The solid-state stability of amorphous quinapril in the presence of beta-cyclodextrins.
The major objective of this study was to investigate the effects of beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the solid-state chemical reactivity of the drug, quinapril, when amorphous samples are prepared by colyophilization of quinapril and each of these beta-CDs. For comparison, a physical mixture with beta-CD and colyophilized mixtures with trehalose and dextran were also prepared and subjected to a similar chemical stability test at 80 degrees C followed by HPLC analysis. Significant inhibition of degradation was observed only for colyophilized miscible mixtures with beta-CD and HP-beta-CD at molar ratios in excess of 1:1. Colyophilized mixtures with trehalose and dextran, shown to have phase separated, and the physical mixture with beta-CD exhibited no inhibiting effects. This suggests that specific molecular complexation is responsible for the significant inhibition by the beta-CDs. The tendency of quinapril to form molecular complexes in solution with the beta-CDs was measured by (1)H solution NMR, by estimating complexation constants from the chemical shift of specific groups on quinapril. Supporting evidence for solid-state complexation was provided by FTIR analysis. DSC and TSC measurements indicated that the beta-CDs do not have high enough glass transition temperatures to reduce reactivity by reducing molecular mobility.
Li
Jinjiang
J
School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53706, USA.
Guo
Yushen
Y
Zografi
George
G
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003505:Cyclodextrins / Q000032:analysis / Q000737:chemistry*; D004347:Drug Interactions; D004355:Drug Stability; D005079:Excipients / Q000032:analysis / Q000737:chemistry; D005503:Food Additives / Q000032:analysis / Q000737:chemistry; D007546:Isoquinolines / Q000032:analysis / Q000737:chemistry*; D011355:Prodrugs / Q000032:analysis / Q000737:chemistry; D000077583:Quinapril; D044005:Tetrahydroisoquinolines; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D005079:Excipients; D005503:Food Additives; D007546:Isoquinolines; D011355:Prodrugs; D044005:Tetrahydroisoquinolines; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C031215:betadex; D000077583:Quinapril