Toxicity Assessment of Oral Liquid Formulations of Novel Ciprofloxacin-Dicarboxylic Acid Salts in Female Albino Rats: Haematological, Biochemical, and Histopathological Parameters

Abstract

Purpose

This study aimed to evaluate and compare the systemic toxicity profiles of novel ciprofloxacin salts synthesised using dicarboxylic acid counterions. To our knowledge, this represents the first in vivo comparative toxicity assessment of these specific crystalline ciprofloxacin–dicarboxylic acid salts. These salts represent previously unreported solid forms of ciprofloxacin with enhanced solubility and potential for improved oral bioavailability. Albino rats were administered oral liquid formulations, and systemic effects were assessed through haematological, biochemical, and histopathological evaluations.

Methods

Aqueous Liquid dispersions of ciprofloxacin salts with succinic, glutaric, adipic, and pimelic acids were prepared and orally administered to female albino rats at doses equivalent to 20 mg/kg (low dose) and 60 mg/kg (high dose) of ciprofloxacin for 14 consecutive days. Haematological, biochemical, and histopathological assessments were conducted to determine systemic toxicity. A composite toxicity score was calculated based on percentage deviations from control values in key biochemical markers, and a Z-score heatmap was generated to visualize overall trends.

Results

Haematological analysis revealed no significant changes in RBC and WBC counts or platelet levels. Biochemical evaluations showed only mild alterations in liver and kidney function markers, lipid profiles, and hormonal levels, largely comparable to the control group. Notably, the GAH and AAH groups exhibited significantly elevated AST and ALT levels compared to the control group (P < 0.05). AST levels in the GAH, AAH, and control groups were 459.00 ± 52.37, 467.33 ± 159.75, and 113.33 ± 32.25 U/L, and ALT levels were 62.33 ± 13.65, 65.00 ± 11.36, and 33.67 ± 11.93 U/L, respectively. The composite toxicity score identified the glutaric acid (GAH) and adipic acid (AAH) salts at high doses as having the most systemic impact (72.4% and 71.95%, respectively), while the pimelic acid salt at high dose (PAH, 21.27%) and adipic acid salt at low dose (AAL, 15.78%) were among the safest. Z-score heatmap analysis supported these findings. Histopathological examination revealed no significant pathological changes in the spleen, kidney, or heart, though minor liver changes were observed.

Conclusion

The novel ciprofloxacin dicarboxylic acid salts demonstrated a favorable safety profile in rats, with minimal systemic toxicity and only mild histological liver alterations at higher doses. These findings provide important foundational preclinical safety data, supporting further development of these novel salt forms as potentially safer and more bioavailable ciprofloxacin formulations.

Graphical Abstract