Co-grinding Effect on Crystalline Zaltoprofen with \u03b2-cyclodextrin/Cucurbit[7]uril in Tablet Formulation

Shanshan Li,Kailin Xu,Jiawei He,Xiang Lin,Hongqin Yang,Hui Li

doi:10.1038/srep45984

Abstract

This work aimed to investigate the co-grinding effects of β-cyclodextrin (β-CD) and cucurbit[7]uril (CB[7]) on crystalline zaltoprofen (ZPF) in tablet formulation. Crystalline ZPF was prepared through anti-solvent recrystallization and fully analyzed through single-crystal X-ray diffraction. Co-ground dispersions and mono-ground ZPF were prepared using a ball grinding process. Results revealed that mono-ground ZPF slightly affected the solid state, solubility, and dissolution of crystalline ZPF. Co-ground dispersions exhibited completely amorphous states and elicited a significant reinforcing effect on drug solubility. UV-vis spectroscopy, XRPD, FT-IR, DSC, ssNMR, and molecular docking demonstrated the interactions in the amorphous product. Hardness tests on blank tablets with different β-CD and CB[7] contents suggested the addition of β-CD or CB[7] could enhance the compressibility of the powder mixture. Disintegration tests showed that CB[7] could efficiently shorten the disintegrating time. Dissolution tests indicated that β-CD and CB[7] could accelerate the drug dissolution rate via different mechanisms. Specifically, CB[7] could accelerate the dissolution rate by improving disintegration and β-CD showed a distinct advantage in solubility enhancement. Based on the comparative study on β-CD and CB[7] for tablet formulation combined with co-grinding, we found that CB[7] could be considered a promising drug delivery, which acted as a disintegrant.

Highlights

Further developments of CB[7]-containing drug dosage forms, such as tablets for oral delivery, have been seldom described
Interactions in co-ground dispersions were investigated by using UV-vis spectroscopy, X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), solid-state NMR spectroscopy, scanning electron microscopy (SEM) and molecular simulation
Microcrystalline ZPF (Fig. S1C) used for tablet formulation was prepared by the same solvent system but with vigorous stirring with n-hexane addition

Summary

Introduction

Further developments of CB[7]-containing drug dosage forms, such as tablets for oral delivery, have been seldom described. Soluble zaltoprofen (ZPF, logP = 4.25, pKa = 4.21; Fig. 1c) was chosen as a model drug because its commercial formulation is oral tablet and its crystal form is obtained. It is a nonsteroidal anti-inflammatory drug (NSAID) that is more potent for the treatment of inflammatory conditions accompanied by pain than other NSAIDs23. Numerous methods, including co-evaporation, co-crystallization, freeze-drying, spray-drying, and co-grinding, have been widely utilized to prepare drug–excipient dispersions Among these methods, co-grinding drugs with macrocycles is regarded as the most suitable for scale-up and environmentally friendly industrial production. This work provided a basis for the development of new dosage forms by co-grinding method and explored the features of using CB[7] as a tablet excipient in pharmaceutical production

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Conclusion