Solubility characteristics of three fluoroquinolone ophthalmic solutions in an in vitro tear model

• Published in: International journal of pharmaceutics 1998-04, Vol.164 (1), p.119-128
• Main Authors: Firestone, B.A, Dickason, M.A, Tran, T
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Corneal deposits; Fluoroquinolones; General pharmacology; Medical sciences; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Precipitation; Solubility; Tear film; Tear model
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/S0378-5173(97)00427-4

The solubility characteristics of three commercially available fluoroquinolone ophthalmic solutions CILOXAN™ (Ciprofloxacin 0.3%), CHIBROXIN™ (Norfloxacin 0.3%) and OCUFLOX™ (Ofloxacin 0.3%) were evaluated using an in vitro tear turnover model. The model was used to simulate the effects of ocular dosing of each product on the temporal changes in tear pH and drug concentration in relation to the saturation solubility of the drug in the tear film and the possible formation of precipitates. Results showed that tear pH immediately following fluoroquinolone dosing was dominated by formulation pH with CILOXAN™ decreasing tear pH to 4.7 (formulation pH 4.5), CHIBROXIN™ to pH 5.3 (formulation pH 5.2) and OCUFLOX™ to pH 6.4 (formulation pH 6.4). Tear pH normalized to baseline (pH>6.8) within 15 min for all formulations due to tear turnover and drainage. Following CILOXAN™ dosing, rapid precipitation of ciprofloxacin was observed in the model beginning at 8 min post-dose (tear pH 6.1) producing turbidity and a significant decline in soluble drug concentration. Precipitation was quantitatively shown to be driven by ciprofloxacin supersaturation in tears. The tear drug concentrations of ofloxacin and norfloxacin remained below solubility at all pH values so that precipitation was neither observed nor predicted in the model. Analysis of ciprofloxacin precipitates by dark field microscopy with image analysis revealed polydisperse crystalline needles of 183 μm average length (SD=54 μm). These findings highlight the impact formulation properties can have on physicochemical changes in the tear film following ocular drug dosing and explain in part the reported clinical occurrences of precorneal deposits associated with the use of CILOXAN™.