Original Article ASSESSING THE RATIONALE OF FDC CONTAINING OFLOXACIN AND AZOLES: DISSOLUTION, PERMEATION AND ANTIMICROBIAL STUDIES ATMARAM PAWAR 1* , AKSHAY KAMBLE 2 , SWATI KORAKE 1 , VIVIDHA DHAPTE-PAWAR 1 1 Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune 411038, Maharashtra, India, 2 Department of Drug Regulatory Affairs, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune 411038, Maharashtra, India Email: p_atmaram@rediffmail.com Received: 22 Aug 2019, Revised and Accepted: 18 Nov 2019 ABSTRACT Objective: To study fixed-dose combinations (FDC) of antibacterial and antiprotozoal products (ofloxacin and azoles), prescribed for the treatment of diarrhea. Methods: Rationality of these FDC products was verified by assessing parameters such as drug content and release by assay and dissolution tests, respectively mentioned in the Indian Pharmacopoeia (IP). Amount of drug solubilized and permeated as per the Biopharmaceutics Classification System (BCS) was determined. Ex vivo permeation study was performed on the gut of goat using the everted gut sac technique. Antimicrobial efficacy in terms of minimum inhibitory concentration (MIC) was assessed using agar well diffusion method against Shigella boydii, the causative agent for diarrhea. Comparative studies were performed on an individual as well as combination doses of antibacterial and antiprotozoal products for the synergistic effects to assess the rationale of these FDC. Results: The BCS solubility of ciprofloxacin (CPX), norfloxacin (NFX) and tinidazole (TNZ) was high in acidic medium (pH 1-5) and decreased at pH above 5. The assay studies showed that the individual drug contents of FDC were within the IP limits. In vitro dissolution results for both, individual drugs and their combination illustrated 99 % drug release within 30 min in 0.01N HCl. Ex vivo permeation of TNZ was higher than CPX and NFX in individual drugs. No significant change in the permeation rate was observed for individual drugs and their FDC. CPX and NFX exhibited more antimicrobial activity in terms of inhibitory zones than their FDC with antiprotozoal TNZ, above 2.5 µg/ml MIC. The pharmaceutical, biopharmaceutical and antimicrobial evaluation study showed the similarity of FDC with the individual drugs. Conclusion: The study showed no significant data to justify the therapeutic advantage of FDC over individual drugs. Keywords: Fixed-dose combination, Ciprofloxacin, Norfloxacin, Tinidazole, Dissolution, Permeation, Antimicrobial © 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijpps.2020v12i1.35440. Journal homepage: https://innovareacademics.in/journals/index.php/ijpps INTRODUCTION Fixed-Dose Combinations (FDC) comprised of two or more different drugs as a single formulation are explored for a plethora of diseases for synergistic effects and patient compliance [1, 2]. The rationality of FDC is defined by similar pharmacokinetics, yet the diverse mechanism of action; without supra-additive toxicity of the individual actives and formulation components [3]. As per the modified approval process for FDC in India (2013); the manufacturer of various FDC like analgesics, antacids, antihypertensive, antipsychotics and anti-diabetics have to obtain permission from Central Drug Standards Control Organization (CDSCO) based on the essential data supporting the rationality for FDC [4, 5]. Ciprofloxacin (CPX) and norfloxacin (NFX) are broad-spectrum quinolone antibiotics known to inhibit bacterial DNA replication by impeding the functions of bacterial DNA gyrase enzyme. They are mainly explored in the treatment of urinary tract infection, cystitis, prostatitis, respiratory tract skin and joint infections [6, 7]. Tinidazole (TNZ) is a nitroimidazole derivative used in the treatment of intestinal amoebiasis, giardiasis, trichomoniasis, active against anaerobic bacteria and protozoa [8, 9]. In the proposed study, we assessed the rationality of antibacterial and antiprotozoal FDC used in the treatment of diarrhea. In India, physicians prescribe FDC of ciprofloxacin and tinidazole (CPX+TNZ) as well as norfloxacin and tinidazole (NFX+TNZ) for diarrheal treatment [10]. However, these FDC are neither a part of WHO essential medicine list 2017 nor recommended in European and US countries [11, 12]. So, the aim of our study was to study the rationality in combining the selected ofloxacins and azoles for synergistic effects by comparing individual and combination products using parameters such as in vitro dissolution, ex vivo permeation, and antimicrobial study. MATERIALS AND METHODS Materials Ciprofloxacin hydrochloride and tinidazole were received as generous gift samples from BDH Industry Ltd, Kandivali (East), Mumbai. Norfloxacin was purchased from Shree chemicals, Pune. HPLC grade methanol, acetonitrile, water were purchased from Merck. All other chemicals and reagents used were of analytical grade. Marketed tablets of ciprofloxacin (CPX) 500 mg/250 mg of 2 brands C1 and C2, respectively, norfloxacin (NFX) 400 mg of 2 brands N1 and N2, respectively, tinidazole (TNZ) 600 mg/300 mg of brands T1 and T2, respectively, combination tablets of ciprofloxacin (CPX) 500 mg and tinidazole (TNZ) 600 mg of brands CT1 and CT2 and combination tablets of norfloxacin (NFX) 400 mg and tinidazole (TNZ) 600 mg of brands NT1 and NT2, respectively were purchased from local retail pharmacy at Ratnagiri, India. Methods BCS solubility (as per WHO guidance) The BCS solubility of drugs was determined in the aqueous medium with pH in the range of 1.2-6.8. Results for the solubility were calculated on the basis of drug soluble in the volume of 250 ml at 37 °C for 24 h. Highest unit dose of individual drugs, CPX (500 mg), NFX (400 mg), TNZ (600 mg) was weighed accurately and transferred in conical flask containing 250 ml of water and solutions of pH 1.2, 4.5 and 6.8, kept for 24 h under continuous agitation using Brunswick International Journal of Pharmacy and Pharmaceutical Sciences Print ISSN: 2656-0097 | Online ISSN: 0975-1491 Vol 12, Issue 1, 2020