engleski

Comparative study of co-grinded complexes of zaleplon with natural and polymeric ß-cyclodextrin

Grinding is one of the most common manufacturing techniques used in pharmaceutical industry. The mechanical energy supplied to the solid material by grinding will induce particle size reduction, resulting in powders with higher surface area and corresponding faster dissolution properties. However, this process may cause several undesired phenomena such as formation of an electrostatic charge, change of the drug polymorphic form, chemical instability or drug degradation, development of cohesive powders with poor flow properties and consequent reduction of the effective surface area due to particle agglomeration. Such phenomena might be avoided by a co-grinding of the drug with a suitable hydrophilic carrier. Several studies have already demonstrated that cyclodextrins, cyclic oligosaccharides obtained by bacterial starch degradation, can successfully be employed as carriers in co-grinding process, resulting in highly soluble, amorphous products with an increased oral bioavailability. In this study, we have compared the suitability of parent β-cyclodextrin (βCD) and its water soluble polymeric derivative (PβCD) as co-grinding additives which would increase the poor dissolution properties of zaleplon (ZAL), a hypnotic drug. Equimolar drug/carrier mixtures were co-grinded in a high-energy micromill for different time intervals. Differential scanning calorimetry (DSC), supported by X-ray powder diffractometry (XRPD) and scanning electron microscopy (SEM) showed higher affinity of ZAL for the solid state interaction with PβCD, resulting in powders with lower relative drug crystallinity compared to that obtained with natural βCD (RDC= 51.10 and 12.5 for complexes with βCD and PβCD co-grinded for 90 min, respectively). In the same time, grinding of the drug alone did not result in a significant reduction of the drug crystallinity (RDC=99.87% for the sample grinded for 90 min). Although 1H-NMR spectroscopy confirmed that both co-grinded products were readily converted into inclusion complexes upon dissolution in water, they presented different dissolution properties. The dissolution velocity of co-grinded complex with PβCD was 25% faster compared to that prepared with the parent βCD and almost double compared to that of the drug alone, irrespective of the pH value of the dissolution media. This clearly demonstrated a suitability of co-grinded ZAL/PβCD complex in the development of an immediate release oral formulation of ZAL.

zaleplon; cyclodextrins; co-grinding; solid-state analysis; solubility

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