Differential scanning calorimetry as an analytical tool in the study of drug-cyclodextrin interactions

The interactions of trimethoprim, sulphadiazine and sulphamethoxazole with natural (a- b-, g- ) and amorphous (RAMEB) or crystalline (DIMEB) methylated b-cyclodextrins were investigated both in aqueous solution (using phase-solubility analysis) and in the solid state (using DSC supported by X-ray analysis). In particular, DSC studies enabled determination of the relative degree of crystallinity of each drug in its physical and ground mixtures with the different cyclodextrins on the basis of the variation of its heat of fusion in comparison with that of the pure drug. In all cases, the host cavity size was a prevalent factor for the inclusion complexation in liquid state. On the contrary, it had a negligible effect on solid-state interactions in terms of drug amorphization. DIMEB and RAMEB exhibited similar performances in aqueous solution, showing that the presence of methyl-groups improved the complexing and solubilizing properties of b-cyclodextrin. However, DSC studies revealed that RAMEB was clearly more active in performing solid-state interactions, i.e. drug amorphization, and as stabilizing agent for the amorphous state brought forth. This revised version was published online in July 2006 with corrections to the Cover Date.     

Native and polymeric β-cyclodextrins in performance improvement of chitosan films aimed for buccal delivery of poorly soluble drugs

β-Cyclodextrin (βCD) and its soluble polymeric derivative (EPIβCD) were used to improve the effectiveness of chitosan-based bucco-adhesive film formulations containing bupivacaine hydrochloride and triclosan as poorly-soluble model drugs. The film formulations were characterized in terms of swelling, mucoadhesion and in vitro drug release, while possible interactions between the components were investigated by DSC and FTIR analyses. For both drugs EPIβCD showed a higher solubilizing efficiency than βCD; however cyclodextrin effectiveness in improving the release rate from film formulations was influenced by their different interactions with chitosan. Free βCD acted as a channelling agent, favouring the film swelling, while EPIβCD due to interaction with chitosan caused an opposite effect. βCD was the optimal partner for bupivacaine-loaded films in terms of film swelling, mucoadhesion and drug release. Contrariwise, EPIβCD was the best partner for triclosan-loaded films, allowing the highest drug release rate increase, due to its higher solubilizing ability with respect to βCD. Addition of the suitable cyclodextrin enabled formulation of buccal films with suitable drug release properties.     

Solid-state characterization of glyburide-cyclodextrin co-ground products

Natural crystalline (α-, β-, γ-) and amorphous derivative (hydroxypropyl-β- and methyl-β) cyclodextrins were selected as potential carriers for obtaining, through a co-grinding technique, a stable activated amorphous form of glyburide with improved dissolution properties. Differential scanning calorimetry (DSC) was used to investigate solid-state modifications of the drug induced by co-grinding with the selected carriers in a high energy vibrational micro-mill. X-ray powder diffraction and FTIR spectroscopy were employed as additional techniques to support DSC data. Equimolar drug : cyclodextrin physical mixtures were co-ground for different times (up to 60 min) at constant vibration frequency (24 Hz). A progressive drug amorphization with increasing grinding time was observed in all binary systems, but, interestingly, different degrees of sensitivity to the mechanical-chemical activation were evident. In fact, blends with natural cyclodextrins, despite the initial higher crystallinity than those with the amorphous derivatives, required the same or shorter co-grinding times (60 min) to achieve complete drug amorphization. Stability studies indicated no appreciable drug recrystallization in co-ground products after 4 months storage in sealed containers at 25°C or 1 month at 25°C and 75% RH. No stability differences were detected between products with natural or derivative cyclodextrins. The results accounted for the suitability of cyclodextrin co-grinding technique to obtain and stabilize glyburide in the activated amorphous form. This revised version was published online in July 2006 with corrections to the Cover Date.     

Physical chemical characterization of binary systems of prilocaine hydrochloride with triacetyl-β-cyclodextrin

Interaction products of prilocaine hydrochloride (PRL), a local anesthetic agent highly soluble in water, with triacetyl-β-cyclodextrin (TAβCD), a hydrophobic CD derivative practically insoluble in water, were prepared to estimate their suitability for the development of a prolonged-release dosage form of the drug. Equimolar PRL-TAβCD solid systems were prepared by different methods (physical mixing, kneading, co-grinding, sealed-heating, coevaporation, spray-drying), in order to investigate their effectiveness and influence on the physical chemical properties of the end products. Differential scanning calorimetry, X-ray powder diffractometry, FTIR spectroscopy and environmental scanning electron microscopy (ESEM) were used for the solid-state characterization of the different PRL-TAβCD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. On the basis of the overall solid-state studies results, the ability of the different methods to bring about effective drug-TAβCD interactions varied in the order: spray-drying > co-grinding ≈ coevaporation > sealed-heating > kneading > physical mixing. This rank order was not observed in dissolution studies, where coevaporated, kneaded and sealed-heated products exhibited very similar profiles, practically superimposable to that of pure drug and physical mixture, all reaching 100% dissolution in less than 10 min. Evidently, all these techniques gave rise only to weak surface interactions, rapidly destroyed in solution. Some decrease in dissolution rate was observed for co-ground system (100% dissolved drug after 40 min), probably due to electrostatic and aggregation phenomena associated with the high-energy mechanical treatment. A very different behaviour was shown by the spray-dried system, which give rise to an almost linear slow-dissolving profile, reaching 100% of dissolved drug after 420 min, suggesting in this case the formation of an actual inclusion compound. Thus, the drug-TAβCD product obtained by spray-drying was selected as the best candidate for the future development of a suitable prolonged-release oral dosage form of PRL.     

Comparative Study on Triclosan Interactions in Solution and in the Solid State with Natural and Chemically Modified Cyclodextrins

The aim of this study was to investigate the interactions of triclosan (TRI), a poorly water-soluble antimicrobial drug, with natural crystalline cyclodextrins (α-, β- and γ-Cd) and the corresponding hydroxypropylated amorphous derivatives (HPα-, HPβ-, and HPγ-Cd) and evaluate their effectiveness as complexing and solubilizing agents towards the drug. Equimolar solid systems were prepared using different techniques (physical mixing (PM), kneading (KN) and coevaporation (COE)) in order to evaluate the influence of the preparation method on the performance of the end products. Drug–carrier interactions were investigated both in aqueous solution, using phase-solubility analysis, fluorescence and circular dichroism (CD) techniques, and in the solid state, using differential scanning calorimetry (DSC) supported by thermograumetric analysis (TGA), X-ray powder diffractometry (XRPD) and scanning electron microscopy (SEM) analysis. Among the native cyclodextrins, β-Cd seemed to have the most suitable cavity to fit the drug molecule, whereas the α-Cd cavity was too small and the γ-Cd cavity too large to establish stable interactions with the guest. However, due to the B _S -type phase solubility diagram, its solubilizing efficiency was very limited. The presence of the hydroxypropylic substituents improved, in all cases, Cd solubilizing and complexing efficacies towards the drug. This was particularly evident in the case of HPγ-Cd, whose stability constant was about 200-fold higher than that of the native γ-Cd. HPβ-Cd was the most effective carrier for TRI, showing a solubilizing power about 20 times higher than the corresponding native Cd and about 2-fold that of the other hydroxypropyl derivatives. Moreover, a clear influence of the preparation method on the properties of the final products was observed. The COE method with hydroxypropylated cyclodextrins seemed the most suitable technique in achieving the complete drug amorphization and/or inclusion complexation. Received in final form: 24 January 2005     

Comparative study of oxaprozin complexation with natural and chemically-modified cyclodextrins in solution and in the solid state

The complexing, solubilizing and amorphizing abilities toward oxaprozin (a poorly water-soluble anti-inflammatory agent) of some β-cyclodextrin derivatives (hydroxypropyl-βCd, heptakis-2,6-di-O-methyl-βCd (DIMEB) amorphous randomly substituted methyl-βCd (RAMEB) and semi-crystalline methyl-βCd (CRYSMEΒ)) were investigated and compared with those of natural (α-, β-, γ-) cyclodextrins. The role of both the cavity size, the amorphous or crystalline state and the presence and type of substituent on the ability of cyclodextrins in establishing effective interactions with the drug has been evaluated. Equimolar drug-cyclodextrin solid systems were prepared by blending, kneading, co-grinding, sealed-heating, coevaporation, and colyophilization. Drug-carrier interactions were studied in both the liquid and solid state by phase-solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy and scanning electron microscopy. βCd showed the best performance among the natural Cds, indicating that its cavity was the most suitable for accommodating the drug molecule. The presence of substituents on the rim of the βCd cavity significantly improved its complexing and solubilizing effectiveness towards the drug, and methylated derivatives were better than the hydroxy-propylated ones The amorphous nature of the partner was also important: among the examined methyl-derivatives, RAMEB proved to be the most effective in performing solid state interactions and in improving drug wettability and dissolution properties.     

The influence of chitosan on cyclodextrin complexing and solubilizing abilities towards drugs

The present work was performed to investigate the effect of chitosan, a well known hydrophilic polymer with both enhancer and solubilizing properties, on the solubilizing and complexing abilities of cyclodextrins towards drugs. With this aim, phase-solubility studies were carried out with a series of model drugs, both of acid and basic nature and with different water-solubility and lipophilicity values, in the presence of chitosan and cyclodextrin (ß- or hydroxypropyl-ß-cyclodextrin), both separately (binary systems) and in combination (ternary systems). Unexpectedly, differently from the favorable effect reported in literature for various hydrophilic polymers, the addition of chitosan to the cyclodextrin complexation medium caused a decrease in the cyclodextrin complexing power towards all the examined drugs, independent from their very different physicochemical properties. On the contrary, the influence of the polymer on the cyclodextrin solubilizing efficiency was found to be dependent on the type of drug and both positive, or negative or non-significant effects were observed. The overall results are explained in terms of a common basic mechanism due to the presence of chitosan–cyclodextrin interactions, which hindered the drug–cyclodextrin complex formation, thus causing the binding constant reduction; the simultaneous presence of drug–chitosan and/or chitosan–(drug–cyclodextrin complex) interactions, different from drug to drug, were considered responsible for the distinct (and sometimes opposite) effects observed in the drug solubilizing efficiency of ternary systems.