Understanding API-Excipient Interactions in Pharmaceutical Formulations

Pharmaceutical formulations consist of active pharmaceutical ingredients (APIs) and excipients. Appropriate excipient selection is critical to the final quality of pharmaceutical products. When designing pharmaceutical preparations, the choice of excipients should not only consider the dosage form factors and excipient functions but also the interaction and compatibility between APIs and excipients.

Therefore, during the research and development process of pharmaceutical preparations, comprehensive and reliable interaction studies are essential. These studies not only serve as a foundation for dosage form screening and design but also generate research insights for the improvement of pharmaceutical products.

Common preparations include tablets, solutions, granules, pills, and similar forms. Excipients can serve as lubricants, disintegrants, antioxidants, and binders. While formulating commonly used preparations, it’s vital to examine the compatibility between APIs and excipients to select excipients that do not adversely effects the drug.

Solid Dosage Forms

Interactions between drug substances and excipients in solid dosage forms involve both physical and chemical interactions. The former can induce changes in the appearance, odor, solubility and polymorphic form of the drug. Chemical interactions with excipients generally result in drug degradation or the formation of impurities that adversely affect drug stability and safety. Recent studies have shown that chemical reactions in pharmaceutical preparations may occur not only between APIs and excipients but also between APIs or excipients and their impurities. The extent of chemical reactions is influenced by factors such as the present form, water content, pH, light, oxygen, etc.

In compatibility studies, APIs and excipients are usually mixed at 1:1 ratio to maximize contact between excipients and drugs, increasing the probability of interaction reactions. However, in recent years, scientists have also found that interactions in pharmaceutical preparations may be affected by the actual preparation process of APIs and excipients.

Liquid Dosage Forms

In liquid dosage forms, physical or chemical interactions between APIs and excipients can exert either beneficial or detrimental effects on product quality. For example, some studies reveal that the nonionic polymer hydroxypropyl methylcellulose can adsorb onto the pyrimidine pamoate particles’ surface, forming an adsorption layer that prevents drug particle aggregation in space. At the same time, this alters the zeta potential of the drug particles, making the suspension more stable. Jin Wei et al. reported that adding disodium edetate to the carboplatin injection formulation accelerates carboplatin degradation and produces platinum-containing impurities such as 1,1-cyclobutanedicarboxylic acid and ethylenediaminetetraacetic acid disodium, leading to drug safety concerns.

In addition, soluble and ionizable excipients can interact with ionizable drug substances in liquid systems, resulting in insoluble precipitate formation. Sodium alginate and sodium carboxymethylcellulose, which are water-soluble, can generate numerous negatively charged ions that precipitate with positively charged neomycin and polymyxin. Bentonite (negatively charged) and stevensite (positively charged) are excipients derived from minerals that interact with oppositely charged drugs. Variations in aqueous media can also impact API stability in liquid formulations. Captopril, for instance, displays poor stability in aqueous media. Under high humidity conditions, trace metals present in excipients catalyze its oxidation to form captopril disulfide. However, due to the presence of ionic species that interact with metals and can accelerate the degradation of captopril, mineral water is more conducive to maintaining drug stability than distilled water.

Carrier-Based Formulations

To address issues related to inadequate solubility, stability, and bioavailability, APIs and excipients can be incorporated into carrier-based formulations such as clathrates, co-crystals, solid dispersions, phospholipid complexes, and microparticulate drug delivery systems. These are collectively referred to as carrier preparations. In recent years, research on drug-excipient interactions has expanded to include the influence of excipients on the formation of excipient formulations and interactions between different excipients. Such research significantly influences formulation design and optimization.

Understanding API-Excipient Interactions in Pharmaceutical Formulations