Formation and Characterization of Crystals Containing a Pleuromutilin Derivative, Succinic Acid and Water

Abstract

An unusual pharmaceutical solid containing a pleuromutilin derivative, succinic acid and water is studied with a combination of physiochemical methods. The parent pleuromutilin derivative creates a host structure that contains large channels, which are occupied by variable amounts of both succinic acid and water. The inherent disorder of the system does not lend itself to detailed single-crystal X-ray diffraction studies; hence a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) techniques were used to characterize this system and understand its behavior. A variety of one and two-dimensional SSNMR experiments were used to understand the proton transfer and the hydrogen bonding network, including 1 H-13 C heteronuclear correlation experiments and measurements of the principal components of 13 C chemical shift tensors. This crystal system can exist as two distinct phases; a hemisuccinate phase containing a doubly ionized succinate molecule with two cations of the pleuromutilin derivative, and a succinic acid rich phase which contains a singly ionized succinate molecule hydrogen bonded to another fully protonated succinic acid for every mole of the pleuromutilin derivative. Individual particles can contain mixtures of these two phases, leading to a range of apparent stoichiometries between the succinic acid and pleuromutilin derivative. Both phases are variable hydrates and were characterized by gravimetric vapor sorption and variable humidity 13 C SSNMR techniques.

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

“…10 Multiple stoichiometries of succinic salts of a pleuromutilin derivative have also been characterised. 11 The ciprofloxacin salts obtained by Reddy et al were of 1:1 drug:acid stoichiometry only. 6 Succinic acid, due to its pK a values close to each other (4.21 and 5.64) 12 and thus greater likelihood of di-anion formation, may be a better counterion to study the potential of ciprofloxacin (pK a values of 6.09 and 8.74) 13 to form salts with multiple stoichiometries.…”

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution 1H Solid-State NMR Spectroscopy

“…1-3 While 13 C crosspolarisation (CP) MAS is an established workhouse technique, the power of high-resolution 1 H solidstate NMR experiments is starting to be recognised: 1 H chemical shifts have been determined from onedimensional fast-MAS spectra and two-dimensional 1 H- 13 C correlation spectra, [4][5][6][7][8][9][10][11][12][13] with H-H proximities being identified in two-dimensional 1 H-1 H DQ (double-quantum) MAS and DQ CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra. [10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures.…”

Detection of low-level PTFE contamination: An application of solid-state NMR to structure elucidation in the pharmaceutical industry

“…SSNMR is becoming an increasingly important tool for studying polymorphism of drugs [2,3], which was in fact the original aim of this work. At GlaxoSmithKline, SSNMR has continuously expanded from studies of polymorphs and solvates of APIs [4] to more advanced studies of organic co-crystals and complexes [5,6] and determination of crystal structure from powder samples [7]. In the following discussion we show that SSNMR evidence can be valuable for structure elucidation of unknown insoluble materials.…”