Selecting Excipients Forming Therapeutic Deep Eutectic Systems—A Mechanistic Approach

Abstract

The majority of all newly identified active pharmaceutical ingredients (APIs) have a low solubility in water (partly smaller than marble). In order to enhance their solubility and bioavailability, the formulation of these APIs, as part of therapeutic deep eutectic systems (THEDES), has been recently shown to be a promising approach. By choosing the right excipient, the melting point of the API/excipient mixture can be lowered below body temperature or even room temperature, resulting in a liquid formulation. To date, because of a lack of mechanistic understanding of how THEDES are formed, the identification of suitable excipients for a given API is almost exclusively based on heuristic decisions and trial-and-error-based approaches. This is both very time-consuming and expensive. The purpose of this work is to reduce the experimental effort to identify suitable excipients for a given API solely based on the melting properties (melting temperature and melting enthalpy) of the API and excipient and accounting for intermolecular interactions via a predictive thermodynamic model [in this case, UNIFAC­(Do)]. Lidocaine, ibuprofen, and phenylacetic acid were considered as model APIs, whereas thymol, vanillin, lauric acid, para-toluic acid, benzoic acid, and cinnamic acid were considered as model excipients. The formation of THEDES from these components was predicted and confirmed using differential scanning calorimetry. The results indicate that the experimental effort for the identification of suitable API/excipient combinations can be drastically reduced by thermodynamic modeling, leading to more efficient and tailor-made formulations in the future.

Design of Deep Eutectic Systems: A Simple Approach for Preselecting Eutectic Mixture Constituents

“…The slightly higher liquidus temperatures measured in this study might be due to the greater heating rate; in this study, a heating rate of 5 K min -1 was used, while in Martins et al [49], 1 K min -1 was used. As demonstrated in previous studies [35][36][37][38], the lower the melting enthalpy of the pure components, the higher the depression at the eutectic point. This could be confirmed by comparing the eutectic temperatures of eutectic systems formed between l-menthol and acids presented in Figure 2.…”

“…Abranches et al [34] proposed Conductor like Screening Model for Real Solvents (COSMO-RS) to predict the SLE of eutectic mixtures. Wolbert et al [35] used UNIFAC (Do) to model the activity coefficient of constituents in binary eutectic mixtures.…”

“…As seen in Equation 1, SLE calculations require information about the pure components melting properties, namely, the melting enthalpy ∆h m,i and temperature T m,i , as well as information about the behavior of the components in the liquid phase (i.e., activity coefficients γ L i ). Strong intermolecular interactions between unlike molecules in the liquid phase-low activity coefficient values of components-and/or low melting enthalpy values of pure components lead to a deep depression of the melting temperature of the mixture at the eutectic point [35][36][37][38]. The melting enthalpy of components is not always easily measured because of polymorphism, kinetic limitations, and/or thermal instability.…”

“…The objective of this study was to test a simple approach that could be used to select potential eutectic system constituents based on their melting enthalpies. It is assumed that mixtures of components with a lower melting enthalpy would result in eutectic mixtures with a larger melting temperature depression, as previously demonstrated [35][36][37][38]. This approach aims to reduce the experimental efforts required to measure pure components' melting enthalpy, as well as the SLE of eutectic mixtures.…”

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound

“…Successful stabilizers can be categorized into two groups. Stabilizers of the first category, consisting of low molecular weight compounds such as: acetylated sugars [9,13], organic acids [14][15][16], or even different drugs [17][18][19][20][21][22], have proved to be very effective in inhibiting recrystallization. However, the vast majority of stabilizers are large molecular weight compounds (the second group), such as polymers [5,7,[23][24][25][26][27][28].…”