The Investigation of Flory-Huggins Interaction Parameters for Amorphous Solid Dispersion Across the Entire Temperature and Composition Range.

Gavin P Andrews,Lorenzo Stella,Esther Amstad,Yiwei Tian,David S Jones,Kaijie Qian,Esther Jacobs

doi:10.3390/pharmaceutics11080420

Gavin P Andrews, Lorenzo Stella + Show 5 more

Open Access

https://doi.org/10.3390/pharmaceutics11080420

Copy DOI

Abstract

Amorphous solid dispersion (ASD) is one of the most promising enabling formulations featuring significant water solubility and bioavailability enhancements for biopharmaceutical classification system (BCS) class II and IV drugs. An accurate thermodynamic understanding of the ASD should be established for the ease of development of stable formulation with desired product performances. In this study, we report a first experimental approach combined with classic Flory–Huggins (F–H) modelling to understand the performances of ASD across the entire temperature and drug composition range. At low temperature and drug loading, water (moisture) was induced into the system to increase the mobility and accelerate the amorphous drug-amorphous polymer phase separation (AAPS). The binodal line indicating the boundary between one phase and AAPS of felodipine, PVPK15 and water ternary system was successfully measured, and the corresponding F–H interaction parameters (χ) for FD-PVPK15 binary system were derived. By combining dissolution/melting depression with AAPS approach, the relationship between temperature and drug loading with χ (Φ, T) for FD-PVPK15 system was modelled across the entire range as χ = 1.72 − 852/T + 5.17·Φ − 7.85·Φ2. This empirical equation can provide better understanding and prediction for the miscibility and stability of drug-polymer ASD at all conditions.

Highlights

Low solubility and bioavailability are significant issues for currently marketed drug products, as well as new chemical entities in pharmaceutical development
The IR spectra of FD-PVPK15 amorphous solid dispersion (ASD) containing different weight fractions of FD were shown in PFhiagrmuraceeu3tiac.s 2A019c,le11a,r42i0ndication of the drug-polymer interaction can be observed at the –NH s1t0reoftc2h5 region (FD), where the vibration peak position was shifted from
When the FD loading was lowered than 70% w/w, FD-PVPK15 intermolecular interactions were dominated in the ASDs

Summary

Introduction

Low solubility and bioavailability are significant issues for currently marketed drug products, as well as new chemical entities in pharmaceutical development. Extensive efforts have been made to assess the feasibilities of these enabling formulations and to maintain the product’s qualities and performances throughout its life cycle. These sound understanding can be effectively built into the Quality by Design (QbD) framework and implemented for the development of process understanding and process control with predefined objectives. The importance of amorphous-amorphous phase separation (AAPS) in ASD has been highlighted in relation to the drug releases and physical stability of the formulation [11,12]. It is clear that further development of the informative framework is imperative, for its role in establishing a useful strategy to pre-define the achievable quality attributes of ASD systems (performance and physical stability)

Methods

Results

Conclusion