Ann Newman - "Characterization of API : Polymer Mixtures Using X-ray Powder Diffraction" A. Newman, D. Engers, S. Bates, I. Ivanisevic, R. C. Kelly, G. Zografi

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      Publication Details (including relevant citation   information):

      J. Pharm. Sci., 2008, 97(11),  4840-4856


      Recognizing limitations with the standard method of determining   whether an amorphous API-polymer mixture is miscible based on the   number of glass transition temperatures (Tg)   using differential scanning calorimetry (DSC) measurements, we   have developed an X-ray powder diffraction (XRPD) method coupled   with computation of pair distribution functions (PDF), to more   fully assess miscibility in such systems. The mixtures chosen   were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran,   both prepared by lyophilization; and indomethacin-PVP, prepared   by evaporation from organic solvent. Immiscibility is detected   when the PDF profiles of each individual component taken in   proportion to their compositions in the mixture agree with the   PDF of the mixture, indicating phase separation into independent   amorphous phases. A lack of agreement of the PDF profiles   indicates that the mixture with a unique PDF is miscible. In   agreement with DSC measurements that detected two independent   Tg values for the dextran-PVP mixture, the   PDF profiles of the mixture matched very well indicating a phase   separated system. From the PDF analysis, indomethacin-PVP was   shown to be completely miscible in agreement with the single   Tg value measured for the mixture. In the   case of the trehalose-dextran mixture, where only one   Tg value was detected, however, PDF analysis   clearly revealed phase separation. Since DSC can not detect two   Tg values when phase separation produces   amorphous domains with sizes less than approximately 30 nm, it is   concluded that the trehalose-dextran system is a phase separated   mixture with a structure equivalent to a solid nanosuspension   having nanosize domains. Such systems would be expected to have   properties intermediate to those observed for miscible and   macroscopically phase separated amorphous dispersions. However,   since phase separation has occurred, the solid nanosuspensions   would be expected to exhibit a greater tendency for physical   instability under a given stress, that is, crystallization, than   would a miscible system.

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