Acid-Base Reactions in Different Solid-State Forms

Haichen Nie, Purdue University


Most drug substances are reported to be either weak acids or weak bases. Hence, acid-base reactions are commonly observed in pharmaceutical systems with samples including salts, amorphous solid dispersions, and in formulated products. Salt formation of active pharmaceutical ingredients (APIs) is widely recognized as one of the most commonly used approaches to modify the solubility and dissolution rate. Formulating poorly water-soluble weak acids or weak bases into salts can not only increase bioavailability, but also improve the stability and manufacturability of APIs by changing their solid-state properties. However, from a formulation perspective, acid-base reactions might occur between APIs and ionizable excipients, which would induce deleterious form conversions or chemical degradation of the APIs during storage or manufacturing. Therefore, understanding the fundamentals of acid-base reactions is critical to design a robust formulation and to avoid drug-excipients incompatibility issues in multicomponent pharmaceutical products. This research is divided into two parts to comprehensively understand the acid-base reaction in different solid-state formulations. The first part focuses on utilizing acid-base interactions between drug and polymer to stabilize a drug in the amorphous solid dispersion system. The key moiety of each component, the binding motif, and the underlying mechanism of solid state acid-base interactions are illustrated in this part. In the second part, the focus is on the salt disproportionation, an adverse effect of an acid base reaction between drug and excipients in different formulations. The impact of properties of different excipients, hygroscopicity of formulation, and reaction products on the kinetics and extent of disproportionation are investigated herein. Furthermore, feasible formulation approaches are developed to effectively slowdown salt disproportionation process during storage and manufacturing. The overall goal of this research is to reveal the mechanisms of acid-base interactions in different pharmaceutical systems and to better understand the dominant factors influencing these reactions. An additional objective is to better understand proton transfer and interaction patterns between drug and excipient, and to develop effective formulation strategies to minimize the risk of salt disproportionation. Moreover, this thesis also reports efforts of developing new validated analytical methods to monitor and detect the salt disproportionation in multicomponent drug products.




Byrn, Purdue University.

Subject Area

Pharmaceutical sciences

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