Many active pharmaceutical ingredients (APIs) display poor powder properties and cannot be directly compressed into tablets with sufficient strength. The desired powder properties are often difficult to achieve through conventional particle engineering approaches, such as particle size and habit modification during crystallization. Co-processing of API with excipients can significantly improve the functional properties to overcome these difficulties. Herein, a co-processing technology was developed to improve powder properties in which the polymer is precipitated and coats the crystalline API particles resulting in discrete, nearly spherical agglomerates. Critical process parameters were identified and scalability up to 50 kg scale was demonstrated in the pilot plant. The co-processed APIs generated under various process conditions were formulated into blends at 50−90 wt % loading and successfully processed by direct compression.
We show that the behavior of a polymorphic transformation under high shear can be predicted up to pilot scales on the basis of laboratory experiments. Solubility measurements indicate that the transformation rate is promoted at higher temperatures and that within the studied temperature range, the thermodynamically preferred form exhibits retrograde solubility. High shear, introduced both by a rotor-stator combination and by the use of high-surface area seeds, promotes the transformation, resulting in shorter transformation times. Raman spectroscopy data indicate that the transformation is dissolution limited. Correlations of the transformation time with changes in the total energy input to the crystals by collisions with the mill demonstrate that accounting for the seed surface area is necessary to model the experimental laboratory data. The transformation time for all pilot scale runs (10 3 scale higher than lab experiments) is well represented by the aforementioned model. This strategy for the promotion of a kinetically limited polymorphic transformation can potentially be extended to describe other solid−liquid suspensions under high shear.
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