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

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, ketoco...

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Bibliographic Details
Published in:	Molecules (Basel, Switzerland) Vol. 24; no. 15; p. 2731
Main Authors:	Edueng, Khadijah, Mahlin, Denny, Gråsjö, Johan, Nylander, Olivia, Thakrani, Manish, Bergström, Christel A S
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 27-07-2019 MDPI
Subjects:	Aging Amorphization amorphous Calorimetry Calorimetry, Differential Scanning Chemical Phenomena crystal growth Crystal lattices Crystal structure Crystallinity Crystallization crystallization kinetics Differential scanning calorimetry dissolution Drug dosages Drug Stability Energy Farmaceutisk vetenskap Glibenclamide Humidity Hydrochlorothiazide Hydrocortisone Indapamide Ingredients Ketoconazole Kinetics nucleation pathway Oral administration Pharmaceutical Preparations - chemistry Pharmaceutical Science Pharmaceuticals physical aging Preservation, Biological Raman spectroscopy Relative humidity Solid state Solubility solvent shift Spectrum Analysis, Raman spray-drying Sulfathiazole Supersaturation supersaturation potential Time Factors X ray powder diffraction X-ray diffraction physical aging amorphous supersaturation potential crystallization kinetics dissolution crystallization crystal growth solvent shift nucleation pathway spray-drying
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Summary:	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 (C ), 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 C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1431-5157 1420-3049
DOI:	10.3390/molecules24152731