Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage.

Khadijah Edueng,Denny Mahlin,Christel A.S. Bergström,Johan Gråsjö,Olivia Nylander,Manish Thakrani

doi:10.3390/molecules24152731

Abstract

This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

Highlights

Oral administration of medicines is the most commonly used route owing to its convenience, good patient compliance, relatively low cost, less stringent manufacturing requirements, and wide selection of dosage form design [1]
The spray-dried amorphous active pharmaceutical ingredients (APIs) demonstrated different physical stability profiles when stored at 75% RH
Two compounds remained amorphous for 168 days, i.e., they were highly resistant to crystallization

Summary

Introduction

Oral administration of medicines is the most commonly used route owing to its convenience, good patient compliance, relatively low cost, less stringent manufacturing requirements, and wide selection of dosage form design [1]. For solid dosage form design, a crystalline form of the active pharmaceutical ingredient (API) is often preferred due to its excellent physical and chemical stability [2]. In order for a solid crystalline API to dissolve in aqueous media, three major processes have to take place. The crystal lattice of the crystalline API has to be disrupted so that individual molecules can be separated and be solvated in the subsequent step. Hydrogen bonds binding water molecules together need to be broken to accommodate the solute (API) molecules [3]. Limited aqueous solubility of an API may be caused by high lattice energy, poor hydration, or a combination of the two [4]

Methods

Results

Conclusion