Fletcher, John Graham; (2006) The use of a second excipient to alter the characteristics of PVP-drug solid dispersions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Many drugs are poorly water soluble and this can limit bioavailability. One way of increasing the dissolution rate and apparent saturation solubility of a poorly water soluble drug is to prepare a solid dispersion. The ideal solid dispersion is one in which the drug and excipient (typically a polymer) are molecularly dispersed. This dispersion may be unstable. Phase separation and recrystallisation of the drug may occur. The aims of this work were to investigate how the use of a second excipient affects the dissolution of a stable amorphous PVP-drug dispersion, how the use of a second excipient affects the amorphous stability of unstable PVP-dispersions and whether near infrared spectroscopy (NIRS) could be used as a technique to detect crystallisation. Indomethacin was spray-dried with PVP and a variety of second excipients. Characterisation was performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and dissolution studies at pH 1.2, 6.5 and 7.0. At pH 6.5, indomethacin dissolved from all the solid dispersions bar one containing Eudragit S. This dispersion proved to be soluble above pH 7.0. When the dispersion was prepared by dissolving the components of the dispersion in a different order prior to spray drying the dispersion was then found to dissolve suggesting that differences in non-covalent bonding were occurring. Griseofulvin, flavanone and clotrimazole were all spray-dried with PVP and a variety of second excipients. Characterisation was performed using DSC, XRPD and TGA. The addition of poly(2-hydroxypropylmethacrylate) (PHPMA) was found to improve the amorphous stability of griseofulvin dispersions when stored at 0% and 30% relative humidity (RH) though this was later found to be dependent on the order in which components were dissolved. PHPMA was also found to improve the amorphous stability of flavanone when stored at 0% RH. Sucrose was found to improve the amorphous stability of clotrimazole when stored at room temperature, 0% RH. When dispersions containing lower concentrations of clotrimazole were prepared this benefit was lost although the addition of poly(acrylic acid) to the dispersion did seem to improve the amorphous stability. NIRS investigations of the amorphous stability of griseofulvin dispersions showed that the technique was less sensitive than XRPD, though it may provide some information about the mechanism of stabilisation.

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