Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid.
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.
School of Pharmacy and Pharmaceutical Sciences and ‡School of Chemistry, Trinity College Dublin , College Green, Dublin 2, Ireland.
Krzysztof J
KJ
Paluch
Thomas
T
McCabe
H
H
Müller-Bunz
Owen I
OI
Corrigan
Anne Marie
AM
Healy
Lidia
L
Tajber
D002152:Calorimetry, Differential Scanning; D002939:Ciprofloxacin / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008401:Gas Chromatography-Mass Spectrometry; D015394:Molecular Structure; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D019802:Succinic Acid / Q000737:chemistry*; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D012492:Salts; D002939:Ciprofloxacin; D019802:Succinic Acid