Physico-chemical characterization of binary and ternary solid dispersions of itraconazole and indomethacin

Compounds with poor aqueous solubility are posing challenges in the development of new drugs. It is well known that drug dissolution rather than permeation through the epithelia of the gastrointestional tract is responsible for a low oral absorption. One of the pharmaceutical strategies to improve the oral bioavailability is the formulation of solid dispersions. In our project, itraconazole and indomethacin were selected as model drugs, because both of them have an extremely low aqueous solubility and dissolution rate, but they are well permeable through the membranes of the gastro-intestinal tract (class II compounds in the Biopharmaceutical Classification System). Although the formulation of solid dispersions is generally accepted as a method to enhance the dissolution characteristics of class II drugs, only few products using solid dispersions are marketed, mainly because of stability problems. Chapter I gives a short introduction to the formulation, preparation and characterization of solid dispersions. The aims and objectives of the current research project, the physicochemical and pharmaceutical characterization of binary and ternary solid dispersions in order to contribute to the development of stable drug delivery systems for poorly soluble drugs, are formulated in chapter II. Section II reports on the preparation, formulation and characterization of solid dispersions of the model drug itraconazole. In chapter III, the phase behavior of binary solid dispersions (PEG 6000-itraconazole and PVP VA64-itraconazole) is reported. PEG 6000-itraconazole solid dispersions were prepared by solvent evaporation. All dispersions investigated showed the presence of crystalline itraconazole indicating that the drug is not molecularly dispersed in the polymer matrix. However, the presence of an endothermic peak in DSC curves of all solid dispersions at approximately 85°C-90°C showed that at least a second phase of pure itraconazole is present also: glassy itraconazole. The protective effect of the polymer is clear at low concentration of drug since no recrystallisation exotherm can be detected. However, at drug concentrations above 80%, a recrystallization exotherm at approximately 117°C can be detected. At least three different phases can be distinguished at room temperature: a polymer phase, crystalline itraconazole and glassy itraconazole. Binary solid dispersions made up of itraconazole and PVP VA64 are forming a molecular dispersion since only one single Tg and no melting peak or transition due to the presence of the itraconazole mesophase could be observed. These Tg’s are in agreement with the corresponding theoretical Tg’s calculated with the Gordon-Taylor equation. UV-spectroscopy could not prove any interaction between itraconazole and PVP VA64. The preparation method plays a significant role in the dissolution process since the solid dispersion containing 10% itraconazole prepared by spray drying leads to a release of 80%, which is a two fold increase compared to the co-evaporate with the same composition. In chapter IV, the solid state properties of ternary solid dispersions made up of PVP VA64, Myrj 52 and itraconazole were investigated. The solid dispersions were prepared by dissolving the materials in methylene chloride, followed by evaporation of the solvent in a rotavapor. The ternary solid dispersions were characterized by standard and modulated temperature DSC and x-ray powder diffraction. Although PVP VA64 and itraconazole were found to be completely miscible in the solid state, addition of a small amount of Myrj 52 to the drug-polymer system leads to separation of itraconazole thus demonstrating that Myrj 52 expels the drug from the polymer phase. Ternary solid dispersions made up of itraconazole, Myrj 52 and PVP VA64 are not forming a complete molecular dispersion since a separate drug phase can be observed. As a result, this ternary solid dispersion did not show improved dissolution behavior compared to the binary system. It was also found that the binary solid dispersions made up of itraconazole and different polymers like PEG 6000, Eudragit E100, HPMC, PVP K30 showed a sharp drop in their dissolution profiles after adding surfactants like SLS, Myrj 52, Cremophore RH40, Cremophore RH60, Tween 80, TPGS, Brij 58, and Gelucire 14/44. It seems that ternary solid dispersions made up of itraconazole, a polymer and a surfactant can not improve the dissolution behavior compared to the corresponding binary system. In chapter V and VI, the compaction behavior of the PVP VA64-itraconazole solid dispersions and the stability of both the solid dispersion and its formulation into tablets were investigated. Orthogonal design was used to optimize the tablets. The solid dispersion shows a relatively higher yield pressure than any of its starting materials. This is because after spray-drying a fine, light powder was obtained which is relatively poorly compressible. Decreasing the percentage of solid dispersion in the tablets can decrease the disintegration time dramatically. However, no tablets with acceptable characteristics could be obtained, even if the amount of solid dispersion was decreased to 40%. The dissolution profiles of the aged and non-aged solid dispersions were comparable. No crystallinity of itraconazole was observed in both the x-ray powder diffraction and modulated temperature DSC experiments, except for the solid dispersions stored at a relative humidity of 98%. These observations suggest that PVP VA64 protected amorphous itraconazole from recrystallization during aging. In the tablets, itraconazole remained in the amorphous state and did not recrystallize during the six months storage period. It can be concluded that the solid dispersion composed of PVP VA64-itraconazole-primojel (9:1:1 w/w/w) and its tablets are stable after six months storage in the following conditions: 4°C 0%RH, 25°C 0% RH, 25°C 52% RH. Storage at higher temperature (40°C) only decreased the dissolution rate at the initial time points. PVP VA64 is an adequate inhibitor of recrystallization of amorphous itraconazole in the solid dispersion prepared by spray drying. However, when the relative humidity increased to 98%, both the solid dispersions and tablets became a gel because of the absorption of moisture from the environment. Indomethacin was used as a model drug in the third section of this thesis. In chapter VII, the preparation and characterization of indomethacin in ternary solid dispersions with PVP VA64 and a surfactant (Myrj 52 or Tween 80) are described. The solid dispersions were prepared by dissolving the materials in methylene chloride, followed by solvent evaporation in a rotavapor. Binary and ternary solid dispersions were characterized by standard and temperature modulated DSC, thermogravimetry and x-ray powder diffraction. The latter showed that the initial indomethacin was in its γ-form, while it was transformed into the β-form and an amorphous fraction in the solid dispersions. A mixture of the β-form and amorphous indomethacin was also obtained in the binary systems containing less than 30% polymer. In order to study the complex thermal behavior, indomethacin without polymer was subjected to the same experimental procedures as the ternary solid dispersions, and used as a model to characterize the solid state transformations. The following order of transitions was observed: from the initial γ-form, the β-form was obtained with some amorphous content, then the crystalline β-form desolvates, forming the α-form which melts and recrystallizes into the stable γ-form. Contrary to the ternary system of itraconazole, the addition of surfactant increased the dissolution of indomethacin. This is due to the fact that ternary solid dispersions made up of indomethacin, a surfactant (Myrj 52 or Tween 80) and PVP VA64 are forming a molecular dispersion. In chapter VIII, the compaction into tablets of ternary solid dispersions made up of PVP VA64, Tween 80 and indomethacin in a ratio 9:1:1 (w/w/w) is reported. Optimization of the tablet formulation was performed using orthogonal design of experiments. When the percentage of the solid dispersion in the tablets was lowered to 20%, tablets with improved disintegration time and dissolution time were obtained. In chapter IX, the stability of both the ternary solid dispersion and its tablets is described. After six months storage under accelerated conditions, no recrystallization of amorphous indomethacin was observed. The dissolution profiles of the aged and non-aged solid dispersions were comparable. The optimized tablets were stored for six months in different conditions of temperature and humidity. It was found that the dissolution profiles of the tablets stored at 25°C and 40°C were not similar to those of freshly prepared tablets. The dissolution of indomethacin increased because of the decrease of the hardness of the tablets. It was observed that PVP VA64 and Tween 80 can protect amorphous indomethacin from recrystallization. The most important findings and conclusions of this project are described in chapter X.nrpages: 182status: publishe