Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

• Published in: Molecular pharmaceutics 2013-10, Vol.10 (10), p.3640-3654
• Main Authors: Paluch, Krzysztof J, McCabe, Thomas, Müller-Bunz, H, Corrigan, Owen I, Healy, Anne Marie, Tajber, Lidia
• Format: Article
• Language: English
• Subjects: Calorimetry, Differential Scanning; Ciprofloxacin - chemistry; Crystallography, X-Ray; Gas Chromatography-Mass Spectrometry; Molecular Structure; Salts - chemistry; Solubility; Spectroscopy, Fourier Transform Infrared; Succinic Acid - chemistry; Thermogravimetry; X-Ray Diffraction
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp400127r

Multi-ionizable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallize ciprofloxacin, a poorly water-soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ∼215 and ∼228 °C, while the glass transition temperatures of CHS-III and CS-III were ∼101 and ∼79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve noncongruently leading to high and sustainable drug solution concentrations in water at 25 and 37 °C, with the ciprofloxacin concentration of 58.8 ± 1.18 mg/mL after 1 h of the experiment at 37 °C. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically relevant properties, including molecular, solid state, and solubility characteristics.