Structures of cefradine dihydrate and cefaclor dihydrate from DFT-D calculations

Abstract

The crystal structure of cefradine dihydrate, C16H19N3O4S·2H2O, is considered in the pharmaceutical sciences to be the epitome of an isolated-site hydrate. The structure from single-crystal X-ray data was described in 1976, but atomic coordinates were not published. The atomic coordinates are determined here by combining the information available from the published single-crystal data with a dispersion-corrected density functional theory (DFT-D) method that has been validated to reproduce molecular crystal structures very accurately. Additional proof for the correctness of the structure comes from comparison with cefaclor dihydrate, C15H14ClN3O4S·2H2O, which is isomorphous and for which more complete single-crystal data are available. H-atom positions have not previously been published for either compound. The DFT-D calculations confirm that both cefradine and cefaclor are present in the zwitterionic form in the two dihydrate structures. A potential ambiguity concerning the orientation of the cyclohexadienyl ring in cefradine dihydrate is also clarified, and on the basis of the calculated energies it is shown that disorder should not be expected at room temperature. The DFT-D methods can be applied to recover full structural data in cases where only partial information is available, and where it may not be possible or desirable to obtain new experimental data.

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

“…During hydrate examination, a specific accent must be put on the H-bonding investigation. This is because these are the H-bonds which are one of the main reasons for the structural alteration of a non-hydrate [ 128 , 129 ], as they are formed not only between water and API molecules, but also in the form of water bridges [ 130 ]. All these aspects contribute to the formation of complex H-bond networks.…”

“…[ 87 , 116 , 132 , 146 ]. To name an example, gabapentin anhydrate is more stable at lower water fractions and rising temperatures when compared with the drug’s hydrate, whereas gabapentin monohydrate is favorable at higher water fractions and lower temperatures [ 129 ]. Such behaviour concerning anhydrate being more stable at lower RH and a hydrate at higher RH is a general rule.…”

New Salt and Cocrystal of Mequitazine: Impact of Coformer Flexibility and Hydrogen Bond Donors on Polymorphism

“…Moreover, the positions of hydrogen atoms cannot be identified from powder diffraction. Theoretical calculations 19,20 and solid-state NMR 21−26 are often used to overcome such drawbacks. Among these techniques, the simplest method is to validate the structure using the root-mean-square deviation (RMSD) of the optimized structure obtained by dispersion-corrected density functional theory (DFT-D) calculations, as in the study by van de Streek et al 20 Mequitazine (MQZ), which is a phenothiazine antihistamine, is an insufficiently water soluble drug, and no studies have been conducted to examine its improved solubility obtained using the multicomponent crystallization approach.…”

“…Theoretical calculations , and solid-state NMR − are often used to overcome such drawbacks. Among these techniques, the simplest method is to validate the structure using the root-mean-square deviation (RMSD) of the optimized structure obtained by dispersion-corrected density functional theory (DFT-D) calculations, as in the study by van de Streek et al…”

Periodic DFT Calculations—Review of Applications in the Pharmaceutical Sciences

“…Sometimes, after application of the periodic DFT calculations, a question emerges whether the old, dating back to the 1970s available in CSD data, should be redefined. A report on cefradine dihydrate and cefaclor dihydrate serves as an example [80]. For those chemotherapeutics, the theoretically obtained structures have been subsequently confirmed by the single crystal experiments and as a result the previously not available atomic coordinates have been determined.…”