Recent Research on Amorphous Solid Dispersions

Insights into underlying mechanisms of ASDs

Researchers from the University of Basel in Switzerland and The Peoples’ Friendship University of Russia (RUDN University), investigated the underlying drug absorption mechanisms of amorphous solid dispersions (ASDs), proving the effectiveness of a novel, particle-forming ASD drug-delivery system for poorly soluble compounds (1).

In the study, Andreas Schittny et al. employed a model ASD formulation of efavirenz, which is an antiretroviral medication that is classified on the biopharmaceutics classification system as a class II drug—one with poor solubility but high permeability. The model formulation comprised hydroxypropyl methylcellulose phthalate (HPMCP) as a polymer with sucrose palmitate and polysorbate 80 as surfactants in a hot-melt extrusion process.

Sixteen healthy male patients were included in the study and were randomized to receive efavirenz in three different ways: intervention 1 was ASD of efavirenz (50 mg) as a capsule with 500 mL buffer solution; intervention 2 was dissolved ASD of efavirenz (50 mg) in 500 mL of buffer solution, forming drug-rich particles; and intervention 3 was efavirenz (3 mg) solution in a 500 mL buffer solution. The study participants were randomly selected to receive the interventions in different orders (either 1-2-3, 2-3-1, or 3-2-1) and a washout period of 14 to 21 days was performed between interventions.

Blood samples were obtained pre-dose and at multiple time points post-dose so that the plasma concentration of efavirenz could be determined through bioanalysis techniques. The pharmacokinetic profiles of efavirenz plasma concentrations compared to time were used as the primary study endpoints, with further pharmacokinetic analysis and modeling used as secondary endpoints. Furthermore, study results were compared with existing pharmacokinetic data available for a marketed formulation of efavirenz (Stocrin).

Based on the study results, it was found that the dissolved ASD of 50 mg of efavirenz (intervention 2) pharmacokinetically behaved nearly identically to the solution of efavirenz 3 mg (intervention 3). Therefore, intervention 2, which comprised a supersaturated aqueous solution containing drug-rich particles, behaved as a solution, and assuming passive absorption, the researchers deduced that the dissolved drug concentration in the intestine of intervention 3 was higher by a factor of 16.7 than intervention 2.

As a result of the drug concentration exceeding that of the aqueous solubility of efavirenz, it was concluded that drug-rich particles from ASDs are efficient oral drug delivery systems and drug absorption was fast and complete in humans. Additionally, the findings of the study confirmed the conceptual models of how drug molecules are released from ASDs and how they are subsequently absorbed into the intestinal tract.

Non-classical nucleation theory and application on ASD design

A group of international researchers (from Northern Ireland, China, Switzerland, and the United States) have recently reviewed the potential theory behind the formation of drug-rich phases of ASDs with a focus on non-classical nucleation (2). In the study, Kaijie Qian et al. specifically assessed the associated thermodynamics and kinetics of the formation of drug-rich phases from the dissolution of an ASD, as well as the in-vitro permeability enhancement and in-vivo bioavailability enhancement of the ASD formulation, among other aspects associated with drug-rich phases.

Elaborating on the mechanistic understanding of ASDs solubility, dissolution, and potential phase separation process during dissolution and storage, the researchers found that if amorphous drug particles are suspended in solution, the drug concentration can temporarily reach beyond the drug crystalline solubility threshold, as a result of their higher Gibbs free energy, and achieve a higher solubility than their crystalline counterparts. The resultant high supersaturation of drug solution leads to phase separation, which the researchers noted will typically happen via a classical nucleation and growth process.

However, as a result of the imperfect miscibility of drug and excipients, there is the possibility for an amorphous-amorphous phase separation (AAPS) phenomenon to occur during manufacture or storage of ASDs. The researchers revealed that several models have been described on the drug-polymer-water interactions, in relation to moisture/solvent presence. Using the same concept, the researchers found that when dissolving the ASD in water the presence of excipients played an important role in the drug’s phase separation. Furthermore, it was found that certain excipients can kinetically stabilize the drug-rich metastable phases of ASDs for a considerable period of time, which may promote oral absorption of the drug due to high concentration levels in solution. Additionally, it was highlighted that the properties of polymeric excipients were important to drug permeability enhancement of ASDs.

Based on their work, the researchers suggested that the enhanced oral bioavailability achieved with supersaturated ASD solutions is aided by the excipient-assisted formation and stabilization of drug-rich metastable phases, which follow a non-classical nucleation pathway. ASD formulations that are designed to enable synergistic effects of a variety of different mechanisms could provide benefits for drug oral absorption and, as such, future medicine development, the researchers concluded.

References

1. A. Schittny, et al., Pharmaceutics, 13 (3) 401 (2021).
2. K. Qian, et al., Pharmaceutics, 13 (6) 889 (2021).

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.