Binder-Free Twin-Screw Melt Granulation: An Effective Approach to Manufacture High-Dose API Formulations

COTABARREN, IVANA M.; OMAR, THAMER A.; MUZZIO, FERNANDO J.

Boston

Congreso; AIChE Annual Meeting; 2021

Purpose: Granulation is an important process step applied in manufacturing of numerous pharmaceutical products because it improves flowability, compressibility, content uniformity and, in some cases, the dissolution rate of the materials once they are formulated into a final solid dosage form (e.g., tablets). Granulation processes are usually classified according to the binder nature as wet, dry or melt. The absence of water or other solvents in melt granulation processes makes this approach quite valuable for moisture-sensitive ingredients and since it completely avoids the disadvantages associated with solvent recovery and final disposal. Among the available granulation technologies, twin-screw granulators have recently brought attention to both academic scientists as well industrial researchers since they present a homogeneous powder and energy distribution within the unit to every portion of material processed, resulting in a consistent product quality even at low binder concentration levels. Furthermore, as an inherently continuous process, twin-screw granulators can be readily integrated into the continuous manufacturing of pharmaceutical dosage forms using existing continuous granulation equipment. In this context, 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. Ibuprofen and guaifenesin, which are commonly used in high-dose formulations, were chosen as model drugs to test this novel application of twin-screw melt granulation. Method: 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 (600 mg) attributes (tensile strength and in-vitro dissolution) were thoroughly studied. Results & Conclusion: By granulating pure API powder, it is shown that BFMG can successfully be used to produce granules that contain 100% API. Furthermore, 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 granules formations. Tabletability was also tested by preparing tablets for all samples. Surprisingly, the resulting granules were highly compactible, requiring only 1% lubricant to form strong tablets containing 99% API. The results also showed that tablets become harder as the granule size increased, especially for guaifenesin. Different increasing behavior was observed for both drugs, indicating that a thorough analysis should be performed regarding the nature of the generated bonds between particles and the granules strength. Based on previous experience, this effect should level off for a certain granule size due to the likely formation of failure-inducing voids for very large granules. As expected, in-vitro dissolution results indicated that tablets and capsules showed slightly slower dissolution rates than the granules. Nevertheless, all dissolution profiles were in agreement with the USP requirements for immediate release dosage forms, being faster the release of guaifenesin since its water solubility is higher than for ibuprofen. In conclusion, it is proved that BFMG of low melting point drugs can be used in to make tablets that are almost 100% API with excellent mechanical and dissolution behavior. This suggests that BFMG can be an important enabling technology for many high dose pharmaceutical products.