Drug Solubility in Carrier

The amount of a drug released from a lipid-based solid dispersion formulation is often determined by the solubility of the drug in the excipient matrix, which should be sufficient to allow complete solubilization of the drug dose in the volume of a single oral capsule. In instances where the drug cannot be fully solubilized in the formulation, a properly chosen surfactant can improve the dissolution rate of a poorly soluble drug. In one instance, the authors showed that the dissolution rate of a poorly soluble compound, SB-210661, was higher in the presence of 0.5% polysorbate 40, as compared to 0.5% SDS, despite the fact that contact angle measurements indicated better wettability with SDS. The superior dissolution rate from the polysorbate 40-containing formulation was attributed to its 100-fold lower critical micelle concentration, which may have solubilized a higher fraction of the dispersed drug during dissolution (72).

Compared to a fully-solubilized solid dispersion formulation of a drug, a suspension formulation requires more stringent manufacturing controls on parameters, such as concentration and particle size of the dispersed phase and formulation viscosity. Rowley et al. (73) studied the rheology and capsule filling properties of molten PEG6000, 8000, 10000, and 20000 dispersions of lactose monohydrate, which was selected as a model drug compound due to its low solubility in PEG. Hard gelatin capsules were filled with the molten formulations at 70°C using a semi-automatic filling machine. Satisfactory capsule filling was achievable, but was constrained by the apparent viscosity of the formulation, which was dependent upon the concentration and particle size of the dispersed phase (lactose) and the molecular weight of the PEG continuous phase.

Thus, preliminary solubility screening studies should seek to identify those excipients that are not only physically and chemically compatible with one another, but also those which can provide the maximum solubilizing power for the drug as well. The solubility of a drug in surfactant or polymer excipients, which are semi-solid at ambient room temperature, can be estimated by extrapolation from solubilized concentrations obtained from temperatures at which the excipients are molten. However, it is necessary to confirm preliminary solubility estimates with multiple analytical techniques and construction of phase diagrams for assessing phase miscibility (74-76). Microscopic detection of crystalline drug material in the excipient matrix is useful for detecting concentrations >2% crystalline drug in the polymer matrix, but may not be reliable when the excipient matrix itself is crystalline in nature (77). DSC and XRD have also been used to detect the existence of crystalline drug in the excipient matrix (25,26,78). However, when using DSC to study a semi-solid drug dispersion, a control consisting of a simple physical admixture of drug and excipient at identical composition should be run before drawing phase miscibility diagrams, since the drug could dissolve in the excipient during heating, leading to erroneous conclusions (79). Confocal Raman spectroscopy has also been used to assess the physical state and distribution of drugs in solid dispersions. Using this technique, Breitenbach et al. (80) determined that the physical state of ibuprofen, dispersed in a solid matrix of polyvinylpyrrolidone, was equivalent to that of a solution of the drug in dimeric vinylpyrrolidone.

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