Chemical stability of esters of nicotinic acid intended for pulmonary administration by liquid ventilation.
OBJECTIVE
It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated.


METHODS
The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated.


RESULTS
Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4.


CONCLUSIONS
The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.
Hsu
Cheng-Hsuan
CH
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA.
Jay
Michael
M
Bummer
Paul M
PM
Lehmler
Hans-Joachim
HJ
D000465:Algorithms; D002021:Buffers; D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D021061:Liquid Ventilation; D009539:Nicotinic Acids / Q000008:administration & dosage* / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature
D002021:Buffers; D004952:Esters; D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D009539:Nicotinic Acids; D011355:Prodrugs; D012997:Solvents; C003072:perflubron