Studies on structure and mechanism at formation of solid solutions and solid dispersions of hydrophobic drugs in polymers

Abstract: The aim of the studies was to investigate the structures formed and mechanisms involved, when a hydrophobic drug is dispersed in a polymer carrier. The effect of different additives, like surfactants and cyclodextrins, was evaluated. The dispersions were prepared by the melting method. The phase composition and structure of the samples were studied by X-ray powder diffraction (XRD) and solid-state NMR. The thermal analysis was made by differential scanning calorimetry (DSC) and temperature-modulated DSC (MTDSC).The structure of the systems formed upon addition of surfactants was found to depend on several factors. The critical surfactant concentration for formation of solid solutions with different counterions correlated very well to the relative size of the counterions. The ion with the highest charge-to-radius ratio, Li+, formed bonds that were different from those formed with the Na+ and K+ ions. This could explain the observed increased crystallinity and the deviation in the thermal behavior of the Li+ compounds, compared to that obtained for the Na+ and K+ systems. The critical surfactant concentrations in different PEGs were correlated to the structure of the PEGs. The polymers contained varying amounts of folded and extended chains, which influences the amorphous parts of the polymer structure, where the surfactant-drug aggregates are likely to dissolve. The solid solubility of griseofulvin was found to be much higher in PEG 6000 than in PEG 3000 or PEG 20000 with surfactant added, implying that a certain balance between the amount of folded chains and surfactant concentration is crucial for the creation of the solid solution. The prerequisites of the formation of a solid solution were given already in the melt.The melting method was introduced as a new method for producing cyclodextrin (CD) inclusion complexes of hydrophobic drugs. The structures formed when cyclodextrins were added to the solid dispersions depended on the character of the CD. The results demonstrated the different competition between the polymer, the drug and the CDs when forming bonds to each other. Since the interaction between α-CD and PEG is stronger than between β-CD and the polymer, β-CD can form a stronger bond to indomethacin (IM) than α-CD. In the γ-CD case, a new phase with tetragonal structure was formed where the indomethacin molecule was bound to the CD in an inclusion complex. The interactions resulted in a delayed release of indomethacin from PEG 6000 in the order α-CD < γ-CD <=CD.The specific information on the relative crystallinity obtained by the NMR, XRD, DSC and MTDSC techniques was emphasized for the γ-CD system.The selection of operational parameters for proper measurements by MTDSC is crucial. A dimensionless quantity, degree of oscillation, was introduced to be able to predict the reproducibility of the heat of fusion determinations. A degree of oscillation ~1-2 gave reliable results for a variety of combinations for the systems examined. With proper operational settings MTDSC can be used for determining the relative crystallinity of certain compounds. It is recommended to test a number of variations of the parameters whenever examining a new type of sample.