Ke, Peng; (2010) Investigation of the effect of preparation methods on the surface properties, dissolution rate and stability of solid dispersions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Formation of solid dispersions is frequently used as an important strategy to improve the dissolution properties of poorly water-soluble drugs. In addition, the carriers used to prepare solid dispersions can help stabilise the drugs if they appear in the amorphous form. Preparation method is a key factor affecting both dissolution and stability of a solid dispersion due to difference in dispersivity and molecular arrangement of the drug and carrier. The objectives of this work were to study the effect of preparation method on the physical properties, stability and dissolution of solid dispersions containing indometacin as the model drug. The surface energy state of the solid dispersions during aging was studied. Molecular mobility at the surface and in the bulk of the solid dispersions was determined and correlated to the stability and dissolution properties. Solid dispersions with different carriers were prepared using different methods and their stability and dissolution profiles were investigated. Solid dispersions of polyvinylpyrrolidone (PVP) and indometacin (30%:70%) were prepared using melt quenching or ball milling and subjected to physical aging. It was found that the surface energy state of the samples decreased as a function of time and this energy reduction was temperature dependent, as determined using inverse gas chromatography (IGC). A novel method which utilises the retention volume of decane (Vmax) to measure surface relaxation by IGC was developed. The surface relaxation of PVP and indometacin solid dispersions prepared by ball milling, spray drying, and melt quenching were measured using the Vmax method and compared to their bulk relaxation measured using step-scan differential scanning calorimetry. The surface appeared to have higher molecular mobility than the bulk irrelevant of which preparation method was used. However, preparation method appeared to have an impact on both surface and bulk molecular mobility. Relaxed samples sorbed less moisture and dissolved slower than the initial ones as determined by dynamic vapor sorption and dissolution experiments, and a faster bulk relaxation rate led to a more significant reduction in the dissolution rate of the solid dispersions after aging. The glass fragilities of the systems were obtained using the heating rate dependence of the glass transition method. The values were found to be preparation method specific. The zero mobility temperatures (T0), of the systems were calculated using the fragility parameter. With a similar glass transition temperature (Tg) at c.a. 64 to 67 °C, the T0 of the ball milled, spray dried and melt quenched samples were -4.2, 16.7, and 21.6 °C, respectively. Physical stability test showed that the ball milled sample was the least stable while the melt quenched one was the most, which correlated well with their T0 values. It is suggested that T0 might be a better indicator of stability than Tg. Carriers which were miscible or immiscible with indometacin were used to form solid dispersions with the drug prepared by ball milling and spray drying. Improved stability and dissolution rate of indometacin were noticed. Intermolecular interactions between the drug and carrier were found to be crucial to the stability of the amorphous drug no matter whether the carrier was miscible or not. The effect of preparation methods on the dissolution rate of the sample was found to be carrier dependent.

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