Assessment of Complexation Between API and Excipient

Drug development researchers use a variety of strategies to address the poor aqueous solubility of modern drugs. Complexation of APIs with excipients is a common strategy to enhance the solubility by forming an inclusion complex with the excipient that readily dissociates prior to absorption. The process by which an excipient interacts with active pharmaceutical ingredients (APIs) to form a complex is usually reversible. When the excipient-API is in a complex, the API cannot dissolve freely because it must first dissociate from the complex. In many cases, the excipient-API complex dissociates upon coming into contact with gastrointestinal fluids, releasing the API, which can then be absorbed across the gastrointestinal membrane. However, these solubility enhancement strategies are often employed without proper consideration of whether the drug substance and the excipient material are truly compatible. BOC Sciences offers API-excipient complex evaluation services to help ensure that your API and drug formulation strategies are adequately evaluated and adjusted to ensure optimal final product properties (biopharmaceutical, physicochemical and stability).

Figure 1. Inclusion Complexation Between Drug and Cyclodextrin. (Choudhury, H.; et al. 2018)

Our Capabilities

BOC Sciences has introduced several analytical techniques for determining complex formation. In the solution state, we chose Nuclear Magnetic Resonance (NMR), Circular Dichroism Spectroscopy (CD), and UV-Vis for the analysis. To determine the formation of solid complexes, thermal analysis (DSC, TGA), solid-state ¹³C NMR are more accurate.

UV-Visible Study

The binding and complex formation between API and excipients can be monitored by electron absorption. The presence of complexation between drug and excipient molecules is determined by comparing the enhancement of the intensity of the absorption peaks on the UV-Vis spectra of API, excipient and API-excipient.

Tensiometeric Titration Method

Surface active agents, or surfactants, can reduce interfacial tension and are often used as drug carriers in formulations to deliver drugs to precise locations, which can reduce harmful side effects and improve their bioavailability. Drug and surfactant have the same charge on the head group, so they can form mixed amphiphiles. To study drug-surfactant interactions, our experts use tensometric titration to calculate the surface tension of single and drug-surfactant mixtures.

Circular Dichroism Spectroscopy

Cyclodextrins are very important excipients in the pharmaceutical industry. Given the wide variety of natural and semi-synthetic cyclodextrin derivatives available on the market, a fast and reliable method is required to select the best cyclodextrin to achieve the optimal complexation with drug molecules. We use a straightforward induced circular dichroism - based approach for the qualitative and quantitative evaluation of complexation of APIs with different cyclodextrins. For different cyclodextrins, the sign and intensity of the induced circular dichroism signal provide useful information about the general structure of the complexes and their stability with respect to each other.

Thermal Analysis

At BOC Sciences, thermal analysis methods include differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), which are suitable for determining the interaction between drug and excipient molecules. The unique molecules formed by complexation between API and excipient have different physical properties including melting point, heat capacity, heats of reaction, decomposition kinetics, and flow properties. Our experts use DSC technology to determine the formation of inclusion complexes, and to calculate the stoichiometric ratios of the complexes. In addition, when TGA is used in combination with DSC, we can quantify the amount of API involved in the inclusion complex by monitoring the melting points.

Nuclear Magnetic Resonance

Proton and ¹³C-NMR have been used to determine the formation of inclusion complexes, and to understand how the drug substrate is positioned in the cavity of the excipient. ¹H-NMR helps to further elucidate the orientation of the API in the cavity of the excipient molecule. We use this information to establish the molecular modeling of inclusion complexes.