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid-liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition,...Continue Reading

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Citations

Sep 10, 2020·Pharmaceutics·Naoya MatsumuraKiyohiko Sugano
Feb 18, 2021·Molecular Pharmaceutics·Lynne S TaylorJonathan W Steed

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