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.