Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties

Edueng Edueng,Bergström Bergström,Mahlin Mahlin,Gråsjö Gråsjö

doi:10.3390/pharmaceutics11090425

Edueng Edueng, Bergström Bergström + Show 2 more

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https://doi.org/10.3390/pharmaceutics11090425

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Abstract

This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability of the resulting amorphous solids, and (iii) to investigate the relationship between physicochemical properties and the GFA of spray-dried solids and their long-term physical stability. The spray-dried solids were exposed to dry (<5% RH) and humid (75% RH) conditions for six months at 25 °C. The crystallization of the spray-dried solids under these conditions was monitored using a combination of solid-state characterization techniques including differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. The GFA/GS class assignment for 85% of the model compounds was method-dependent, with significant differences between spray-drying and melt-quenching methods. The long-term physical stability under dry condition of the compounds was predictable from GFA/GS classification and glass transition and crystallization temperatures. However, the stability upon storage at 75% RH could not be predicted from the same data. There was no strong correlation between the physicochemical properties explored and the GFA class or long-term physical stability. However, there was a slight tendency for compounds with a relatively larger molecular weight, higher glass transition temperature, higher crystallization temperature, higher melting point and higher reduced glass transition temperature to have better GFA and better physical stability. In contrast, a high heat of fusion and entropy of fusion seemed to have a negative impact on the GFA and physical stability of our dataset.

Highlights

The transformation of solids from a crystalline to amorphous form has gained attention as a formulation strategy for driving the absorption of orally administered, poorly water-soluble compounds [1,2,3]
The 26 compounds selected for inclusion in the study were diverse in their physicochemical properties to obtain as general conclusions as possible
Ten of the 26 compounds were classified as unstable glass formers (GFs) (Class II), while the remaining 16 compounds were classified as stable GFs (Class III) by the melt-quenching method

Summary

Introduction

The transformation of solids from a crystalline to amorphous form has gained attention as a formulation strategy for driving the absorption of orally administered, poorly water-soluble compounds [1,2,3]. The amorphization process involves the disruption of the long-range order of molecules in the crystal form to a solid composed of disordered molecules. The energy-optimized packing of molecules in the crystalline state governs the thermodynamic physical stability of the substance, and relatively high energy is required to disrupt the inter-molecular interactions. This energy-demanding process limits the dissolution of the crystalline material. The absence of long-range order in an amorphous solid reduces the strength of the molecular interactions, resulting in higher kinetic solubility for amorphous solids than for their crystalline counterparts. Crystallization of an amorphous solid is a thermodynamically driven transition that is unwanted due to its detrimental effect on the in vivo performance of amorphous formulations

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Conclusion