A Comprehensive Study of a New 1.75 Hydrate of Ciprofloxacin Salicylate: SCXRD Structure Determination, Solid Characterization, Water Stability, Solubility, and Dissolution Study

Ilma Nugrahani,Hidehiro Uekusa,Billgerd Tjengal,Tutus Gusdinar,Ayano Horikawa

doi:10.3390/cryst10050349

Ilma Nugrahani, Hidehiro Uekusa + Show 3 more

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https://doi.org/10.3390/cryst10050349

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Abstract

One problem that often arises during the formulation of a dosage form is the solubility and dissolution of the active ingredients. This problem arises in ciprofloxacin, which is a BCS class IV fluoroquinolone antibiotic. A pseudopolymorph is a kind of polymorph in which the number of hydrates is different. In this study, a new pseudopolymorph comprised of ciprofloxacin and salicylic acid was found, namely the salt ciprofloxacin salicylate 1.75 hydrate form. This new solid phase was analyzed by Fourier-transform infrared spectroscope (FTIR), Raman spectroscopy, and thermal analysis and proven by Powder X-ray Diffractometry (PXRD) analysis. The crystal structure was successfully determined by Single Crystal X-ray Diffractometry (SCXRD) analysis. It was found that the piperazinyl group of ciprofloxacin is protonated by H+ from the carboxylic group of salicylic acid. In the unit cell, two ciprofloxacin and two salicylic acid molecules were independent with four water molecules, in which one water molecule had 0.5 occupancy due to inversion symmetry. Interestingly, this hydrate crystal dehydrated by grinding for 105 minutes forms an anhydrous crystalline phase, which was analyzed with FTIR, Raman spectroscopy, thermal analysis, and PXRD. The solubility and dissolution tests were carried out using UV-Visible spectrophotometry and a multiple linear regression method. This new hydrate solid phase has a better profile than the original ciprofloxacin crystal, according to the solubility and dissolution tests.

Highlights

IntroductionFluoroquinolones are one of the most widely used synthetic antibiotics nowadays and they are the first line therapy for the infection of Gram-negative bacteria, such as Pseudomonas aeruginosa [1]
Fluoroquinolones are one of the most widely used synthetic antibiotics nowadays and they are the first line therapy for the infection of Gram-negative bacteria, such as Pseudomonas aeruginosa [1].Antibiotics in this group work by inhibiting enzymes that are involved in DNA replication: DNA topoisomerase IV and DNA gyrase [2]
Ciprofloxacin HCl (Merck, Berlin, Germany), salicylic acid (Merck, Berlin, Germany), methanol (Sigma Aldrich, Darmstardt, Germany), ethanol (Sigma Aldrich, Darmstardt, Germany), KBr Fourier-transform infrared spectroscope (FTIR) grade (Merck, Tokyo, Japan), sodium hydroxide (Merck, Berlin, Germany), sodium dihydrogen phosphate (Sigma Aldrich, Darmstardt, Germany), and distilled water was prepared by School of Pharmacy, Bandung Institute of Technology

Summary

Introduction

Fluoroquinolones are one of the most widely used synthetic antibiotics nowadays and they are the first line therapy for the infection of Gram-negative bacteria, such as Pseudomonas aeruginosa [1]. Antibiotics in this group work by inhibiting enzymes that are involved in DNA replication: DNA topoisomerase IV and DNA gyrase [2]. Ciprofloxacin is one of the most popular fluoroquinolones and it is taken via the oral route. The drug is mostly marketed in the form of solid dosage forms, especially tablets. The problem that arises when formulating an oral drug is its solubility and permeability

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