Crystallographic evaluation of the conformation of quetiapine included in ß-cyclodextrin.

Single-crystal X-ray diffraction and theoretical calculations were conducted for insights into the ß-cyclodextrin (ß-CD)-quetiapine inclusion complex structure. ß-CD and quetiapine form a host-guest inclusion complex at a ratio of 2:1 in which the ß-CD molecules form head-to-head dimers with their secondary hydroxyl groups linked by multiple hydrogen bonds. Quetiapine is totally contained within the ß-CD cavity and exhibits two kinds of disorder (parts 1 and 2) in opposite directions in the ß-CD complex. To clarify the mobility of the guest molecule in the ß-CD cavity, theoretical molecular conformational calculations, crystal optimization and crystal energy calculations were conducted using CONFLEX software. The results of theoretical molecular conformation calculations showed that the mobility of quetiapine is restricted because its tricyclic structure is covered by ß-CD. The results of crystal energy calculations indicated that the conformation of disorder part 1, which has high occupancy, was more stable.

Quetiapine free base complexed with cyclodextrins to improve solubility for parenteral use.

Quetiapine, an antipsychotic drug used for schizophrenia treatment, is poorly water soluble, and therefore, administration of the more water-soluble quetiapine fumarate is preferred. Absorption of quetiapine through biological membranes may be improved by enhancing the solubility of the quetiapine base, the non-ionic form. In this study, the currently used salt form was converted into the free base (oily material). We employed cyclodextrins (CDs) as pharmaceutical additives to improve the solubility of the quetiapine base. The formation of quetiapine-ß-cyclodextrin (ß-CD) complexes was studied by phase solubility studies, continuous variation method, NMR spectroscopy, and powder X-ray diffraction. The formation of a poorly water-soluble complex was confirmed by the phase solubility study, and the interaction between quetiapine and ß-CD in water was confirmed by NMR spectroscopy. In addition, the effects of ß-CD derivatives (glucosyl-ß-CD, maltosyl-ß-CD, 2-hydroxypropyl-ß-CD, dimethyl-ß-CD, and trimethyl-ß-CD) on the solubility of the quetiapine base were studied. The findings indicated that the aforementioned hydrophilic ß-CD derivatives could be used as pharmaceutical additives of quetiapine for parenteral formulations as a result of the improved solubility of the quetiapine base because of inclusion complexation. Therefore, converting the currently used salt form into the free base, investigating the free base as a candidate for CD inclusion, and converting the oily material such as the free base into a powder by forming an inclusion complex that is easy to deal with is considered a worthwhile approach that may lead to novel formulations of the drug in question.