Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative

Abstract

New 1,2,4-thiadiazole derivative displaying neuroprotective potential and high activity in the treatment of Alzheimer's disease has been synthesized. The objective of this study was to improve the aqueous solubility of this drug-like compound by means of complex formation with native and hydroxypropylated b-cyclodextrins. To this end, aqueous solubility of 1,2,4-thiadiazole derivative was investigated in the presence of b-cyclodextrins. It was shown that the phase solubility diagrams are of B s type demonstrating the initial increase in thiadiazole solubility in solutions of cyclodextrins (concentration up to 0.01 mol kg -1 ) followed by a solubility decrease due to the precipitation of the complexes formed. In comparison with b-cyclodextrin, hydroxypropyl-b-cyclodextrin displays more pronounced solubilizing action since it forms more stable complexes with thiadiazole. Solid complexes of 1,2,4-thiadiazole derivative with b-cyclodextrins were prepared by grinding and freeze-drying methods. DSC, TG, hot-stage microscopy, solid-state 13 C MAS CP/TOSS NMR, powder X-ray diffractometry and FTIR spectroscopy were used to prove the existence of complexes in the solid state. Solubility of the obtained formulations was also examined. It was found that complexes of thiadiazole with hydroxypropyl-b-cyclodextrin exhibited higher solubility in phosphate buffer (pH 7.4) compared with pure thiadiazole and its complexes with b-cyclodextrin.

Grinding as Solvent-Free Green Chemistry Approach for Cyclodextrin Inclusion Complex Preparation in the Solid State

“…Grinding of a drug/CD mixture often produces amorphous products [31,32,33,34,47,51,54,55,56,57,58,59,60,61,62,63,64,65] or products containing only traces of crystalline drug [33,37,53,66,67,68,69,70,71,72,73,74,75,76], depending on the time and intensity of grinding and on the physicochemical properties of both drug and CD subjected to grinding. Several authors have demonstrated, by the use of 13 C MAS CP/TOSS NMR spectroscopy, the actual inclusion complex formation in amorphous drug/CD products obtained by co-grinding; examples from the literature included two thiadiazole-based anti-Alzheimer drug candidates co-ground with βCD and HPβCD [27,37], a fentanyl/βCD [59], and a bisacodyl/βCD [54] co-ground system. However, even if the product contains a significant fraction of residual crystalline drug, it could be readily converted into inclusion complex upon dissolution in water, as demonstrated by Jablan et al [77].…”

“…Moreover, when compared to the complexes prepared by other techniques, amorphous products obtained by grinding in some cases presented superior solubility and dissolution properties, like that observed in case of co-ground products of oxaprozin with RAMEB, bile acids and chitosan [23] or with βCD or DIMEB [34], or of clonazepam with natural and derivative βCDs [32], or even of naproxen with acetylated CDs [64]. However, in other cases, complexes prepared by solvent based methods like coevaporation or freeze-drying showed superior dissolution properties and bioavailability [27,33,37,61,62,64,68,75]. Here, it must be taken into account that freeze-dried products, which often present superior performance over co-ground and coevaporated ones, have a highly porous structure that additionally contributes to the improvement in its dissolution rate and bioavailability [50,78].…”

“…Such a setup resulted in the successful complex preparation in the solid state of different 1,2,4-thiadiazole anti-Alzheimer drug candidates [25,35]. However, it is here interesting to note that in both cases, although the inclusion complex formation by grinding was confirmed by 13 C MAS CP/TSOO NMR, complexes prepared by freeze-drying presented higher dissolution rate and consequently better bioavailability [27,37]. Such a result can be attributed to the higher porosity of the freeze-dried sample compared to that obtained by grinding, which additionally contributed to the solubility of the complex formed; on the contrary, grinding lead to the formation of highly compacted particles [76,91].…”

“…However, such a method often results in only partial drug/CD complexation [14]. Methods in the solid state , where CD complexation is achieved by microwave irradiation (MWI) [33] or by gentle heating at temperatures below the fusion point of the compounds in a sealed container, eventually in the presence of a minimum water amount, according to the so-called “sealed-heating” method (SH) [34,35] or by mechanochemical activation through grinding (GR) with different types of mills [36,37] of the drug/cyclodextrin physical mixture. The drawback of both MW and SH technologies is in the possibility of drug degradation during microwave irradiation or heating [38].…”

Particle size effect in the mechanically assisted synthesis of β-cyclodextrin mesitylene sulfonate

“…CDs are recognized as effective excipients in the formulation of numerous drugs [ 7 – 10 ]. Upon grinding, CDs form inclusion complexes with the drugs in the solid state, resulting in a significantly faster dissolution rate and increased bioavailability [ 11 – 13 ]. In our previous studies, CDs acted either as reactants [ 14 – 15 ], or as additives [ 16 – 17 ], and were shown to display supramolecular interactions with the other reaction partners.…”