Understanding the effect of plasticizers in film coat materials on the physical stability of amorphous solid dispersions

Abstract

Amorphous solid dispersions (ASDs) have been extensively utilized to improve the bioavailability of drugs that have low aqueous solubility. The influence of different excipients on the conversion of amorphous drugs into their crystalline forms in ASDs has been extensively researched. However, there is limited knowledge examining the impact of film coating materials on the physical stability of oral tablet formulations containing ASDs. In this study, we demonstrate that plasticizers present in film coats can have a detrimental impact on the physical stability of ASDs.

We systematically compared two frequently used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). To gain mechanistic insights into the detrimental effects of plasticizers on the physical stability of ASDs, plasticizer leaching studies and physical stability studies of solvent-evaporated and spray-dried intermediates (SDI) using two BCS class II drugs were conducted. Triacetin was found to leach into the tablet core within one week when stressed at 40 °C/75 % RH, whereas no leaching was observed for PEG 3350, as discerned from spectroscopic studies.

We also found that triacetin-containing ASDs exhibited greater amorphous to crystalline form conversion of the drug compared to PEG 3350-containing ASDs after stability testing. Moreover, the incorporation of triacetin into polymers was found to cause a significant depression of glass transition temperature and upon equilibration with moisture, a drop below room temperature. Overall, these observations underscore the importance of carefully selecting plasticizers to be present in film coatings when developing ASD pharmaceutical products.

Introduction

In the development of orally-delivered pharmaceutical drugs, a significant amount of drugs face difficulties due to their poor solubility in water.¹^,² This poses tremendous challenges in achieving adequate oral bioavailability and translating them into safe and efficacious drug products.³ To address this critical issue, amorphous solid dispersions (ASDs) have been employed to improve the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs).4, 5, 6 ASDs improve drug bioavailability by trapping the API in an amorphous form inside a polymer matrix, which is thermodynamically unstable compared to the stable crystalline state.⁷ These single-phase amorphous dispersions are typically prepared via hot melt extrusion or spray drying techniques.8, 9, 10, 11 The polymer matrix discourages the drug’s conversion from amorphous to crystalline form and stabilizes the ASD by reducing molecular mobility and increasing its glass transition temperature (T_g).⁴^,⁵ The presence of polymers affects the crystal lattice structure of the drug, which, in turn, impacts the physical stability of the ASD.⁴ Therefore, it is imperative to have a comprehensive understanding of what affects the physical stability of an ASD-based drug product to ensure that this critical quality attribute is maintained throughout its shelf stability.

Materials

Hydroxypropyl methylcellulose (Shin-Etsu, PHARMACOAT 606), Triacetin (98.5 %, Spectrum Chemicals), PEG 3350 (USP, Spectrum Chemicals), Methanol (HPLC Grade, Fisher Scientific), hydroxypropyl methylcellulose acetate succinate (L-grade, Ashland), Plasdone K-29/32 (Ashland), Probucol (>98.0 %, TCI), Kollidon VA-64 (Molecular weight: 45,000–70,000, BASF) were used as received without further purification. Ultrapure water was used in all the experiments as required having a resistivity of 18.2 MΩ cm.

Kaustav Chatterjee, Ashish Punia, Alex M. Confer, Matthew S. Lamm,
Understanding the effect of plasticizers in film coat materials on the physical stability of amorphous solid dispersions, Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549,
https://doi.org/10.1016/j.xphs.2024.10.024.