Document Detail

Formation of itraconazole-succinic acid cocrystals by gas antisolvent cocrystallization.
MedLine Citation:
PMID:  23054991     Owner:  NLM     Status:  MEDLINE    
Cocrystals of itraconazole, an antifungal drug with poor bioavailability, and succinic acid, a water-soluble dicarboxylic acid, were formed by gas antisolvent (GAS) cocrystallization using pressurized CO(2) to improve itraconazole dissolution. In this study, itraconazole and succinic acid were simultaneously dissolved in a liquid solvent, tetrahydrofuran, at ambient conditions. The solution was then pressurized with CO(2), which decreased the solvating power of tetrahydrofuran and caused crystallization of itraconazole-succinic acid cocrystals. The cocrystals prepared by GAS cocrystallization were compared to those produced using a traditional liquid antisolvent, n-heptane, for crystallinity, chemical structure, thermal behavior, size and surface morphology, potential clinical relevance, and stability. Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy analyses showed that itraconazole-succinic acid cocrystals with physical and chemical properties similar to cocrystals produced using a traditional liquid antisolvent technique can be prepared by CO(2) antisolvent cocrystallization. The dissolution profile of itraconazole was significantly enhanced through GAS cocrystallization with succinic acid, achieving over 90% dissolution in less than 2 h. The cocrystals appeared stable against thermal stress for up to 4 weeks under accelerated stability conditions, showing only moderate decreases in their degree of crystallinity but no change in their crystalline structure. This study shows the utility of an itraconazole-succinic acid cocrystal for improving itraconazole bioavailability while also demonstrating the potential for CO(2) to replace traditional liquid antisolvents in cocrystal preparation, thus making cocrystal production more environmentally benign and scale-up more feasible.
Courtney A Ober; Ram B Gupta
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-09
Journal Detail:
Title:  AAPS PharmSciTech     Volume:  13     ISSN:  1530-9932     ISO Abbreviation:  AAPS PharmSciTech     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-04     Completed Date:  2013-05-15     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  100960111     Medline TA:  AAPS PharmSciTech     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1396-406     Citation Subset:  IM    
Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, Alabama 36849, USA.
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MeSH Terms
Biological Availability
Calorimetry, Differential Scanning / methods
Carbon Dioxide / chemistry
Crystallization / methods
Dicarboxylic Acids / chemistry
Drug Stability
Furans / chemistry
Gases / chemistry
Heptanes / chemistry
Itraconazole / chemistry*
Particle Size
Powder Diffraction / methods
Solutions / chemistry
Solvents / chemistry
Spectroscopy, Fourier Transform Infrared / methods
Succinic Acid / chemistry*
X-Ray Diffraction / methods
Reg. No./Substance:
0/Dicarboxylic Acids; 0/Furans; 0/Gases; 0/Heptanes; 0/Solutions; 0/Solvents; 110-15-6/Succinic Acid; 124-38-9/Carbon Dioxide; 3N8FZZ6PY4/tetrahydrofuran; 456148SDMJ/n-heptane; 84625-61-6/Itraconazole

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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