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Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid
Paluch, Krzysztof J. McCabe, T. Müller-Bunz, B. Corrigan, O.I. Healy, A.M. Tajber, L.
Paluch, Krzysztof J.
McCabe, T.
Müller-Bunz, B.
Corrigan, O.I.
Healy, A.M.
Tajber, L.
Publication Date
2013-08
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This document is the Accepted Manuscript version of a Published Work
that appeared in final form in Molecular Pharmaceutics, copyright © 2013 American Chemical
Society after peer review and technical editing by the publisher. To access the final edited and
published work see http://dx.doi.org/10.1021/mp400127r
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2013-08-15
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Abstract
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.
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Accepted manuscript
Citation
Paluch KJ, McCabe T, Müller-Bunz H et al (2013) Formation and physicochemical
properties of crystalline and amorphous salts with different stoichiometries formed between
ciprofloxacin and succinic acid. Molecular Pharmaceutics. 10(10): 3640-3654.
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Article