Binder-free twin-screw melt granulation: An effective approach to manufacture high-dose API formulations

Abstract

This study investigates the use of twin-screw binder-free melt granulation (BFMG) in the development of high- dose solid dose formulations for low melting point thermally stable drugs. Both ibuprofen and guaifenesin are examined. By granulating pure API powder, it is shown that BFMG can successfully be used to produce granules that contain 100% API. A design of experiments (DoE) response surface methodology was used to establish the design space for the end-product. The effects of the most relevant process variables (barrel operating temperature, powder feed rate, screw speed and screw configuration) on granule properties (outlet temperature, size distribution, morphology, flowability, compressibility, porosity) and tablet attributes (tensile strength and in-vitro dissolution) were thoroughly studied. Barrel temperature (alone or in interactions with the other variables) represented the most significant variable for both drugs since it governs the formation of granules by partial melting and subsequent agglomeration of the fed powder. Interestingly, the shear action originated by screw speed and screw configuration resulted in various significant responses depending on the drug substance, indicating that it can also be affected by the nature of the processed molecule. Flow properties were improved (i.e., lower Hausner ratio) for both drugs after formation of granules. Tabletability was also tested by preparing 600 mg tablets for all samples. Surprisingly, the resulting granules were highly compactible, requiring only 1% lubricant to form strong tablets containing 96% API and 3% disintegrant. The results also showed that tablets become harder as the granule size increased, especially for guaifenesin. As expected, in-vitro dissolution results indicated that tablets and capsules showed slightly slower dissolution rates than the granules.