Stabilization of Metastable Indomethacin α in Cellulose Nanocrystal Aerogel Scaffolds.

Manali Banerjee,Blair Brettmann

doi:10.3390/pharmaceutics13040441

Manali Banerjee, Blair Brettmann

Open Access

https://doi.org/10.3390/pharmaceutics13040441

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Journal: Pharmaceutics	Publication Date: Mar 24, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Georgia Institute of Technology

Abstract

Indomethacin (IM) is a small molecule active pharmaceutical ingredient (API) that exhibits polymorphism with the γ-form being the most thermodynamically stable form of the drug. The α-form is metastable, but it exhibits higher solubility, making it a more attractive form for drug delivery. As with other metastable polymorphs, α-IM undergoes interconversion to the stable form when subjected to certain stimuli, such as solvent, heat, pH, or exposure to seed crystals of the stable form. In this study, IM was crystallized into cellulose nanocrystal aerogel scaffolds as a mixture of the two polymorphic forms, α-IM and γ-IM. Differential scanning calorimetry (DSC) and Raman spectroscopy were used to quantitatively determine the amount of each form. Our investigation found that the metastable α-IM could be stabilized within the aerogel without phase transformation, even in the presence of external stimuli, including heat and γ-IM seed crystals. Because interconversion is often a concern during production of metastable forms of APIs, this approach has important implications in being able to produce and stabilize metastable drug forms. While IM was used as a model drug in this study, this approach could be expanded to additional drugs and provide access to other metastable API forms.

Highlights

IM was directly drop-casted from a saturated ethanol solution into cellulose nanocrystals (CNCs) aerogels, held within the silicone mold (SI Figure S1), and the samples were cooled to induce supersaturation. α-IM and γ-IM both crystallized into the aerogels and they can be seen in γ-IM crystals are more plate-like and distinguishable from the α-form, and they have been circled in red in Figure 1 [56]
Crystallization of α-IM within Cellulose Nanocrystal Aerogels held within the silicone mold (SI Figure S1), and the samples were cooled to induce supersaturation. α-IM and γ-IM both crystallized into the aerogels and they can be seen in γ-IM crystals are more plate-like and distinguishable from the α-form, and they have been circled in red in Figure 1 [56]
Because the CNC aerogels can provide spatial constrains to the α-IM needles, it is possible that these crystals are further prevented from conversion. These results show the effects of the CNC aerogels on stabilizing the metastable αform of the model drug indomethacin

Summary

Introduction

Academic Editor: Il Won Kim. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Active pharmaceutical ingredients (APIs) often exhibit polymorphism, the phenomenon of packing into different crystal structures while having the same chemical composition. Each polymorph has unique physical and chemical properties, including shape, purity, and free energy [1,2,3], which can alter their behavior in terms of stability and solubility [4,5,6]

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